1 Drug Product Development in the Pharmaceutical Industry G u r vi n d e r S i n gh R ek h i L e o n Sh a r ge l
I. INT...
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1 Drug Product Development in the Pharmaceutical Industry G u r vi n d e r S i n gh R ek h i L e o n Sh a r ge l
I. INTRODUCTION A. Ac t i ve p h a r ma c eu t i ca l i ng r e d ie n t ( AP I ) 1 . A d ru g su b s ta n ce i s th e A P I o r c om po n en t th at p r od uc es ph a rm ac o lo gic a l a c ti vi t y. 2 . Th e A P I m a y b e p r o du c e d b y c h e m i ca l s y n t he s is , r e co v e r y f r om a na tu r a l p r o du c t, en z y m a t ic re ac ti o n , r ec om b in an t D N A tec h no l og y , fe r m e n ta t io n , o r a c om b in a ti o n o f t he s e p roc es s es . F u rt h e r p u ri fi c at io n of t he A P I m a y b e n ee d e d b e f o re it c a n b e u s e d i n a d r ug pr o du c t. 3 . A new c he m ic a l e n ti ty ( N C E ) i s a d ru g s ub s tan c e wi t h u nk no wn c li ni c al , t o xi c o l og ic , p h y s i c al , a nd c h em ic a l p r op e r ti es . I n a d di t io n , t he U . S . F oo d a n d D ru g A d m in is t ra t io n (F D A ) c on s id e rs an N C E a s a n AP I t ha t ha s n ot be e n a ppr o ve d fo r m a rk e ti n g i n t he U ni t ed S t a t es . 4 . Th e id e n ti t y, s t r e n g th , q ua l i t y, a n d p u r i t y o f a d ru g s ub s ta nc e d e pe nd o n p r o pe r c o n tr o l o f t h e m an u f ac tu r i ng an d s y n th e tic p ro ce s s . B . D r u g p r od u c t 1 . A d r u g p r od uc t i s t h e f i n i s he d d o sa g e f o r m (e . g . , ca ps u le , ta bl e t, in j ec t ab l e ) t h a t c on t ai ns th e A PI , gen e r al l y in as s o c i a ti on wi t h o th e r e xc i p i en ts , or in er t i n g re d ie n ts . 2 . Th e e xc i pi en t s i n t he d r u g p r od uc t m a y af f ec t t h e fu nc t io na l it y a nd pe r fo r m an ce o f t he dr u g p r od uc t , i nc lu d in g m o di fi ca t io n o f th e r a t e o f d r ug s u bs t an c e re l ea s e, i m p ro vi ng d ru g s t ab il i t y , a n d m as k i ng t he dr u g t as t e . 3 . D i ff e re n t a p p r oa c he s a r e ge ne r a ll y us e d t o p ro d uc e d r ug p ro d uc ts th a t c on t ai n N C E s , p ro du c t l in e e xt e n s i on s , ge n e ri c d r ug pr o du c ts , a n d s p ec i al t y d ru g p r o du c ts . C . N ew d r u g p r o du c t d eve l o p m en t D r u g p ro du c ts c on t ai n ing N C E a re de ve l op e d s eq u e nt i a l l y i n th e f o ll o wi ng p ha s e s . 1 . P r ec l i ni c al . A ni m a l ph a r m a c o lo g y a nd to xi c o lo g y d at a a r e o b ta i n e d t o d e te r m i n e t h e s a fe t y an d e f f ic ac y of t h e d ru g . Be c a us e l i tt l e i s k no wn a b ou t t h e h um a n an d t h e t h e r ap eu t ic / to xi c o l og ic po t e nt i al , m an y d r ug p ro du c ts wi l l n o t r ea c h t he m a r k et p la c e . N o a t te m p t i s m ad e t o de v e l o p a f i na l f o rm ul a ti on d u ri ng t he pr ec l in ic a l st a g e. N o n c l in i ca l st u d ie s a r e n o nh um a n s tu di es t ha t m a y co n ti nu e at an y s tag e of r e s ea r ch to ob t ai n a d di tio n al in f o rm a ti on c o nc e rni n g t h e p ha r m a c o lo g y a nd t o xi c o l og y o f t h e d r ug . 2 . P ha s e I a . A n I n ve s t ig a t io n al New D r ug ( I N D ) a pp l ic at io n fo r hu m a n t e st i ng i s su b m i t te d to t h e F D A. C li n ic al te s t i ng t a k e s p la c e af t e r t he I ND a p pl ic a ti o n is s u bm it t ed . P.2
b . H e al t h y v ol u nt e e rs a re us e d i n p ha se I c li ni c a l s t ud ie s t o d e te r m i n e d rug t o l er a nc e a nd t o xi c it y . c . Fo r or a l d r ug ad m i ni s tr a t io n , a s im p le ha r d g ela t i n ca ps u le fo r m u l at i on c o nt a in in g t h e A PI is us ua ll y u s e d fo r I N D s t ud i es . d . To xi c o l o gi c s t u di es — in c lu di n g a cu t e, c h r on ic , s u bc h ro ni c , a nd m u ta g en i c i t y — a nd o t h e r su c h s t u di es in v a ri o us an im al s p ec i es a r e p l an n ed du r in g th is ph as e . 3 . P ha s e I I a . A l im i te d n um b e r o f pa t i en ts wi t h th e d is e as e o r c o n di t io n f o r wh ic h t he d r ug wa s d e ve l op ed a re t re a te d un d e r c lo s e s u pe r v i s i on . b . D os e - re s p o ns e s tu d ies , bi oa va i la bi l it y , a nd pha r m a c ok in e ti cs a r e p e r for m e d t o d e t e rm in e t h e o pt im um do s ag e re gi m e n fo r t re a tin g th e d is e as e. c . S af e t y i s m ea s u r ed b y a t t em pt i ng to de t e rm in e t h e t h e r ap e u ti c i n d ex (r a t io o f t o xi c d os e t o e f f ec ti v e do s e ). d . A dr u g f o rm ul a ti o n h av i n g go o d p h ys ic o -c h em ic a l s ta bi l it y i s d e vel op e d. e . C h ro n ic to xi c i t y s t u di es a re s t a r te d i n t wo s pe c i e s ; su c h s t ud i es n o rm a lly l a s t m o r e t ha n 2 y e a rs ' du r a ti o n . 4 . P ha s e I I I a . La r g e- s c a le , m u l ti c ent e r c l in i ca l s t u d ie s a r e p e r f or m e d wi t h t h e f in a l d o s a g e f o r m d e vel o pe d i n p ha s e I I . Th es e s tu d ie s a r e d on e to de t e rm in e t h e s af et y a n d e f f ic ac y o f t h e d ru g p r o du c t i n a l a r ge pa t ie n t p op u la t io n wh o ha v e th e d is e as e o r c o nd i ti on f o r wh i c h t he dr u g wa s d e v e lo p ed . b . S id e e f f ec ts ar e m on i to r e d . I n a l a r ge po pu l at io n , n e w t o xi c e f fe c t s m ay o c cu r t h a t we r e n o t e v i de n t i n p r e v i ou s c li ni c a l tr i al s. 5 . S ub m i s s io n o f a N ew D r u g Ap p l i c a ti o n ( N D A) . A n N D A i s s ub m i t te d t o t h e F D A f o r r e vie w a n d a p pr o v a l a f t e r t he c o m p le t io n o f c li n ic al t ri a ls th a t s h o w t o t h e s a ti s fa c t i on of t he m e di c a l c om m u n it y t h at t he dru g p ro du c t is e ff ec t i v e by a l l p a r am e te r s a nd is re as on a bl y s af e a s d em o ns t rat e d b y a ni m a l a n d h um an s tu di es . 6 . P ha s e I V a . A f te r th e N D A i s s u bm i t t ed , a n d b e fo r e a pp r o va l to m a rk e t t h e p r od uc t i s o b ta i ne d f r o m t he F D A , m an u fa c t ur i n g s ca l e -u p ac ti v i t ie s o c c u r . S c al e -u p i s t he inc r e as e i n t h e b a tc h s i z e f r om th e c l i ni c a l b a tc h , s u bm is s i o n b a tc h , o r b o th to t he fu ll- s c a l e p r o du c ti on ba t c h s i z e , us i ng th e fi ni sh e d, m a r k e te d p ro du c t. b . Th e d ru g p r od uc t m a y b e i m p r o v e d as a r es u lt o f eq u ip m e n t, r eg u la t or y , s up pl y , o r m a r ke t d em a nd s . c . A dd it i on a l c l i ni c a l s tud i es m a y be p er f o rm ed in s p ec i al po p ul a ti on s , s uc h a s t h e e l de r l y, pe di a t ri c , an d ren a l -i m p a ir e d, t o o bt a in i n f o rm a ti o n o n t he ef f ic ac y o f t he d r u g i n t h es e s u b je c t s . d . A dd i ti o na l c li ni c a l s t ud i es m a y be p er f o rm ed to d e t e rm i ne if th e d r u g c a n be us ed f o r a n e w o r a d di t io n al l ab e li n g i nd ic a ti o ns . 7 . P ha s e V a . A f te r th e F D A g ra n ts m a rk e t a pp r o v a l o f t he dr u g , p r od u ct de ve l op m e nt m a y c o nt i nu e . b . Th e d r ug f o rm u l at i o n m a y be m o di f ie d s li gh t l y a s a re s ul t o f d a ta ob t ain e d d u r in g th e m an u fa c t u ri n g s c a le - u p a nd v a li da t io n p r o c e ss es .
c . C ha n ge s i n d ru g f o rm u l a ti o n s ho ul d al wa y s b e wi t h in th e s ca le - u p an d po st a p p ro va l c ha n ge ( S U P AC ) g u id el i ne s . D . P r o d uc t l in e e x t en s io n s a r e d os a ge fo r m s in wh i c h th e p h ys i ca l f o rm o r s t r en g th , b u t n o t t he us e o r in di c at io n , o f th e p r od u ct ch a ng es . P ro du c t l in e e xt e n s i on is u s ua ll y p e rfo r m ed du r in g p h as e I I I, IV , o r V. 1 . D e vel o pi n g a t r a ns de rm a l p at ch wh e n on l y ta b le t s h a ve b e en a v ai la b le , f o r e xa m p l e :
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P r o g es t er o ne
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N i c ot i ne
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E s t r ad io l
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N i t r o gl y c e ri n
2 . Ad d i t i o na l s t r e ng t h s— a s l o ng as th es e s t re ng t hs a re wi t h in t he to t al d a il y d os e , f o r e xa m pl e :
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I b u p ro f en
P.3
3 . C o n t ro l l ed - r e le a se or m o d i fi e d - re l ea s e d os ag e fo r m s wh e n o nl y a n im m e d ia t e r e l ea se do s a g e f o rm is av a i l ab l e. Th i s is an on g oi n g p r oj ec t fo r al l b r an d c om p an i es ; a lm os t e v e r y N C E h as o r wi l l e ven t ual l y h a ve a m od i fi e d -r e le as e d os a ge f o r m o f t h e im m e d ia t e- r el e as e p r od uc t . E . B i o l og i c p r o du c t s 1 . A b i ol o gi c p ro d uc t i s an y v i r u s , se r um , to xi n , an t i to xi n , va c c i ne , b l oo d , b l oo d c om p on e nt o r d e ri v a t i v e, a l le r ge n ic p r o du c t , o r an a lo g ou s p r od uc t ap pl ic a b le t o t he p r e ve n ti on , t re a tm en t , o r c u re of di s e a s e s o r i nj u ri e s . 2 . B io l og ic pr o du c t s a r e a s ub s e t o f d r ug p ro d uc ts , di s t i ng ui sh e d b y t he i r m a nu f ac tu r i ng p ro c e s s es ( b io l og ic v s . c h e m i c a l ). I n ge n e ra l , t he te r m d r ugs in cl u de s b i ol o gi c p r od uc ts . 3 . B i ol o g ic l ic e ns e a p pli c a t io n ( B L A) . B io lo g ic p r o du c ts a r e a p pr o v e d fo r m a rk e ti n g u nd e r t h e p rov i s i on s o f t h e P u bl ic H eal t h Se r vi ce ( P H S ) A c t. F . G e n e ri c d r u g p ro d uct s 1 . A f te r pa t e nt ex p i r a ti on o f t h e A P I a n d / o r b r and d r ug pr o du c t, a g en e ric d ru g p r o du c t m a y b e m ar k et ed . A g e ne r ic d ru g p r od uc t i s t he r ap e ut ic a ll y e qu i va l en t to t h e b r a nd na m e d ru g p r od u c t an d c o nt ai n s t he s am e a m o u nt o f t he d ru g in t he s a m e t yp e o f d os ag e f o rm ( e. g. , t ab le t , l i qu id , i n je c ta ble ) . 2 . A g e ne r ic d ru g p r od uc t m us t b e b i oe q u i va le n t ( i . e. , ha v e th e s am e r a te a nd e xt e n t o f d r u g a bs or p ti on ) t o t he b ra n d d r ug pr od u c t . Th e re f o re , a g en e ric d ru g p r o du c t is e xp e c te d t o g iv e t h e s am e c l i ni c a l r e s po n s e ( C ha p te r 7 ). Th es e s t ud ie s a r e no rm a ll y p e rf o rm e d wi t h h e al t h y h u m a n v ol un t e e rs . 3 . S om e g en e r ic p r od u c ts a re no t a b so r be d ; f o r so m e o th e rs bi o eq ui va l enc e i s n o t a g o o d m a r k e r . Un d e r t ho s e c o n di t io ns , c o m pa r a t ive c l i n ic a l t r i a ls or s t u di e s wi t h
p h a r ma c o d yn a m i c e nd p o i n ts a re c o ns id e r ed to m ea su r e th e e qu i v a le nce o f t wo p r o du c ts . I n ha la t io n p r od u c t s a n d n on ab s o r b ed d r u g p r od uc t s f al l i n to thi s c a te go r y. 4 . Th e ge ne r ic d ru g p r odu c t m a y d i ff e r fr om t he br a n d p r od uc t i n ph ys i c a l a p p ea r a nc e (i . e. , s i z e , c o l o r, s h a pe ) o r in th e am o u n t a nd t y pe o f e xc i p ien t s u s e d i n t h e fo rm u la t io n . 5 . A g e ne r ic d ru g p r od uc t m a y n o t d if f e r i n b ot h th e qu al i ta t i ve a n d t he qua n t it a ti v e c om p os it i on s f o r l iq u id s , i n je c t a bl es , s em is ol i ds , t r a ns d er m al p a tc h es , i nha l a ti on p r o du c ts , a nd op h th a lm ic p ro d uc ts , u n le ss a d equ a t e s a f e t y s t ud ie s h a v e b e en p e r f or m e d . 6 . B ef o r e a g e ne r ic dr u g p r o du c t is m a rk e te d , t h e m a nu f ac tu r e r m us t s ub m i t an Ab b r e vi a t e d N ew D r u g Ap p l i c a t i on ( AN D A) t o t h e F D A f o r a pp r o v a l. B ec a us e p r e cl in ic a l s a f e t y a n d e f fi c ac y s t u di es ha v e al r ead y b e en pe r f o rm ed fo r the N D A a p p ro ve d b r a nd p ro du c t, h um a n b io e qu i v al e nc e st u d ie s, in s te ad o f cl i ni c al t r ia ls , a r e ge ne r a ll y r eq u i re d f or t h e A N D A . Th e c he m i s tr y, m an u f ac tu r in g , a nd co n t r ol s r e q ui r em e nt s f o r t h e g ene r i c d ru g p r o du c t a re s im i l a r to th os e fo r th e b r an d na m e d r u g p r od uc t . G . S p e ci a l t y d r u g p r o d u c t s a r e e xi s t i ng pr o du ct s de v e lo p ed as a n e w de l i ve r y s ys t em o r fo r a n e w t h e ra p e ut ic in di c at io n . Th e sa f e t y an d e f fi c a c y of t he d r u g p r o du c t we r e es t ab l is hed i n t he in i ti al N D A - ap p ro v e d do sa g e f o rm . F o r exa m p l e , th e n i t ro g l yc e r in t ra ns d e rm al d e li v e r y s y s t em ( pa tc h ) wa s d e v e lo p ed af t e r e xp e r i en c e wi t h n i t ro g l yc e ri n s u bl in gu a l t a bl e ts .
II. PRODUCT DEVELOPMENT. F o r ea ch d ru g , v a r i ou s s t u d ie s a r e r eq u i re d t o d ev e l o p a s a fe , ef f ec t i v e, an d s t ab l e d o sa g e f o rm . A. N e w c he m ic a l e n ti t i es 1 . P r e fo r m u la t i on is th e c ha r ac t e ri z a t io n o f th e p h ys ic al an d c he m i c a l p ro p e r ti es of t h e a c ti v e dr u g s ub s t a nc e a nd do sa g e f o rm . Th e t h e r ap eu t ic in di c a t io n o f t h e d r u g a n d t h e r o ut e o f ad m i ni s tr a t io n di ct a te th e t y pe of d r u g p ro d uc t o r dr u g d eli v e r y s ys t em (e . g. , im m e di a te r e l ea s e , c o nt r ol l ed r el eas e , s up p os it o r y , p a r en t era l , t r a ns d er m al ) th a t n ee ds t o be de v e l op e d. a . P r ef o rm u la ti o n a c t i v i tie s a r e u su a ll y p e rf o rm ed d u ri n g t h e p re cl i ni c a l s ta g e . H o we ve r , t h es e a c ti v i ti es m a y c o n ti n ue in t o p ha se s I a nd II . b . Th e fo l lo wi n g i n fo r m a ti o n i s o bt a in ed d ur i ng p re f o rm u la ti o n . P.4
( 1 ) P h ys i c a l , i nc lu di n g pa r t ic le si ze an d s ha p e, cr y s t a ll in i t y, p o l ym o r ph is m , de ns i t y, s u r fa ce a re a , h y g r os c o pic i t y (a b il i t y to ta k e up and r e ta i n m o is t u re ) , a n d po wd e r flow ( 2 ) S o lu b i li t y, i n c lu di n g i n t ri ns ic di s s o lu ti o n , p H s o lu bi l it y p r o f i le , a n d g en e r al s o lu bi l it y c ha r ac t er is t ic s i n v a ri o us s o l v en ts ( 3 ) C h em i ca l , i nc lu d in g s u r fa c e en e r g y , p H s t ab il i t y p ro f il e , p K a, te m p e r at u r e s t ab i li t y ( d r y o r un d er v ar i o us hu m i di t y c o n di t io ns ) , a nd e xc i pi e nt in t e ra c t io n s
( 4 ) An a l yt i c a l m e t ho d s d e v e l op m e n t, in cl u di ng de ve l o pm en t o f a s t a bi li t y i n di ca t in g m e th o d ( m e as u r es b o th th e A P I a nd th e re l at e d su b s t a nc es ) , a nd c l ea n ing m e t ho ds 2 . F o rm u la t i o n d e ve lo pm e n t i s a c on t in u in g p r oc es s . I ni t ia l d r ug f o rm ul at i o ns a r e d e ve l op ed f or ea r l y c l in ic a l s tu di es . W he n t he s ub m iss i on of an N D A is co n s i d er e d, t h e m an u fa c tu r e r a t te m pt s to de v e l op th e fi na l (m a r k et e d) d os ag e f o rm . Th e do se of t h e d r u g a nd th e ro u te of a dm i ni s t r a ti o n a re im po rt a n t i n d e te rm i ni ng t he m o di f ic at i on s n ee d ed . a . I nj e c ta b le ( 1 ) A fi na l i n je c t a bl e d r ug p r od uc t i s u s u al l y de vel o p e d i n th e p r ec li n ic al ph a s e . ( 2 ) Ma j o r c o nc e rn s i nc lud e th e s t ab il i t y of th e d ru g in s o lu t io n a n d t he s te r i li t y o f t he p r o du c t. ( 3 ) B ec au s e f e w e xc i p ien t s a r e a ll o we d in in je c ta b le p ro d uc ts , th e f o rm ula t o r m us t c h oo se a f in a l p r od uc t ea r l y in t he de v e l op m e n t p r o c e ss . ( 4 ) I f t he f o rm ul at i on is c h a n ge d , b io a vai l ab il i t y s tu d ie s a r e n o t r eq u i re d f or i n t ra ve n ou s s ol u ti on in j ec t io ns be c au se th e p r o du c t i s i nj ec t ed di r ec tl y i nt o t he b o d y. ( 5 ) F or m u l at i on c h an g es m a y re q ui r e a cu t e t o xi c it y s t ud i es . b . T op i ca l ( fo r l oc a l a pp l i c at i o n ). In c l u de s a n tib a c t e r ia ls , a n ti f un g al s, c o r ti co s te r oi ds , a n d l oc al a ne s t h et ic s . ( 1 ) Th e fi n al d o s a ge f orm f or a t o pi c a l d r ug p ro du c t i s us u al l y de v e lo p ed d u r in g p h as e I s t u di es be c a us e a n y m a j o r f o rm ul a ti on c ha n g es m a y re q ui r e f u r the r c l in ic a l t r i al s . ( 2 ) Th e re l ea s e of t he d ru g f ro m t he m a t ri x i s m ea s u re d i n v it r o wi t h va r i ou s d i f fu si o n c e l l m o d el s . ( 3 ) S ig n if ic a nt p ro bl em s e n c o u nt e re d wi t h l oc a ll y a c ti n g t op ic a l d r ug pr o duc t s i n cl ud e l oc a l i r ri t a ti on , s k i n s e n is ti z a t io n a n d s y s t e m i c d r ug ab s o r p ti o n. c . To p i ca l (f o r s ys t e m i c d r u g a b s o rp t i o n) . In c l ud e s d r ug de li ve r y t h ro u gh t he s k in ( t r a ns de r m a l ) , m u c o u s m e m b ra ne s (i nt r a na s a l ) , an d r ec ta l m uc os a . ( 1 ) A pr o to t y p e f o rm u la tio n is d e ve lo p ed fo r ph ase I . ( 2 ) A fi na l to pi c a l d r u g pr o d uc t i s d e v el o pe d d u rin g p h as e I I I a f t er t he a va i la b le t e ch n ol o g y a n d d es i re d s y s t em ic l e ve ls a r e c on s i d e re d . d. Oral ( 1 ) P r ot o t y pe do s ag e f o rm s a r e o f te n d e v e lo pe d d u r in g th e p r e cl i n ic a l ph a s e t o e n su r e t h at t he dr u g is op t im a ll y a v a il ab l e a nd tha t t he pr o du c t di s s o l ves i n th e g a st r o in t es ti n al t ra c t . ( 2 ) I n t he ea r l y s t ag es o f p r o du ct de ve l op m e n t, ha r d g el a t in ca p su l e d os a g e f o rm s a r e of t en de v e l op ed f o r p h a se I c li ni c a l tr i al s. I f t h e d r u g sh o ws e ff ic ac y , t h e s am e d r u g f o rm ul a ti o n m a y b e u s ed in ph as e I I s t ud i es . ( 3 ) Fi n al p ro d uc t d e v el op m en t b e gi ns wh e n th e dr u g pr o c e ed s d u ri n g p has e II an d b e f o re in it i at i ng ph as e III c li ni c a l s t ud ie s . 3 . M a r k et e d P ro d uc t . Co n s i d er a ti o ns i n th e d e ve l op m en t o f a f in al do s ag e fo r m i n cl ud e th e f o ll o wi n g : a . C ol o r , s ha pe , s i z e , t as t e , v i s c os i t y , s en si ti vi t y , sk i n f ee l , a nd ph y s ic al a p p ea r an c e o f t he do s a ge f o rm b . S i ze a nd s h a pe of th e p ac k a g e o r c on t ai n e r
c . P ro d uc ti o n e qu i pm en t d . P r od uc t io n s i te e . C ou n t r y of o ri gi n i n wh i c h th e d r u g is to b e m an u f ac tu r e d f . C o un t r y in wh i c h t he dr u g wi l l b e m ar ke t e d B . P r o d uc t l in e e x t en s io n s a r e g e ne r al l y de f in ed as d ru g p r o du ct s c on t ai n in g a n N D A - a p p ro v e d d r u g i n a d i f fe r e nt do s a g e s tr e ng th o r i n a di f fe r e nt do s a ge f o rm ( e . g ., m o di f ie d re l ea s e , o r a l l iq ui d ) . 1 . O r a l p r o d uc t li n e e x te n s io n s a . Th e s im p le s t do s a g e fo r m t o d e v e lo p i s a di f fer e n t d os a ge s t r en g th of a d r ug in a t a b le t o r c a ps ul e . O n l y bi o eq u i v al e nc e s tu di es a re n ee d ed . P.5
b . A mo d i fi e d - re l ea s e do s ag e f o rm is m o re di f f ic u l t t o d e ve lo p wh e n o nl y a n i m m e di a te - r el e as e d os ag e fo r m e xi s t s . C li n ic al tr i a ls a r e n o rm a ll y r eq u i re d . c . C on si d er a ti o ns i n d e ve l op i ng th e s e do sa ge f o rm s a r e s i m i l a r t o t ho s e fo r t he fi n al d r u g p r od uc t (s ee I I. A . 3 ). d . M a r k e ti n g h as a r ol e i n th e c ho ic e o f th e d os ag e fo r m . e . B ec au s e t he o ri gi n al b r a nd d ru g p r o du c t in f o rm a ti o n co n t ri b ut es t o t he b o d y o f k n o wl e dg e a b ou t t h e d r ug , no p re f o rm ul a ti on is ne e d ed . Al l o t he r fa c t o rs c o ns id e re d f o r th e o r i gi na l p r o du c t ar e s i m i la r . If t he re l at i on b e t we e n in vi t r o di ss ol ut i o n a nd i n vi vo b i oa v a il a bi li t y is k n o wn , th e i n no v a t or c an p r og r e s s t o a fi ni s h e d d o s a g e f o r m r e la t i v el y q ui c k l y . f . R e g ul a t o r y a p p r o va l is ba s e d on th e f o ll o wi n g: ( 1 ) A na l y t ic al an d m an u fa c tu r i ng c o nt r ol s ( 2 ) S t ab il i t y i n fo r m a t io n ( 3 ) B io a v a il ab i li t y an d b io e q ui v a le nc e s t ud ie s ( 4 ) C li n ic al t ri al s (i n t h e c as e o f m o di f ie d - re le a se d os a ge fo r m s ) g . A ne w t h e r ap eu t ic in dic a ti o n f o r a d r u g r e qu i res ne w e f f i c ac y s t u d i e s a n d a ne w N D A. 2 . L iq u i d p r o du c t l i n e ex t e n si o ns a . I f t he c u r r en t m a rk e ted p r od uc t i s a l i qu i d p re pa r a ti o n , t he n t h e s am e fa c to r s a s f o r th e s ol i d o r al do s a ge f o rm s a r e c on s i de r e d ( s e e I I. B . 1. a , b , c , d , e , f an d g ). b . I f t h e m a r k e t ed p ro duc t is a s o li d o r al do s a g e f o r m a nd th e p r o du ct li ne e xt e n si o n i s a li q ui d , p ro d uc t d e v e lo p m e n t m u s t p r oc ee d wi th c a u ti o n b ec au se t he rat e an d e xt e n t o f a bs o r pt i on fo r li q ui d a n d s ol id do s a g e fo r m s m a y n ot be th e s am e . c . R eg u l at o r y a p p r o va l r e q ui r es ( 1 ) A na l y t ic al an d m an u fa c tu r i ng c o nt r ol s ( 2 ) S t ab il i t y i n fo r m a t io n ( 3 ) B io a v a il ab i li t y an d b io e q ui v a le nc e s t ud ie s ( 4 ) S a fe t y s t u di es (e . g ., d e p en di n g o n t he d ru g s u b st a nc e , lo c al i r r i ta t io n) ( 5 ) C li n ic al t ri al s , i f t h e ra t e a n d e xt e n t of d ru g ab s o rp t io n a r e d r as ti ca l l y a l t er e d f r o m t he o ri g in al do s a g e f o r m C . C o m b in a t io n p r o d uct s a re m a de u p o f t wo o r m o re r eg ul a te d c om p one n ts ( e. g . , d r u g /d e v ic e , b io lo g ic /d e vi c e, d ru g /b i ol og ic , or d ru g / d e vic e/ b io l og ic ) th a t a re
p h ys ic al l y , c h em i c al l y , or o t he r wi s e c om bi n ed o r m i xe d a nd p ro du c ed as a si n gl e e n t it y. 1 . Th e se m a y be t wo o r m o r e s e p a ra t e p ro d uc ts p a ck ag e d t og e th e r i n a s i n gl e p a ck ag e o r as a un i t a nd m a y be c om p os ed o f d ru g an d d e vic e p r o du c t s , d e v i c e an d b i ol o gi c p r od uc ts , or bi o lo g ic an d d r ug p ro d uc ts . 2 . A n e xa m pl e i s a n i nha l a ti on s t e r oi d ( e .g . , b ec l o m e t ha so n e i nh al a ti o n a e r os ol ) in wh i c h th e de v i c e c om p on e n t is im po r t an t fo r d e liv e r y o f t he s t e ro i d.
III. PREAPPROVAL INSPECTIONS (PAIs) A. Th e m a n uf ac t u ri n g f ac i li t y is i ns p ec t ed b y th e F D A a f te r an N D A , a bb r evi a t e d a n t ib io t ic dr u g a pp l ic at i on ( A A D A ) , o r A N D A i s s ub m it t ed an d b e fo r e t h e ap p li c a t io n i s a p p ro v e d . B . A P A I m a y al s o be in it i a te d i f a m a jo r ch an g e is r ep o r te d i n a s u pp l em en t a l a p pl ic a ti o n t o a n N D A, AA D A , o r A N D A . C . D u r in g th e PA I , t h e FD A i n v es t ig a to r : 1 . P e r fo r m s a ge ne r a l c u r r e nt go o d m an u fa c t u rin g p ra c t ic e (c G MP ) i n s pe c ti o n r e l at i ng s p ec i fi c a ll y t o t he d r ug pr o du c t in t e nd ed f o r th e m a rk e t 2 . R e vi ew s t h e d e v el opm e nt r ep o r t t o v er i f y th a t t h e d r ug p ro du c t h as e no u g h s u pp o r ti ng do c um en t at i on t o e ns u re a v al id a te d pr o d uc t a n d a ra t io n al e f or t h e m a nu f ac tu r i ng di r ec ti o ns 3 . C o ns u l ts th e c h em is tr y , m an u f ac tu r in g , a nd c o n t r ol ( C MC ) s ec t io n o f th e N D A , A A D A , o r A N D A a nd de te r m in es th e c ap a bi li t y o f t h e m an u fa c t u r er t o p rod u c e th e d r u g p r od uc t as d es c ri b ed P.6
4 . V e r if i es t he t ra c e a bi lit y o f th e i n fo r m a t io n s ubm i tt e d i n t he C MC s e c ti on t o t h e o r i gi n al l a bo r a to r y n ot e bo o k s , e le c t ro ni c i n fo rm a ti o n , a nd ba tc h re c o r ds 5 . V e r if i es a nd en s u r es t h a t al l th e q u al it y s y s tem s a r e i n p la ce to m a n ufa c tu r e t h e p r o du c t s o it r e ta in s t h e i d en t i t y , s t re ng t h , q ua li t y, a nd pu r i t y o f th e d r u g pr o d uc t t h a t we r e a pp r o v e d b y t he c e n te r . 6 . R ec o mm e n ds ap p ro v a l fo r th e m an u fa c tu r e o f t h e d r ug p ro du c t b as ed o n th e s t a tu s o f t h e i ns pe c t i on
IV. SCALE-UP AND POSTAPPROVAL CHANGES (SUPACs) A. P u r p o s e . Th es e g ui de l in es a re in t en d ed to r ed u c e th e n u m b e r o f m anu f ac t u ri n g c h an g es th a t r eq u i re pr e- a p p ro va l b y t h e F D A . Th e gu id e li n es a r e p u bl ish e d b y t he F D A o n t h e I nt e r ne t (h t tp: / / ww w. f d a . g o v / c de r /g u ida n c e / in d e x. h t m ) . B . F u nc t i o n. Th es e g u ide l in es p ro v i d e r ec om m e nd a t io ns to s p on s o r s o f ND A s , A A D A s , a n d A N D A s d u rin g th e p os t ap p r o v al pe r io d wh e n 1 . Ma k i ng s l ig h t c ha ng e s i n t h e a m o un t of th e e xc i p i en t to ai d i n t h e p r oce s s i ng of t h e p r o du c t du r in g s c a l e-u p 2 . C ha n gi n g t he s it e o f m a nu f ac tu r e
3 . S ca l i ng u p ( in c re as i ng ) o r s ca l i ng d ow n ( d ec r e a s i ng ) th e b a tc h s i ze of t h e f o r m u l at io n 4 . C ha n gi n g t he m a nu f ac t u r in g p ro c es s o r eq u i pm e n t C . Th e F D A m us t b e n o tif i e d a bo u t a p r o po se d c ha n g e t o a d r u g p r od uc t th r o ug h d i f fe r e nt r eg u l a to r y d o c u m e n ta t i on , d e pe n di ng o n th e t y pe of c h an g e p ro p os e d. 1 . An n u a l re p o r t . C h an ge s th a t a re u nl ik el y t o h av e a n y d et ec t ab l e e ff ec t o n f o r m u l at io n qu al i t y a n d pe r f o rm an c e ca n b e i ns t itu t e d wi t h o ut ap p r o v al b y t h e F D A a n d re po r t ed an n ua ll y . Exa m p l e s o f t h es e c h a ng es in c l u de : a . C o mp l ia n ce wi t h an of f i c i al c o m p en d iu m b . L ab e l d es c r i p ti o n o f t h e d r u g p ro d uc t o r ho w i t is s u pp li e d ( n ot in v o l vin g do s a g e s t r en g th o r d os ag e f o rm ) c . D el e ti on o f a n i n g re d ie n t th a t a f fe c t s o n l y t h e c o lo r of th e p r o du c t d . E xt e n s io n o f th e e x pi ra t i o n d a te ba s e d o n fu ll s h el f -l i fe da t a o b ta in e d fr o m a p r o t oc ol ap p ro v e d i n th e a p pl ic a ti on e . C o n ta i ne r an d c l o su re s ys t e m f o r t he d ru g p ro d uc t (e xc e p t a ch a ng e in c o nt a in e r s i z e f o r n on s o li d do s a g e f o rm s ) ba se d o n eq ui v a l en c y to t he app r o ve d s ys t em u n de r a p r ot oc o l a p p ro v e d i n th e a pp l ic at io n o r p ub li s h e d i n a n o f fic i al c om p en d iu m f . A d di t io n o r d e le t io n o f a n a l t e r na t e a na l yt i c a l m e t h od 2 . C h an g es be i n g e f fe ct e d ( C B E ) s u p pl e me n t . C h a n ge s t ha t pr o ba b l y wo u ld no t h a ve an y d e te c t a bl e e f fec t bu t re qu i r e so m e v a li da t i on ef f o rt s r e qu i re s p ec i fi c d o cu m e n ta t io n , d ep e nd in g on th e c ha n ge . A s upp l em e n t is s ub m i t t ed , a nd t he c h an g e c a n b e i m p l em ent e d wi t ho u t p r e v io us ap pr o v a l ( C B E -0 ) b y th e F DA o r , i n s om e c as es , th e F D A has 30 da y s to r e v ie w t h e c h a n ge ( C B E -3 0 ) . F D A m a y r e j ec t t h is su pp l em en t . E xa m ple s o f re a s o ns fo r s u bm it ti n g a s u pp l em en t i nc l ud e a . Ad d i t i o n o f a new s pe c i f ic a t io n o r te s t m e t ho d o r c h a ng es in m e th o ds , fa ci li t ie s , o r co n t ro ls b . L ab e l c ha n g e t o a dd o r s t r e ng t he n a c o nt r a ind i c a t io n , wa r n i ng , pr e c au t i on , o r a d ve r s e r ea c t i on c . Us e o f a d i f fe r e n t f a ci l i t y t o m an u fa c tu r e t he d r u g s ub s t a nc e a nd d ru g p r o du c t ( t h e m an u fa c tu r in g p r oc e s s in t he ne w f a c i l it y d oe s n o t d i ff e r m at e ri a ll y f ro m th a t i n t h e fo rm e r f a c i li t y , an d th e ne w f a c il it y h as r ec eiv e d a s a ti s f ac t o r y c G MP i ns p ec ti o n wi t h i n th e p r e v i ou s 2 y ear s c o v e r in g t h at m a nu f act u r in g pr oc e s s ) 3 . P r e -a p p r o va l s u pp l em e n t . C h an g es th a t c o u ld h a v e a s ig n if ic a nt e ff ec t on f o r m u l at io n qu al i t y a n d pe r f o rm an c e r eq u i re s p ec if i c d oc um en t a ti on . Th is s u pp l em en t m us t b e a p pr o v e d be f o re th e p r op o se d c h a n g e is in i ti a te d . Ap p r op r i at e e xa m p l es fo r p re - ap p r o va l s u pp le m en t a r e : a . A dd i ti o n o r d el e ti o n o f a n in g r ed i e nt b . R e la xa t i o n o f t h e l im its f or a s p ec i f ic a t io n P.7
c . Es t ab li s hm en t o f a n ew r eg u l a to r y a n a l yt i c a l m e t h od d . D e le t io n o f a sp e ci f i ca t i o n o r re g ul a to r y a na l yt i c a l m e th od
e . C ha n ge in th e m e th o d o f ma n u fa c tu r e of th e dr u g pr o du c t, in cl ud i ng cha n gi n g o r r e l a xi n g a n i n - pr oc e s s c o n t r ol f . E xt e n s io n o f th e e x pi r a t i o n d a te o f t he d ru g p ro d uc t b a s e d o n d a ta ob ta i ne d u n d er a n e w o r re v i s ed s t a b il i t y t e s t in g p r o to c o l th a t wa s b e en ap p ro ve d in t he a p pl ic a ti o n D . W hen an y c h a ng e t o a d r ug pr o du c t is p ro po s e d , th e m an u fa ct u r er m us t s h o w t h a t t h e r es ul t an t d ru g p ro d uc t i s b i oe q u i va le n t an d t he r a pe u t ic a l l y e q u i va l e n t to t h e o r i gi na l a p pr o v e d d ru g p ro du c t ( s ee C ha p te r 7 ) . 1 . A m i n o r c h an g e is a c h an g e t ha t h a s m i ni m al p o te n ti a l t o h a v e a n a d ve r s e e ff e c t o n th e i d en t it y , s t r e ng t h, q u al i t y, p u ri t y , or po t enc y o f t h e p r od uc t a s t h e y m a y r e l at e to th e s a fe t y o r e f fe c ti v e n es s o f t he p ro d uc t . I f t h e p ro p os ed ch an ge is c o ns id e re d m in o r b y t h e F D A , bi o eq u i val en c e m ay b e de m o n s t r a te d b y com p a ra t i v e d i ss ol u ti on p ro f il es f or t he o ri g in a l a nd ne w f o r m u l a t io ns . 2 . A m a j o r c ha n g e is one t ha t ha s s u bs t an t ia l p ot e n ti a l t o h a v e a n a d v e rs e e f fe c t o n th e i d en t it y , s t r e ng t h, q u al i t y , p u ri t y, or po t enc y o f a p ro d uc t a s t he y m a y r el a te t o t he s a fe t y o r e f fe c ti v en e s s o f th e p r o du ct . If t he p r op os ed c h a ng e i s c on s id e re d m a jo r b y t h e F D A , b i oe qu i v a le n c e m us t be de m on s t ra t ed b y an in vi v o b i oe q ui v a l en c e s t ud y c om p a ri ng t he or i gi n al a n d n e w f o r m u l at i on s.
V. GOOD MANUFACTURING PRACTICES (GMPs) a r e re g ul a ti o ns d e v e lo ped b y t he F D A. G MP s a r e m i ni m u m r e qu i re m e n ts th a t th e i n du s t r y m us t m ee t wh e n m an u fa c tu r in g , p r oc es sin g , p ac k i n g, o r h ol d in g hu m an an d ve t e r i na r y d ru gs . Th es e r e g ul a ti o ns , a ls o k no wn a s c G M P s, es t ab li s h c ri te r i a f o r p e r so nn e l, f ac il i ti es , a n d m an u fa c tu r in g p r oc es s es t o e ns u re th a t t he f in is h e d d r ug p r o du c t h as th e c o rr ec t id e n ti t y , s t r en g th , q u al i t y, a nd pu r i t y c h ar ac t e ri st ic s . A. G o o d Ma n u f a c t u ri n g P r a c ti c e s a r e d esc r i be d in t he C o de of Fe d e ra l Re g ul a ti o ns ( C F R ) , t it l e 2 1, s e c t io n s 2 1 0 a n d 2 11 . B . Q u a l i t y c o n t r o l ( Q C ) i s th e g r ou p wi t hi n t h e m a n u fa ct u r e r t ha t i s r es p on s ib le f o r e s ta b li sh in g pr oc e s s a n d p r o du ct sp ec i fi c a t io ns . 1 . S pe c i fi c a ti o n s a re t he c ri t e ri a t o wh ic h a d ru g p r o du c t s h ou l d c o n fo r m t o be c o ns id e re d h a v i ng ac c e pt a b le qu al i t y fo r it s i nt e nd e d u s e . 2 . Th e Q C un i t t e st s th e p r o du c t an d ve ri f ie s t hat t h e s p ec i fi ca t io ns a re m e t . Q C t e s ti ng in c l u de s t he ac ce p t a nc e o r r ej e c ti o n o f t h e i nc om i ng r a w m a t e ria l s, p a ck ag i ng c om p on e nt s , d r u g p r od uc t s , wa t e r s ys t e m , a nd en vi r on m e n ta l c o nd i ti on s ( e . g ., he a ti n g, v e n ti la t ion , ai r - c o nd i ti o ni ng , ai r qu a li t y , m i cr o bi al lo a d ) t ha t e xi s t d u r in g th e m an u fa c t u ri n g p r oc es s . C . Q u a l i t y a s s u r a n ce (Q A) i s t h e g r ou p wi t hi n th e m a nu f ac t ur e r t h at de te r m in es t h a t t h e s y s t em s a nd f ac i l it i es ar e a d eq u at e a n d th a t th e wr i t te n p r oc ed u re s a r e f o l lo we d t o e ns u re th a t th e fi n is he d d r ug p ro d uc t m ee t s t he ap p li c a bl e s pe c if ic a ti o ns f o r qu a li t y . P.8
STUDY QUESTIONS
D i r e c t i on s : E a c h s t a te m e n t i n t h is s ec t io n c an be c o r r ec t l y c om pl e te d b y o n e o r m o r e o f th e s ug g es t ed ph r a s e s . C ho o s e th e c o r re c t an s we r , A - E: 1 . H ea l t h y h u m a n vo l u nt e e r s a r e us e d i n d r u g d e ve l o pm e n t f o r I . p ha s e I te s t in g af t e r th e su b m is s io n of a n i nve s t i g a t io n al n ew d r u g ( I N D ) a p p l ic a t io n . I I . ge n e r ic d r ug de ve l op m e n t f o r a n ab b r e vi a te d new d r u g a p pl i ca t i on ( AN D A) s u b mi s si o n . I I I . ph a se II I te s t in g ju st b e f o re t he s ub m is s ion o f a n ew d r u g a p p li c at i o n ( N D A) . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a nd I I a r e c o r r ec t D i f II an d II I ar e c o r re c t E i f I, I I, an d I I I a r e c o r re c t V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . T h e r eq u i r e d i n f o rm a t io n c o n t ai n ed i n a new d r ug a p pl i ca t i on ( N D A) t h at i s no t in c l ud e d i n th e a b b r e vi a te d new d r u g ap p l i ca t i on ( AN D A) c o n s i s t s o f I . p r ec l i ni c al a ni m al t oxi c i t y s t u d i e s . I I . cl i n ic a l e f f ic a c y s t u d i e s . I I I . hu ma n sa f e t y a n d t o l e r a nc e s t u di e s. A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a nd I I a r e c o r r ec t D i f II an d II I ar e c o r re c t E i f I, I I, an d I I I a r e c o r re c t V i e w A n s we r 2 . T h e a n sw e r i s E [s e e] . 3 . A p r o d u c t l in e e x te n s io n c o n ta i n s t h e new d r u g a p pl i ca t i on ( N D A) a p p r o ve d d r ug i n a n ew I . d os a ge f o rm . I I . do s ag e st r e n gt h . I I I . th e r a pe u t ic in d i ca t io n . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a nd I I a r e c o r r ec t D i f II an d II I ar e c o r re c t E i f I, I I, an d I I I a r e c o r re c t V i e w A n s we r 3 . T h e a n sw e r i s C [ se e] . D i r e c ti o ns : E a c h s ta t em e nt in th is s ec t io n c a n b e c o r r ec t l y c om p le t ed b y on e o f th e s u gg es t ed ph r as es . C hoo s e t he b e s t a ns we r . 4 . T he r eg u l at i o ns de ve l o p e d b y t h e U . S . F o o d a n d D r u g Ad m i n i st r a t i on ( F D A) f o r t h e p h a rm a ce u t ic a l i n d u st r y f o r m e e t i ng t he m in i m um r eq u i r em e n ts i n th e m a n u fa c tu r i n g , p r o ce ss i n g , p ac k in g , o r h o ld in g o f h u ma n a n d ve te r in a r y d r u g s a r e kn ow n as ( A ) g oo d m an u fa c tu r in g p r a c t ic es ( G MP s ) . ( B ) q ua l it y a s s ur a nc e ( Q A ) . ( C ) q u al it y c on t r ol ( Q C ) .
( D ) p r e -a p pr o v a l i ns pe c tio n ( P A I) . ( E ) sc a le - up an d p os t - app r o v a l c ha ng e s ( S U P A Cs ) . V i e w A n s we r 4 . T h e a n sw e r i s A [ se e] . 5 . T h e u ni t w i t h i n t h e p h a r ma c eu t i ca l m a n uf ac t u r e r th a t e n su r e s th at t h e fi n is h e d d os a ge fo r m h as m e t al l th e s p ec i f ic a t ion s f o r i t s i n t en d ed u se i s t he ( A ) a na l y t ic al m e t ho ds un i t . ( B ) m ar k e t in g a n d s al es u n i t. ( C ) p r e -a p pr o v a l i ns pe c tio n ( P A I) un i t . ( D ) q u al it y a s s u ra nc e ( QA ) u ni t . ( E ) q ua l it y c on t ro l ( Q C ) u n i t. V i e w A n s we r 5 . T h e a n sw e r i s E [s e e] . 6 . M a n u fac t u r e r s m a y m a k e a c ha n g e i n t h e f o r mu l a ti o n a f t e r m a r ke t ap p r o va l . I f t he c h an g e i n th e fo r m u la ti o n is c o n si d e r ed a m i no r c han g e , th e m a nu f ac t u r e r n e e ds t o re p o r t t h e c han g e to t he FDA only in the ( A ) a nn u al r ep o rt . ( B ) p r e -a pp r o v a l s u p pl em e nt . ( C ) i n v es t ig a ti o na l n e w dr u g ( I N D ) s u bm is s i o n. ( D ) c ha n ge s b ei ng e ff ec te d s u pp l em en t , 3 0 d a y s ( C B E - 3 0 ) . ( E ) n o r e po r t i s r e qu i re d f o r a m i n o r ch a ng e . V i e w A n s we r 6 . T h e a n sw e r i s A [ se e] . P . 9
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C (I , II) [ s e e I. C . 2 .b ; I . F .2 ] . P h a se I t es t in g i s t he f irs t s e t o f h um a n st u di es p e r f or m e d d u r in g n e w d ru g d e ve l op m e n t. P ha s e I s tu d ie s e s t a bl is h t h e t ol e ra n c e an d t o xi c i t y of t he d r u g i n h u m a ns . Bi o eq ui v a l en c e s t ud i es fo r g e ne r ic d ru g d e v e l op m e n t a re m o st o ft e n p e r f or m e d i n h e al t h y h um a n v o l un t ee r s . Th e se st u d ie s es t ab l is h t he bi o eq u i v al e nc e o f t he ge ne r ic d ru g p r odu c t a ga i ns t t h e b r an d d ru g p ro du c t. P ha se I II t es t i n g e nt a il s l a r ge - sc al e , m u l ti c e n te r c l in ic al st u di es pe r f or m ed i n p at i en ts wi t h th e d is e a s e o r c o nd i ti on t o b e t r ea t ed . P h a s e I II s t ud i es d e t er m in e th e s a fe t y an d e f f ic ac y o f t he d r u g i n a l a r ge pa t ie n t po p ul a ti o n. 2 . T he an sw e r is E ( I , II, a nd I II ) [s e e I . C .5 ; I. F .6 ] . Th e d e v e lo pm e nt of a n ew d r u g r e qu i re s e xt e n s i ve t o xi c i t y a n d e f fi c a c y t es t in g i n a n im al s a n d h um an s . Th e N D A d oc um en ts al l s t ud i es pe r f or m e d on th e d ru g . Th e A N D A i s u s e d f o r g e ne r ic d ru g p r o du c t s u bm is sio n s . Th e ge ne r ic d ru g p ro d uc t i s s im i la r to th e o r ig i na l b ra n d d r ug p ro d uc t t h at has al r e ad y b ee n m a rk et e d. B e c a us e t h e e f fi c ac y , s a fe t y , an d t o xi c i t y o f t hi s d r ug p ro du c t h a ve b e en s t ud i ed an d d o cu m e n te d , f u r th e r s tud i es of t hi s n at u re a re un n ec es s a r y . 3 . T he an sw e r is C (I , II) [ s e e I. D ] . P r o d uc t l in e e xt e n s i on s a r e de v e lo p ed af t e r f u r the r s t u di es wi t h th e o r ig i na l N D A a p p ro ve d d r u g p r od uc t . F r o m t he s e s t u di es , th e m a nu f ac tu r e r m a y d e v e lo p a n e w d o sa g e f o rm (e . g. , c o nt ro l le d - re l ea se p ro d uc t ) o r a ne w d o s ag e s t re n gt h . A n e w t h e r ap eu t ic in di c a t io n req u i re s a n N D A.
4 . T he an sw e r is A [ s ee V ] . Q u a l it y c on t r ol an d q ua l it y a s s u r an c e fo l lo w G MP r e g ul a ti on s t o e ns u r e t ha t t he f i n is he d p r od uc t m e et s al l ap pl ic a bl e s pe ci f ic at i on s fo r q u al i t y . Th e F D A m a y i n sp ec t a m a n uf ac t u ri ng s i te ( P A I ) b ef o r e t he d rug a pp li c a t io n i s a p pr o ved . I n a d di t io n , t h e F D A m us t be n ot i fi e d a bo u t a n y p r op o s e d c ha n ge s t o a n a pp r o v e d d r ug p r o du c t. 5 . T he an sw e r is E [ s e e V . B ] . Th e Q C u n it pe r f o rm s t he a pp r op r i at e t es t s o n t he d os ag e f o rm . P A I is per f o r m e d b y F D A c om pl ia nc e i ns p ec to r s , wh o e xa m i ne t he pha r m ac e u t ic al m a nu f ac tu re r a nd r e v i e w t h e p r oc e du r es an d r ec or d s f o r m a n uf ac tu r i ng t he fi ni s he d d os age f o rm b e f o re th e a dm i ni s t r a ti on g r a nt s m ar k e t ap p ro v a l . Th e a na l y t ic al de ve l op m e n t u n it d e ve l op s t he an a l y ti c a l m e th o ds u s ed in te s t i ng t h e d r u g p ro d uc t . 6 . T he an sw e r is A [ s ee I V . C . 1] . A l l c h an ge s i n t h e f o rm ula t i on m us t be re p o rt e d to t he F D A . A m i no r c h ang e is a c h an g e t ha t h a s m i ni m al p o te n ti a l t o h a v e a n a d ve r s e e ff e c t on th e i d en t ity , s t r en g th , q u al i t y , p u ri t y , o r p ot e nc y o f t he p ro du c t a s t he y m a y re la t e t o th e p r o du c t 's s a fe t y o r e f fe c ti v e n es s. C h an ge s t h at a re u nl ik el y t o h a v e a n y de t ec t ab l e e f f ec t o n f o rm u la t io n q ual i t y an d p e r fo r m a nc e c an b e i ns t it u t ed wi t h ou t a pp r o v a l b y t h e F D A a nd ne ed on l y to b e r e po r te d i n th e a n nu a l r e po r t .
2 Pharmaceutical Calculations and Statistics R i c c a r do L . B o n i
I. FUNDAMENTALS OF MEASUREMENT AND CALCULATION. Th e p h a rm ac is t i s o ft e n re q ui r e d t o p e rf o rm o r e va l ua t e a v a r ie t y of c a lc ul a ti on s i n h is o r h er p r ac t ic e. Ma n y o f t he s e c a lc ul a ti on s i n v o l ve t he u s e o f d i re c t o r i n v e rs e p r o po r t io ns . D im e ns i o na l ( o r u n it ) an a l ys i s a n d a p p r o xi m at i o n c a n be us e fu l i n s ol v i n g t he se p ro b le m s . In di m e ns io n al a n al ys is , d im e ns io ns ( o r u n i ts ) a r e i nc lu d ed wi t h e a ch nu m b e r u se d i n t h e c a lc ul a ti on . U ni ts c o m m o n to t he nu m e r a to r a n d d e n om in a to r m a y be c a nc el e d a nd th e re m a i ni n g u ni t s p r o vid e t h e u ni ts f or t he fi n al an s we r . I n a p p ro xi m a t io n , e ac h n um b e r us e d i n t he c a lc ul at i o n is r ou n de d t o a s i ng le s i gn i fi ca n t d ig i t. Fa c to r s c om m o n to th e n um e r at or a n d d en om in a to r m a y be c a nc el e d a nd th e a ns we r t o th is ap p ro xi m a t io n s ho u l d be r ea so n ab l y c l os e t o t he fi n al e xa c t a ns we r . A. R a t i o a n d p r o po r t i o n 1 . R a t io . Th e r e la t i v e m a g ni t ud e of t wo li k e qu an t i ti es is a r a ti o , wh i c h is e xp r e s s ed as a f r ac ti o n. C e r t a in ba si c p r in c i pl es a p pl y t o th e r a ti o , a s t hey d o to al l f r ac t io ns . a . W he n t h e t wo t e rm s of a ra t io a re m u lt i pl ie d o r d i v i de d b y t he s a m e n u m b e r , t he v a lu e o f th e r a t io is u nc h an g ed .
b . Two r a t i os wi t h th e s am e v al u e a r e e qu i v al e nt . E q u i val en t ra t io s h a ve e q u al c r os s p r od uc ts and e qu al r ec ip r oc a ls . F o r e xa m p l e :
and 1 × 6 = 3 × 2 = 6 I f t wo r a ti os a re eq u al , th e n t h ei r re c i p r oc al s a r e e q ua l :
2 . P r o po r t i o n. Th e e xp re s s i on of t he eq u al it y o f t wo r a t i os i s a p ro po r t io n. Th e p r o du c t of t he e xt r em es is eq ua l to th e p r o du c t o f t h e m ea ns fo r an y p r o po r t io n . F u rt h e rm o re , t h e n um e ra t o r o f t h e o ne f r ac ti o n e qu a ls t h e p r o du c t o f i ts de n om in a to r a nd th e o t he r f ra c t i on ( i . e ., on e m is s i ng t er m c a n a l wa ys b e f o un d g i v en t he o th e r t h r ee te r m s ) . Mo s t ph a rm ac eu t ic al c a lc ul a ti on s c an be pe r fo r m ed b y u s e o f p ro p o rt io n . a . P r o pe r r a t io s . S om e p h a rm ac is ts us e p r op e r ra t i os (i n wh ic h s im il a r u n i ts a r e u s e d i n t h e n um e r at o r a nd d en om in a tor o f e ac h ra t io ) in th e ir p r o po r t io n c al c u l at i on s . S e v e r a l e xa m p le s f o ll o w. ( 1 ) I f 2 40 m L of a c o u gh s y r u p c on t ai ns 48 0 m g of d e xt r o m et h or p ha n h yd r o b ro m i d e, t he n wh a t m as s o f d r ug is c o nt ai ne d i n a c h i ld ' s d os e , 1 t e as p oo n fu l (5 m L ) o f s y r u p ?
P.11
( 2 ) I f a c hi l d 's do s e ( 5 m L ) o f a c ou g h s yr u p c o n ta i ns 10 m g o f d e xt r o m e th o r ph an h y d rob r o m i de , wh a t m as s o f dr u g i s c on t ai n ed in 24 0 mL?
( 3 ) I f t he am o un t o f d e xt r o m et h or p ha n h y d r o br o m i d e i n 2 40 m L of c o ug h s yr u p i s 4 80 m g , wh a t wo u ld be t he vo lu m e r eq uir e d fo r a c h i ld ' s d os e o f 1 0 mg?
( 4 ) H o w m an y m il li g ra m s o f de xt r o m e th o rp h an bas e (m ol e c u la r we i gh t = 2 7 1 .4 ) ar e e q ui v a l en t t o 1 0 m g o f de xt r o m e th o rp ha n h y d ro b ro m i d e ( m o le cu la r we i g ht = 3 52 .3 ) ?
b . M i x ed r a t io s . S om e ph a r m a c i st s u s e m i xe d r at i os ( in wh i c h di ss im il a r u n i ts a r e u s e d i n t h e n um e r at o r a nd d en om in a tor o f e ac h ra t io ) in th e ir p r o po r t io n c al c u l at i on s . S u c h c o m p u ta t io n s g en er a l l y g i v e c o r re c t a ns we r s , p r o vi di n g t he c o nd i ti o ns i n wh i c h m i xe d r a ti os c an n o t b e us e d a r e kn o wn . A l a t er e xa m p le s h o ws m i xe d r at i os l e ad in g to fa il ur e in t he c as e of di lu t io n, wh e n i n v e rs e p r op o r ti o ns a re r eq ui r e d. Fo r i n ve rs e p r op o r t i on s , s i m i l a r u n i ts m us t b e u s e d i n the n um e ra t or a nd de no m in a t o r o f e ac h r a ti o . F o l lo wi n g i s a n e xa m p l e o f a m i xe d ra t io c a lc ul a tio n us in g t h e p r e v io us p r o bl em .
Th e s a me an sw e r i s o b ta i ne d i n th is e xa m pl e whe t h e r we u s e p ro p e r r a tio s , wi t h s im il a r u ni t s i n n um e r a t or an d d e no m i n at o r , o r m i xe d r a t io s . Th is is no t t h e c as e wh e n d ea li n g w i t h i n v e rs e p r op o r ti o ns . 3 . I n ve r se p r op o r t i on . Th e m os t c om m o n e xa m p l e o f t h e n ee d fo r i n ve rs e p r o po r t io n f o r t h e p ha r m a c is t i s t he ca s e of d il u ti o n . W he re as in th e p r e vi ou s e xa m p l es o f p ro p o r ti on t he re l at i on s h i ps i n vo l ve d d i re c t p r o po r t io n , t he c a s e of di l u ti on c a ll s f o r a n i n v e rs e p r op o rt i on ( i. e ., as vo l u m e in c re as es , c o nc en t r a ti o n d ec re a s e s) . Th e n ec es s i t y o f u si ng in ve rs e p r o po r t io ns fo r di l ut i on pr o b le m s is s ho wn i n th is e xa m p l e . I f 1 20 m L of a 1 0 % s t o c k s o lu t i on i s d i lu t ed t o 2 4 0 m L, w h a t i s th e fi na l c o n ce n t r a ti o n ? U s i n g i nv e r s e p r o po r ti o n,
A s e xp e c te d , t he fi n al c on c en t r at i on is o n e h al f t he o ri g in a l co nc e nt r a ti o n b e ca us e th e v ol um e i s do u bl e d. H o we v e r , if t he p h a rm ac is t a t t em pt s t o us e d i r ec t p r op o r ti o n a nd neg l ec ts t o es t im a te an app r o p ri a te an s we r , th e
r e s ul ti n g c al c u la t io n wo ul d pr o v i de an an s we r o f 2 0 % , wh i c h is t wi c e t he a c tu a l co n c e n tr a ti o n.
P.12
L i ke wi s e , t h e p ha rm a c i s t u s i n g m i xe d r a t io s f ai ls i n th is c a se .
and
B . Al i q u o t . A p ha r m a c i s t r e q ui r es th e a li q uo t m e th o d o f m ea s ur em e nt wh e n t h e s e ns i t i vi t y ( t h e s m all e s t qu a nt i t y th a t c an be m e as u re d wi t h t he r e q ui r e d ac c u r ac y a nd p re c is io n ) o f t h e m e a s u r ing d e v ic e is no t g re a t e n o ug h f o r t h e r e qu i re d m e as u re m e n t. A li q uo t c al c ul a ti on s c an be us ed fo r m e as u re m e n t o f s ol id s or l iq u id s, al l o wi n g t he pha r m ac is t t o re al i z e th e r e q ui r e d p re c i s i o n t h ro ug h a p r oc ess o f m e as u r in g a m u l ti p le of th e de si re d a m ou n t f ol l o we d b y d il u tio n an d f i na ll y s el ec t io n a n d m ea s u r em e nt of an a l iq u ot pa r t th a t c o n ta i ns t h e d es i re d a m o u nt o f m a t e ri a l. Th i s e xa m p le p r o bl em in v o l v es we i g hin g b y th e a li q uo t m e th od, u s i ng a p r es cr i pt i on b a la n ce . A p r es c ri p ti on ba l an c e ha s a s e ns i ti v i t y r eq u ir em e n t o f 6 m g . H o w wo u l d yo u we i g h 1 0 m g o f d r ug wi t h a n a cc u ra c y o f ± 5% , us in g a s u i ta bl e d i lu en t ? 1 . Fi r s t, c a lc ul a te th e l ea s t we ig h ab l e q ua n ti t y fo r t he ba l an c e wi t h a s e ns it i v i t y re q ui r em e nt of 6 m g , as s um in g ± 5 % ac c u r ac y i s r e qu i re d .
2 . N o w i t i s o b v io us t ha t a n al iq u ot ca lc ul a ti o n is r e q ui r e d b ec au s e 10 m g o f d r u g i s r eq u i re d , wh e r e as t he le as t we i gh a bl e q ua n t it y i s 1 20 m g t o a c hi eve t h e re q ui r ed pe r c e n ta g e o f e r ro r . Us in g t h e l ea s t we i g h a bl e q u an t it y m et ho d o f al i qu o t m e as u r em en t , u s e t he s m al le s t q ua n ti t y we i g h a bl e o n t h e b al an ce a t ea ch s t e p t o p r es e r v e m a te r i al s . a . W ei gh 12 × 1 0 m g = 12 0 m g o f dr u g. b . D il u t e t he 12 0 m g o f dr u g ( fr om s t e p a ) wi t h a s u it a bl e d il u en t b y g e om e t ri c a l d il u ti o n t o ac h ie v e a m i xt u r e t h at wi l l p r o v i de 10 m g o f dr u g in e a ch 12 0 -m g a li q uo t . The am o un t o f di lu e nt t o be us e d c an be de t er m i n ed t h r o ug h p r o p o r ti o n .
c . W eig h 12 0 m g ( 1 /1 2 ) o f t he to t al m i xt u r e , wh i ch wi l l c o nt a in th e re q ui r ed 1 0 m g o f dr u g.
II. SYSTEMS OF MEASURE. Th e p h a rm ac is t m us t b e f a m i l ia r wi t h th r e e s ys t e m s of m e as u re : th e m e t ri c s ys t e m a n d t wo c om m o n s y s te m s of m e as u re ( the a vo i r d up o i s a nd a p o t he c a ri e s' s y s t em s ). Th e p r im a r y s ys te m o f m e as u re in ph a rm ac y a nd m e di ci n e is th e m e tr ic s ys t em . Mo s t s tu d en t s f in d i t e a s i es t t o c o n v er t m e as u re m e n ts i n th e c om m o n s ys te m s to m e t ri c u n i ts . A t ab le o f c o n ve rs io n e q ui va l en t s is p ro v i de d an d s h ou l d b e m e m o r i ze d b y t h e p ha r m a c i s t (s e e A p p en d i x A ) . Th e m e t ri c s y s t em , b ec a us e o f i ts un i v e r s a l a cc ep t an c e an d b r o ad us e , wi l l no t b e rev i e we d h e r e. A. Ap o t h e c a r ie s ' s ys t e m o f fl u i d m ea s u re . Th e a p ot h ec a ri es ' s ys t em of f l u id m e as u re is s um m a ri z e d in A pp en d i x A . B . Ap o t h e c a r ie s ' s ys t e m f o r m e as u r i ng w e i gh t. Th e a po t he c a r ie s ' s ys te m f o r m e as u ri ng we i g h t i nc l u de s u ni t s o f g r ai ns , s c ru p le s , d r am s , ou nc es , an d p o u nd s ( s e e Ap p en di x A ) . C . Avo i r d u p o i s s ys t e m o f m ea s u ri n g w ei g h t. Th e a voi r du p oi s ( A V ) s ys t em o f m e as u ri ng we ig h t i nc l ud es th e g r a in , ou n c e , a n d p ou n d. Th e g r a in is a u ni t c om m o n w i t h t h e a po t he c a r i es ' s ys t e m a nd al l o ws fo r ea s y c o n ve rs io n b e t we e n t he s y s t em s . Th e a v o i r du po is po u nd , h o we v e r , P.13
i s 1 6 A V o un c e s i n c on t ra s t t o t h e a po t he ca r i es ' p o u nd , wh ic h i s 1 2 a p o th ec a ri es ' o un c e s (s ee A p pe nd i x A ) . D . C o n ve r s i on eq u i va l en t s . Se e Ap p en di x A .
III. REDUCING AND ENLARGING FORMULAS. Th e p h a rm ac is t i s o ft e n re q ui r e d t o r e du c e o r e nla r g e a re c i p e. P r ob l em s o f t h is t yp e a re s o l v e d t h rou g h p r op o r ti o n, o r b y m ul t i pl ic a ti on o r d i v is io n b y t h e a p p ro p ri a te fa c to r to o b t ai n t h e r e qu i re d a m ou n t o f ea ch in g re d ie n t t ha t wi l l g i ve t h e d es i re d t o tal m a s s or v o l um e o f t he fo r m ul a . F o rm ul as c a n b e p r o vi de d i n a m o u nt s o r in p a rt s . A. F o r m u l a s t h at i nd i cat e p a r ts . W hen de a li ng wi t h f o rm u la s t h at s p ec ify p a r ts , p a r ts b y we i gh t wil l re q ui r e t h e d et e rm in a ti o n of we i g ht s o f i n g re d ie n ts , wh e re as pa rt s b y v ol um e wa r r a nt th e c al cu l at i on of v o lu m e s of i n g re d ie n ts . A l wa y s f in d t h e to t al nu m b e r o f p a r ts i n di c a t ed in th e fo rm u la , a n d e q ua t e t ha t to t al wi th t he t ot a l m a ss or vo lum e o f th e d es i re d fo r m u la i n o r d e r t o s et up a p r op o r ti o n . S uc h a p ro p or t io n wil l al lo w c a lc ul a ti o n o f t h e
m as s o r v o lu m e of ea c h i n g re d ie n t i n u ni ts c o m m o n to t he to t al m as s o r vo l u m e . W h a t q u a nt i t ie s sh o ul d b e us e d t o p r e p a re 10 0 g o f c am p h o ra t e d p a r a ch l o r o ph e no l ?
Rx
parachlorophenol
7 parts
camphor
13 parts
7 parts + 13 parts = 20 parts total
B . F o r m ul a s t h at i nd i cat e q ua n t i ti e s. Th e pr e vio u s p r esc r i pt i on fo r c o ld c r e am p r o v i de s a 1 0 0 g q u a nt i t y. W h a t m a ss o f e ac h in g re d i en t i s r e qu i r e d t o p ro vi d e 1 p o u nd ( AV ) o f c r e a m?
Rx
white wax
12.5 g
mineral oil
60.0 g
lanolin
2.5 g
sodium borate
1.0 g
rose water 1 lb = 454 g
24.0 g
12.5 g × 4.54
=
56.8 g of white wax
60.0 g × 4.54
=
272 g of mineral oil
2.5 g × 4.54
=
11.4 g of lanolin
1.0 g × 4.54
=
4.54 of sodium borate
24.0 g × 4.54
=
109 g of rose water
IV. CALCULATING DOSES. C a l cu l at i on of do s e s g ene r a ll y c an be pe r fo r m e d wi t h d im e ns io n al an al ys is . P r o b l e ms en c o un t e re d in t he ph a rm ac y i nc lu d e c a lc ul a ti on o f t he nu m b er o f d o se s, q ua n ti ti es in a d os e o r to t al m a ss / vol um e , a m o u nt o f ac t i v e o r i n ac t i ve i ng r ed i en ts , an d s i z e o f d os e . Ca lc ul a ti on o f c h il d r e n' s d o se s i s c om m o n l y p e r fo r m e d b y t h e p h a rm ac is t . D os a ge is op t im al l y c a lc ul a te d b y u s in g t h e c h i ld ' s b o d y we i gh t o r m a s s an d t h e a pp r o p ri a te do se in m i ll ig r am s p e r k i l og r am (m g /k g ). W ith ou t t h es e da t a , t h e f ol lo wi n g f or m u la s b a se d o n a n a d ul t d os e c a n b e u s e d . A. F r i e d ' s r ul e fo r i n fa nt s
P.14
B . C l a r k 's r u le
C . C h i l d' s do s ag e b a sed o n b o d y s u r f a c e a r ea ( B S A )
D . Y o u ng ' s ru l e f o r ch i ld r e n ≥ 2 ye a r s o l d
E . C o n s ta n t ra t e i n t r a ve n o us i n fu s io n s . S om e d r u gs ar e ad m i ni s te r ed i n t ra ve n ou s l y a t a c o ns ta n t ( z e ro - o rd e r ) r a te b y u s in g a c o nt i nu o us - dr i p i n f us io n s et o r a c o ns ta nt - r a t e i nf us i on pu m p . The f lo w r a t e ( v ol um e p e r u n i t t im e ) r e qu i re d c an be c a lc u la t ed f ro m t h e v o lu m e t o b e a dm in is t e re d a n d t h e d u ra t io n o f t h e in f us i on . Th e r a te o f d r ug a dm i ni st r a ti o n c a n b e c a lc ul a te d f r om th e c o nc e n t r at i on of d ru g i n t h e in f us e d s ol ut i on an d t h e f l o w r a t e o f t h e i nf us i on s e t o r p u m p . Co n v e rs i on f a c t o rs m a y be r eq u i re d t o o b t ai n t h e f in a l a ns we r in t he c o r r ec t u ni t s ( d ro ps pe r m i nu t e o r m il li l it e rs p e r ho u r ). A va n co m y c i n s ol u ti o n c o n t ai ni n g 1 00 0 m g o f v an c om y c in h y dr o c h lo r id e d i lu t ed t o 2 50 m L wi t h D5W is to be in f us ed at a c o ns ta n t ra t e wi t h a c o nt i nu o us -d r i p i nt r a v e no u s i nf us i on s e t t h at de l iv e r s 25 d ro ps / m L . W h a t f l ow r a t e ( d r o ps / mi n ) sh o u l d b e u s ed t o i n f use a l l 2 50 m L o f t he va n c o m yc i n h yd r o c h l o ri d e so l u ti o n i n 2 h r ?
V. PERCENTAGE, RATIO STRENGTH, AND OTHER CONCENTRATION EXPRESSIONS A. P e r c e n t a ge w e ig h t in vo l u m e (w / v) 1 . D e f in i t io n . Pe r c e n ta ge , in d ic at i ng pa r ts pe r hu n d re d , i s a n im p or t an t m e an s o f e xp r e s s i n g c o nc e nt r a ti o n i n p ha rm a c y pr a c ti ce . Pe r c e n ta g e w/ v i n di ca t es th e n um b e r o f g r a m s o f a c o ns t it u en t pe r 1 00 m L o f s ol u ti o n o r l i qu i d f o rm ul a ti o n. Th e ph a r m a c i st m a y b e r eq u i re d to pe r f o rm th r e e t yp e s o f ca lc ul a ti o ns : d e te r m i ne t he w e i gh t of ac ti v e ing r e di e nt in a c er t ai n vo l u m e wh e n g i v e n t he pe r c en t ag e s t re n gt h , d et er m i ne th e p e r ce n t ag e w /v wh e n t h e we ig h t o f s ub s ta n c e an d vol um e o f l i qu id f o rm ul a ti o n a re k n o wn , a n d d e te r m i ne t he vo l um e of li q ui d m i xt u r e wh en t he pe r ce n ta g e s tr e ng th a n d a m o u nt of s u bs t an c e a r e k n o wn . 2 . T ol u ba l sa m s yr u p . T o l u b al s a m t i nc tu r e c on ta i ns 20 % w/ v t o lu ba ls am . W h a t i s th e pe r c en t a ge c o nc e n t ra t i o n o f to l u ba l s am i n t h e s yr u p ?
tolu balsam tincture
50 mL
magnesium carbonate
10 g
sucrose
820 g
purified water, qs ad
1000 mL
a . Fi r s t, de t e rm in e wh a t t h e a m o u nt o f t ol u b a ls am is i n th e 5 0 m L q ua n ti ty o f ti n ct u re us e d f o r t he s y r u p . Th e n, b y p ro po r t ion , c a lc ul a te t he c o nc en t r at i on of t ol u b als am in t he s yr u p .
I n an s we r i ng th is on e q ue s ti o n, t he fi r s t t wo t y p es o f p ro b le m s l is t ed a bov e h a ve be e n s o l v e d, wh i l e e xh i b i t in g t wo m e th o ds of s ol v i ng pe r c e n ta g e p r o bl em s —n am e l y , b y d im e n si o na l an a l ys i s a n d p r o p o r t io n . b . F o r a n e xa m p le of th e t h i r d t yp e o f p e rc en t age w/ v p r o b le m , d et e rm ine wh a t v o l u m e of s y r u p c ou l d b e p r ep a r ed if we h ad o nl y 8 g o f m a g ne si um c a r bo na t e . U s e p ro p o rt i on t o f in d th e t o ta l v ol um e o f s y r u p t h at ca n b e m a de us in g o n l y 8 g o f m a gn es i um P.15
c a r bo na t e . I f we ha v e 8 g o f m ag ne si um ca r bo n at e in 10 0 0 m L o f s o l ut i on, t h e n, ac c o r di n g t o t h e r ec i pe , 8 0 0 m L o f s o l ut i on c a n b e p r ep a re d u si n g a ll 8 g o f th e d r ug .
B . P e r c en t a ge vo l um e in vo l u m e ( v/ v) . P e r ce n ta g e v/ v in di ca t es th e n u m b e r o f m il li l it e rs of a c on s ti t ue n t i n 1 00 m L o f l i qu id f or m u l at i on . Th e p e r ce n ta ge s t r e ng t h o f m i xt u r e s o f l iq u id s i n l iqu i ds is i n di c a t ed b y p e rc e n t v/ v, wh i c h in d ic at es t he p a r ts b y v o lu m e of a s ubs t an c e in 10 0 p a r ts of the l i qu i d p r ep a ra t io n . Th e th r e e t yp e s o f p ro b le m s th a t a r e e nc o un t e re d i n vo l ve c al c u l at i ng pe r ce n t a ge s t re n g th , c a lc ula t i ng vo l um e of i ng r e d ie n t ,
a n d c al c u l at i ng vo l um e o f t h e l i qu i d p r e pa r a t i on . U si n g t he sa m e to l u b a ls am s y r u p fo rm u la f rom ea r li e r , we ' l l n o w wo r k a pe r c e n t v / v p r o bl em . W h a t i s th e pe r c en t a ge s t r e ng t h v/ v o f t he t olu b a ls am t i nc t u r e i n the s yr u p p r e p a r a t i on ? B y p r o po r t io n , we c a n so l ve t h e p r ob l em i n o n e s t e p.
C . P e r c en t a ge w e ig h t in w e i g ht (w /w ) . Pe r c e n ta g e w/ w i n d ic a te s t he n u m b e r o f g r am s o f a c on s ti t ue n t p e r 1 00 g o f f o rm u la t io n ( s ol id o r l iq ui d ). S o l u ti on o f p ro b le m s i n vo l v i ng pe r ce n ta g e w/ w i s s t ra i gh t fo r wa r d wh e n the t o t al m a s s o f th e m i xt u r e i s a v a il a bl e o r wh e n t h e t o t al m as s c an be d e t e rm in ed f ro m t h e a v a il a bl e d a ta . In c a lc ul a ti o ns si m i la r to t ho s e fo r p e r ce n ta ge w/ v a n d v / v , t h e p h a rm ac is t m ig h t n ee d to s o l v e s e v e ra l t yp es o f p r o bl em s , i nc lu di n g d et er m i na ti o n o f t h e we i g h t of a c o ns ti t ue n t , t he to t al we i g h t of a m i xt u r e , o r th e pe r c e n ta g e w/ w. 1 . H ow ma n y g r a m s o f d r u g su b s ta n ce sh o u ld b e us e d to p re p a r e 2 40 g o f a 5 % w /w s o l u ti o n i n w a te r ? a . Th e fi r s t s t ep in an y pe r c en t ag e w/ w p r o b le m is t o a tt em p t i de n ti f ic a ti on o f t he to t al m as s o f th e m i xt u r e . In th is p ro bl e m , t h e t o ta l m as s is , o b vi o us l y , p r o v id e d ( 24 0 g ) . b . Th e p ro bl em c a n b e ea s il y s o l v e d t h ro u gh d ime n s io n a l a na l ys i s .
2 . W he n t h e t ot a l m a s s of t h e m i xt u r e is un a v a il ab l e o r c a nn o t b e d e t e rm in ed , an ex t r a s t ep is r eq u i re d i n t h e c a lc ul a t io ns . Be c a us e i t i s u s ua ll y i m p os s i b le to k no w h o w m u c h v o l um e is d i s p l a c ed b y a s o li d m a te r i al , t h e p ha r m a c i s t i s u n ab le t o p r ep a re a sp e c i f ie d v ol um e o f a s o lu t io n g i v e n t he pe r c en t a ge w/ w. H ow m u c h d r u g s ho u l d b e ad d e d t o 3 0 m L o f w a t e r t o m ak e a 10 % w /w s o l u t io n ? Th e v o lu m e o f wa t e r t h at is d is p la c e d b y t h e d r ug is un kn o wn , s o t h e fi na l v ol um e i s u nk nown . L i ke wi s e , e v e n th oug h th e m as s o f s ol ve n t is k n o wn ( 30 m L × 1 g /m L = 3 0 g ) , i t i s n ot k n o wn ho w m u c h d ru g i s n e ed ed , s o th e t o ta l m as s is un k no wn . Th e wa t e r r e pr es e nt s 10 0% - 1 0 % = 90 % o f t h e to t al m i xt u r e . Th en , b y p r o po r ti o n, t he m as s o f d ru g t o b e u s ed c a n be i d en t i fi ed .
Th e c o mm o n e r r o r th a t m a n y s t ud e nt s m a k e i n so l vi ng p ro b le m s o f th is t yp e is to as s u m e th a t 30 g i s t h e t ot a l m a ss of th e m i xt u r e . So l v i ng th e p r o bl em wi t h th a t a s s um p t i on gi ve s t he f ol lo wi n g i n c o r r ec t a ns we r .
D . R a t i o s t r en g t h . S ol i d o r li qu i d f o rm ul a ti o ns t ha t co n ta in lo w c o nc en t r at i on s o f a c t i v e i n g re d ie n ts wi l l o f te n h av e c on c en t ra t io n e xp r e s s e d i n r a ti o s t r e n gt h . Ra t io s t r en g th , a s t h e n am e im p l ie s , is t he e xp r e s s io n o f c o nc en t r at i on b y m ea n s o f a r a ti o . Th e n um er a to r a n d d en om i na t or o f t he r a t io in d ic at e gr am s ( g ) o r m i ll i li t er s (m L) o f a s ol i d o r l i qu id c o ns t it u en t in t h e to t al m as s ( g ) o r v o lu m e ( m L ) of a s ol id o r l iq u id p re p a ra t io n . B ec a us e p e r c en t a ge s t re n g th is P.16
e ss e nt i al l y a r a ti o o f p a rt s pe r h u nd r e d, c o n ve rs io n be t we e n ra t io s t r en g th a n d p e rc en t a ge s t r en g th i s e as il y a cc om pl is h ed b y p r o po r ti o n. 1 . E xp r e ss 0 .1 % w / v as a r a t i o s t r en g t h. a . R a ti o s t re n gt hs a re b y c on v e n ti o n e xp r e s s e d i n r e d uc ed fo r m , s o in s e t ti ng up ou r p ro p or t io n t o s o l v e f o r r a ti o s t re n gth , us e t h e n um e ra l 1 i n t h e n um e r at o r o f th e r i ght h a nd r at i o as sh o wn :
b . Li k e wi s e , c on v e r s i o n fr o m ra t io s t r en g th to pe rc e nt a ge s t r en g th b y p r o po r t io n i s e as y , as s ee n in th e fo ll o wi n g e xa m p l e . K e ep in m i nd th e d e f in i ti on o f p er c en t ag e s t r en g th ( pa r ts pe r hu n dre d ) wh e n s et t in g u p th e p r o po r t io n . 2 . E xp r e ss 1 :2 5 00 as a p e r c en t a ge s t re n g th .
E . O t h e r c o n ce n t r at i o n e x p r es s io n s 1 . M o l a r it y ( M) i s t h e e xp r e s s io n o f t h e n um be r of m ol es of s o lu t e d is s o l ve d p e r l i te r o f s o l ut io n . I t i s c a lc ul a te d b y d i vid i ng the m o l es o f s o lu t e b y t he vo l u m e of s o lu t io n i n l i ter s .
2 . N o r ma l i t y. A c o n v e n ie n t wa y o f d e al in g wi t h ac i ds , b as es , a n d e l ec t r ol y t es in v o l v es t he u s e o f e qu i v a le n ts . O ne e q ui v a l en t of an ac id is +
t h e q u an t it y o f t h at ac i d t h a t s up pl i es o r do n at es 1 m o l e o f H i on s . O n e -
e q ui va l en t of a b as e is th e qu a nt i t y th a t f u rn is h es 1 m ol e o f O H i on s. O ne e q ui va l en t of ac id r ea c t s wi t h 1 eq ui va l en t o f ba se . E qu i v a le n t we i g h t c a n b e c a lc ul a te d f o r a t om s o r m o l ec ul es .
Th e n o r m al i t y ( N ) o f a s o l u ti on is th e n um b e r o f g r a m - e qu i va le n t we i g h ts ( e q ui va l en ts ) of s o lu t e pe r li t e r o f s ol u ti on . N o rm a l i t y i s a na l og ou s t o m o la r it y ; h o we v e r , i t is de f i ne d i n t e rm s o f e qu i v al e n ts ra t he r th a n m o l es .
3 . M o l al i t y ( m ) i s t he m ol e s o f s ol u te di ss ol v e d pe r k i lo g r am o f s o l v en t . Mo l a l i t y is c a lc ul a te d b y d i v i di n g t he nu m be r o f m o l es of s o lu t e b y t he n u m b e r o f k il o gr am s o f s o l v e n t. Mo l a l it y o f fe r s a n a d v a nt a ge o v e r m o l a ri t y b e ca us e i t i s b as e d o n s o l v e n t we i g h t a nd a voi ds p r o bl em s as so c i a te d wi th vo l u m e e xp a ns i on o r c o nt r a c t i on o wi n g t o t h e a ddi t i on of s o lu t es .
4 . M o l e f r a c ti o n ( X) i s th e r at i o o f t he nu m b e r o f m ol es o f o ne c om p on e nt t o t he to t al m o le s o f a m ixt u r e o r s o l ut i on .
VI. DILUTION AND CONCENTRATION. I f t he am ou n t o f d r ug r em a in s c o n s t a nt in a d il u ti o n o r c o nc en t r at io n , t h en a n y ch a ng e i n t h e m as s o r v o l um e o f a m i xt u r e is i n v e rs e l y p r o po r ti o na l t o t h e c on c en t ra t io n . A. D i l u t i o n a n d c o nc e n tr a t i o n p r o b le m s c an be s o l ve d b y: 1 . I n ver s e p ro p o rt i on (a s m en t io n ed ea r li e r ) 2 . Th e eq ua t io n q u an t it y 1 × c o nc en t r at i on 1 = qu an t i t y 2 × c o nc en t r a ti on 2 3 . D e te r m i ni n g t he am oun t o f ac t i v e i ng r ed i en t p re s en t i n th e i ni t ia l m i xt u re a n d , wi t h t he as s um p ti o n t h a t t he in i ti al qu a nt i t y d o es no t c h an ge , c a lc ul a ti ng o f t he f in al c o n c e n t ra t io n o f t h e n e w to t a l m a s s o r v o l um e P.17
4 . Al l i g a t io n m e di a l . A m e th o d f o r c al c u la t in g t he a v e r ag e c on c e n t ra t io n o f a m i xt u r e o f t wo o r m o r e s ub s ta nc es 5 . Al l i g a t io n a l t e rn a t e. A m et h od f or ca lc ul a ti n g t h e n um b e r o f p a rt s o f two o r m o r e c om po n en ts o f k n o wn c on ce n t ra t io n t o be m i xe d wh e n t h e f in al d e si r ed c o nc e nt r a ti on is k n o wn B . D i l u t io n of a lc o ho l s a n d a c i ds
1 . D i lu t i o n o f a l co h o ls . W hen a lc oh ol an d wa t e r a r e m i xe d , a c on t ra c ti on o f vo lu m e oc c u r s . As a re s ul t , t h e f in al vo l um e o f s ol u ti o n ca n no t b e d e t e rm in ed ac c u r a te l y . N o r c a n th e v ol um e o f wa t e r n e ed ed t o d il u te to a c e r ta i n p er c en t ag e v / v be i de n ti f ie d . A c c o rd in g l y , p e rc e nt a ge w/ w i s o f te n u s ed fo r s o lu t io ns o f a lc o h ol . 2 . Th e pe r c en t a ge s t re ng t h o f co nc e nt r a te d a c i ds is e xp r e ss ed as p e r ce n ta ge w/ w. Th e c o nc e nt r a ti o n o f d il u te d a c i ds is e xp r e ss ed as p e r ce n ta ge w/ v . D e t e rm in i ng t he vo lu m e of co nc e n t r at e d ac i d t o b e u s e d i n p r e pa r i ng a d il ut e d a c i d r e q ui r es th e s p ec if ic g rav i t y o f th e c o nc en t ra t e d a c id . C . D i l u t io n a n d c o nc e n tr a t i o n o f l iq u id s a n d s ol i d s . D i lu t io n a n d c o nc en t r at i on p ro bl em s a r e of t en ea si l y s o l v ed by i d e nt i f y in g th e a m o un t o f d r u g i n v ol v e d fo ll o we d by u s e o f a n a p p ro p ri a te p r o po r t io n . 1 . H ow ma n y m i l l i l i t e r s o f a 1 :5 0 s t oc k s o lu t i on o f ep h ed r i n e s ul f a te s h o u ld be u se d i n co mp o u n di n g th e fo l l ow in g p r e sc r i p t io n ?
Rx
ephedrine sulfate
0.25%
rose water, ad
30 mL
2 . H ow ma n y m i l l i l i t e r s o f a 1 5 % w / v c o n ce n t r at e o f b e nz a lk o ni u m c h l o r id e s h o ul d be us ed i n p r e p a ri n g 3 0 0 m L of a s to c k s ol u t i on su c h t h a t 15 m L d i l u te d to 1 L w i l l yi e l d a 1 : 5 00 0 sol u t i o n? a . Fi r s t, de t e rm in e t h e am o un t o f dr u g i n 1 L o f a 1 : 50 0 0 s o l ut i on .
b . N o w, b ec a us e 1 5 m L o f t he s t oc k s o l ut i on is be i ng di l ut e d t o 1 L, a s toc k s o lu t io n i s n ee d ed in wh ic h 1 5 m L c on t ai n 0 . 2 g of d r ug . Th e a m o un t of d r u g r e qu i re d to m ak e 30 0 m L o f th e s t oc k s o lu t io n is fo un d b y p r op o r ti on .
c . Fi n al l y , t o d e te r m i n e th e am ou n t o f 1 5% c o nc en t r a te r eq ui r e d,
3 . W he n t h e r el a ti v e am o u n t o f c om po n en ts m u st b e d e te rm i ne d f o r p r e pa r a ti o n o f a m i xt u r e o f a d es i re d c on c e n t ra t ion , t he pr o bl em is m os t e a si l y s o l v ed us in g a l li ga t i on al t er n a te . H ow m a n y g r a m s o f 2. 5% h yd r o c o r t i s o ne c re am s ho u l d b e m i xe d w i th 3 6 0 g o f 0 .2 5 % c r e a m to m ak e a 1 % h yd r o c o r t i s o n e c r ea m ?
Th e r e la t i v e a m o u nt s o f th e 2. 5 % a nd 1% c r e am s a r e 1 t o 2 , r e sp ec t i v el y. B y p r o p or t io n , t h e m a s s o f 2 .5 % c re a m t o us e c an b e d et e rm i ne d . I f 2 par t s o f 0 .2 5 % c r e a m is r ep r es e n t ed b y 3 6 0 g , t he n th e t o ta l m a ss ( 3 p a r ts ) i s r e p r e se n t ed b y w h a t ma s s ?
P.18
W ith t he t ot a l m a s s k n own , t h e am ou n t o f 2 . 5% c r e am c an be id e nt i fi e d. I f 3 p a r ts r ep r es en t th e t o t al m as s o f 5 4 0 g , t h en 1 p ar t r e pr e s e n ts t h e m as s of 2 . 5 % c re am (x g = 18 0 g) .
VII. ELECTROLYTE SOLUTIONS. E l e ct r ol y t e s o lu t io ns c o nt a i n s p ec i es (e l ec t ro l yt es ) th a t d is so c i a te in t o i on s . Th e m i l li e qu i va l e n t ( m Eq ) is th e u n it us ed t o e xp r e s s t he c o nc en t r at i on of
e l ec t r ol y t es in s o lu t io n . Ta b l e 2- 1 e xh i bi t s so m e p h ys io l og ic al l y im po r t an t i o ns an d t h ei r pr o pe r t ie s . A. M i l l i eq u i va l en t s . Th e m il li e qu i v a le n t is t he am o u n t, in m i ll ig r am s , o f a s o lu t e e qu a l t o 1 /1 0 00 of i t s g ra m -e q ui va le n t we ig h t . Co n v e rs io n o f c o nc en t r at i on s i n t he f orm o f m i ll i eq ui va l en t to co n c e n t ra t io ns in pe r c e n ta g e s t r en g th , m il l ig r am s p er m i ll il i te r s ( m g /m L ) o r an y o t he r te r m s , b e gi ns wi t h c a lc ul a ti on o f t he nu m b er o f m il l ie qu i va le n ts o f dru g . Th e f ol l o wi n g e xa m p l es de m o ns t r at e th e c om p ut a ti o n o f m il li eq u i v a l e nt s a n d m a n ip ul a ti o n o f da t a f r om Ta b le 2- 1 to p e r fo r m t he r eq ui r e d ca lc u la t io ns fo r p re pa r i ng e l ec t r ol y t e s ol u ti o ns . W h a t i s th e co n ce n t r a tio n , in p e rc e n t w / v, o f a s o l u ti o n c o nt a i ni n g 2 m E q o f p ot a ss i um c hl o ri d e pe r mi l l il i t e r ? C a l cu l at i on s i n v ol v i ng m il l ie q ui va le n ts a re ea s i l y s o l ved if t he pr a c t i ti on e r f o l lo ws a p r e de f in ed p roc e du r e t o d e te r m i n e t he m i l l ie q ui v a le n t we i gh t . Th i s i n vo l ves th r e e s te ps . 1 . Fi n d t he m o le c ul a r we i g h t ( m o l wt ) .
Atomic wt K
=
39
Atomic wt Cl
=
35.5
39 + 35.5 = 74.5 g
=
mol wt of KCl
2 . C al cu l at e th e e q ui v a len t we i g ht ( E q wt ) o f K C l.
3 . D e te r m i ne t he m il l ie qu i v a le n t we i gh t , wh i c h i s o f th e e q ui va le n t we ig h t. m E q wt = 7 4 .5 g / 10 0 0 = 0 . 7 4 5 g o r 74 . 5 m g
Table 2-1. Valences, Atomic Weights, and Milliequivalent Weights of Selected Ions
Formula
Valence
Atomic/Formula Weight
Milliequivalent Weight (mg)
Aluminum
A+++
3
27
9
Ammonium
NH4+
1
18
18
Calcium
Ca++
2
40
20
Ferric
Fe+++
3
56
18.7
Ferrous
Fe++
2
56
28
Lithium
Li+
1
7
7
Magnesium
Mg++
2
24
12
Bicarbonate
HCO3-
1
61
61
Carbonate
CO3-
1
60
30
Chloride
Cl-
1
35.5
35.5
Citrate
C6H5O7---
3
189
63
Gluconate
C6H11O7-
1
195
195
Lactate
C3H5O3-
1
89
89
Phosphate
H2PO4-
1
97
97
Sulfate
SO4--
2
96
48
Potassium
K+
1
29
39
Ion
Sodium
Na+
1
23
23
Acetate
C2H3O2-
1
59
59
P.19
N o w t h a t we k no w t h e m il l ie q ui va le n t we i gh t , we c a n ca lc u la t e b y d i m e ns i on al an a l ys is and p r op o rt i on th e c o nc en tr a t i o n i n p e rc e nt a ge in a f o u r th s t ep . 4 . 0 .0 74 5 g / m Eq × 2 m Eq = 0 . 1 49 g o f d r ug
+
H ow m a n y m i l l i e q u i va len t s o f N a w o ul d be con t a i ne d in a 1 5 -m L vo l u m e of t he f o ll ow i n g b u f f e r?
Na2HPO4·7H2O
180 g
NaH2PO4·H2O
480 g
Purified water
ad
1000 mL
F o r ea ch s a lt , th e m as s (a n d m il li e qu i val e nt s ) m us t be fo u nd in a 1 5 -m L d o se .
B . M i ll i os m ol e s ( m O s mo l ) . O s m ot ic p re s s u re is d i r ec tl y p r op o r ti o na l t o th e t o t al nu m b e r o f p a r ti c l es i n s ol u ti o n. Th e m il l io sm o le is th e u ni t of m e as u r e f o r osm o ti c c on c e n t ra t ion . F or no n el ec t r ol y t es , 1 m il li m ol e r e p re s e n ts 1 m i ll io sm ol e . Ho we v e r , f or e le c t ro l yt es , t h e t ot a l nu m be r of pa r t ic le s i n s o lu t io n i s d et e rm i ne d by t h e nu m b e r o f p a r ti c l es p r o du ce d i n s ol u ti on and i n f lu en ce d b y t h e d eg r e e o f di s s oc ia t io n . A s s um ing c o m p l et e d is s oc ia ti o n, 1 m i ll im ol e o f K Cl r ep r es en t s 2 m i ll io s m ol es o f t ota l pa r ti c l e s , 1 m i l li m o le o f C a C l 2 re p r es en ts 3 m il li os m o l es o f to t al pa r t ic le s , e t c . Th e i d ea l o s m ol a r c o nc en t r at i on c a n b e c alc u la t ed wi t h th e f o ll o wi ng e qu a ti o n.
Th e p h a rm ac is t s ho ul d re c og n i z e t he di f fe r e nc e b e t we e n id e al os m o la r c o nc en t r at i on an d a c t ual o s m ol a ri t y. As th e c o nce n t r at i on of s o lu t e i n c re as es , i n te r ac t io n b et we e n d is so l ved pa r t ic les in c re as es , re s ul ti n g i n a r e d uc t io n o f t h e a c t u al os m o l a r va l ue s . C . I s o to n ic s ol u t io n s . An i s ot o n ic s o lu t io n i s o ne t ha t ha s t he s a m e o sm o ti c p r es s u r e a s b ody f l u id s . I so s mo t i c f lu i ds a re fl u id s wi t h t he s am e o sm o ti c p r es s u r e . S ol u tio n s t o b e a dm in is t e re d to p at i en ts s h ou l d b e
i s os m o ti c wi t h b od y f lu i ds . A h yp o t o n i c s o lu t io n is on e wi t h a lo we r o s m oti c p r e ss u re th a n b od y f lu i ds , wh e r ea s a h yp e r t o n i c s ol u ti o n h as a n o s m o ti c p r e ss u re th a t is g re a te r th a n b o d y f l ui ds . 1 . P r e pa r a t io n of i so t on i c so l u ti o ns . C ol li g at i ve p r op e rt i es , i nc lu d in g f r e e zi ng po in t de p re s s ion , a re r ep r es en t a ti v e of th e nu m b e r o f p a r ti c l es in s o lu t io n a n d c o ns i de r ed i n pr e pa r a ti o n o f is o to n ic s ol u ti o ns . a . W he n 1 g m o l wt o f a ny n o n el ec t r ol y t e i s d is s o lve d i n 1 00 0 g of wa t e r , t h e fr e e z in g p o in t o f th e s o lu t io n i s d ep r es s e d b y 1 . 8 6 ° C. B y p ro p o rt i on , t he we i g h t of an y n o ne le c tr ol y t e ne e de d t o m ak e t h e s o l u t io n i so t on ic wi t h b od y f l u id c a n b e c a lc u la t ed . P.20
b . B o ri c a c i d ( H 3 B O 3 ) h as a m ol wt o f 6 1 .8 g. Th us 61 . 8 g of H 3 B O 3 i n 1 000 g o f wa t e r s h o ul d p r od uc e a fr e e zin g p o in t o f 1 . 86 ° C . Th e r ef o r e, k n o wi n g t h a t t h e f r ee z i ng p oi nt de p r es s i on o f b od y f lu i ds i s -0 . 52 ° C ,
a n d 1 7 .3 g o f H 3 B O 3 in 10 0 0 g of wa t e r pr o v i de s a s o l ut i on th a t i s i so t o n ic . c . Th e d e gr e e o f d is s o c ia t i on of el ec t r ol yt es m u s t b e t ak e n i nt o a c c ou n t in s uc h c al c ul a ti on s . F o r e xa m pl e , N a C l i s a pp r o xi m a t e l y 8 0 % d is s o c i at e d i n we a k s ol u ti on s , y i e ld in g 1 8 0 p a r ti cl es in s o lu t io n f o r ea ch 10 0 m ol ec u le s o f N a C l . Th e re f o re ,
i n di ca t in g th a t 9 .0 9 g o f N a C l in 10 0 0 g o f wa t e r ( 0 . 9 % w/ v ) s h o ul d m a k e a s o lu t io n i s o t on ic . L ac k i ng a n y i n fo r m a t io n o n t h e d e g re e o f di s s oc ia t io n o f a n el ec t r ol y t e , t he f ol lo w i n g d i ss o ci a t io n va l ue s ( i ) m a y be us ed . ( 1 ) S ub s ta nc es th a t d is s o c ia t e i nt o t wo io ns : 1 . 8 ( 2 ) S ub s ta nc es th a t d is s o c ia t e i nt o th r ee io ns : 2 .6 ( 3 ) S ub s ta nc es th a t d is s o c ia t e i nt o fo u r i on s : 3 .4 ( 4 ) S ub s ta nc es th a t d is s o c ia t e i nt o fi ve i o ns : 4 . 2 2 . S o di u m c h lo r i de e qui va l e n t s. Th e ph a rm ac is t wi l l of t e n b e r eq u i re d to p r e pa r e a n i s o t on ic s o lu ti o n b y a dd i ng an ap p ro p ri a t e am o un t o f an o th e r s u bs ta n c e (d r u g o r i ne r t e l ec t r ol y t e o r no ne l ec t ro l y t e ) . C o ns id e ri n g t ha t i s ot o ni c f lu i ds c on t ai n the e qu i v al e n t o f 0 .9 % N aC l , t he qu es t io n a r is es , H o w m u c h o f t h e a dd ed in g r ed i en t i s r e qu i re d to m ak e th e s ol u ti on is o to nic ? A c o mm o n m e th o d f o r c o m pu t in g t h e am o un t o f a d d ed i n g re di e n t t o us e f o r r e a ch in g i s o t on ic i t y in v o lv e s t he us e o f s o di u m ch l o r i de e qu i va l en t s . a . D e f in i t io n . Th e s o d ium c h lo r i de eq ui va l en t rep r e s e n ts th e a m o u n t of N a C l t ha t i s e qu i v a le n t to t he am ou n t o f p a r ti cu lar d r ug in qu es t io n . F o r
e ve r y s ub s ta nc e , t he r e is on e q u an t it y t h at s h ou ld h a ve a c o ns ta n t t on ic e f f ec t wh e n d is s o l v ed in 1 0 0 0 g o f wa t e r . Th i s is 1 g m ol wt o f th e s u bs ta n c e di v i de d b y i ts d i s s oc ia t io n val u e ( i ). b . E xa m p le s ( 1 ) C o ns id e ri n g H 3 B O 3 , fr o m t h e l as t s ec ti o n, 17 .3 g o f H 3 B O 3 is eq u i val en t t o 0 .5 2 g of N a Cl in t on ic i t y . Th e re f or e , t h e r e la tive q u an t it y o f Na C l th a t is e q ui va l en t to H 3 B O 3 i n to n ic i t y e f f ec ts i s d e te r m in e d a s f ol l o ws :
A p p l yin g th is m e th o d t o a t r o pi ne s u l fa t e, r ec al l th a t th e m ol ec ul a r we i gh t o f N a C l an d th e m ol ec ul a r we i g h t of a tr o pi n e s u l fa te a r e 5 8. 5 a n d 6 95 g, r e s pe c t i v e l y , a nd t he i r i v a l u es a re 1. 8 a n d 2 .6 , re s pe c t i ve l y. Ca lc u la t e t he m as s o f Na C l re p r es en t ed b y 1 g of a tr o pi n e s u l fa t e ( Ta bl e 2 - 2 ).
Table 2-2. Sodium Chloride (NaCl) Equivalents Substance
NaCl Equivalent
Atropine sulfate (H2O)
0.12
Boric acid
0.52
Chlorobutanol
0.24
Dextrose (anhydrous)
0.18
Ephedrine hydrochloride
0.29
Phenacaine hydrochloride
0.20
Potassium chloride
0.78
P.21
( 2 ) A n e xa m p le o f t he p ra c ti c a l u s e o f s o d iu m ch lo r i de eq u i v al en t s is se en i n th e f o ll o wi n g p r ob l em .
H ow m a n y g r a m s o f b o ri c ac i d s h ou l d b e us e d i n c om p ou n d in g th e f o l l ow i ng p r es c r ip t i o n?
Rx
phenacaine hydrochloride
1%
chlorobutanol
0.5%
boric acid
qs
purified water, ad
60.0 mL
make isotonic solution Th e p r es c ri p ti on c a ll s f o r 0 . 3 g of c h lo r ob u t an ol an d 0. 6 g o f p he na c ai ne . H o w m u c h b o ri c ac i d is re q ui r e d t o p r ep a re t hi s pr e s c r ip t io n ? Th e qu e st ion i s b es t an s we r e d in f ou r s t ep s . ( a ) Fi n d t h e m a s s of s o diu m c hl o r id e r e p re se n te d b y a l l i ng r ed i en ts .
0.20 × 0.6
=
0.120 g
of sodium chloride represented by phenacaine hydrochloride
0.24 × 0.3
=
0.072 g
of sodium chloride represented by chlorobutanol
0.192 g
of sodium chloride represented by the two active ingredients
( b ) F in d t h e m a s s of s o di u m c h l o ri de r eq ui r e d t o p r e pa r e a n e q ua l v ol um e o f is o to ni c s ol u ti on .
( c ) C al c ul at e , b y s u b t ra c t i o n, th e am ou n t o f N a C l r e q ui r ed to m a k e th e s o lu t io n i s o t on ic .
0.540 g NaCl required for isotonicity 0.192 g NaCl represented by ingredients 0.348 g NaCl required to make isotonic solution
( d ) B ec a us e t he p re s c r ipt i o n c a l ls fo r b o r ic a c i d to b e us e d, on e l a s t s t ep i s r e q ui r e d.
VIII. STATISTICS A. I n t r o d u c t io n . S t a ti s t ic s c an be us ed t o d es c r ib e an d c om pa r e d a ta d i st r ib u ti o ns . Su c h f r eq ue n c y d i s t r i b u t i o ns a re c o ns t ru c te d b y cl as si f yi ng i n di vi d ua l o bs e r v a ti o ns in t o c a te go r i es c o r re sp o nd i ng t o f i xe d nu m e r ic i n t er va l s a nd pl o tt i ng th e n um b e r o f o bs e r vat i on s i n ea ch s u ch c a te g or y ( i . e ., i n te r va l f r eq u en c y) v e r s us th e c at e go r y d es c ri p to r ( e. g ., t he in t er v al m e an o r r an g e ). B ec au s e o f r a nd om e r ro rs , r ep ea t e d o bs e r vat i on s o r m e as u re m e n ts (o f th e s am e v al u e ) a re n ot id en t ic a l . Th es e o bs e r v a ti on s h a ve a n o r ma l di s t r ib u ti o n . No r m a l l y d is t r ib u te d d a ta a re de sc r ib e d b y a b e l l -s h a pe d ( Ga u ss i a n) c u r ve wi t h a m a xi m u m , µ ( p o p ul a t io n me a n) , c o r re s po nd i ng to t he c e nt r a l t e nd e nc y o f t he po pu l a ti on an d a s p r ea d c h a ra ct e ri z e d b y t h e p op u l a t io n s t a nd a r d d e via t i o n ( σ ) . S ta t is ti cs de r ive d f r o m a s a mp l e o r s u bs et o f a p op ul a ti o n c a n b e us e d as es t im at es o f t he p o p ul at i on pa r am e te r s . B . F r e q ue n c y d i s t r i b u t io n 1 . E s ti m a te s o f po p u la ti o n me a n. Th e p o pu l at i on m e a n, µ , i s t h e b es t e s ti m a t e o f t h e t r ue v a lue . a . T he sa m pl e m e an . For a fi n it e n um b e r o f o bs er v a t i o ns , t he a ri t hm e ti c a ve r a ge o r m ea n ( [ X w ith b a r a bo ve ] ) i s t he be s t e s ti m a t e o f t he t r ue v a lu e , µ.
wh e r e Σ x i i s th e s um o f a l l ( n ) o bs e r v a ti o ns .
P.22
( 1 ) Ac c u r a c y i s t h e d eg re e to wh i c h a m ea s u r e d v a l u e (X o r [ X w it h b a r a b ov e ] ) a g re es wi t h th e “t r u e ” v al ue ( µ ) . ( 2 ) E r r o r (o r bi as ) is th e d i ff e r en ce be t we e n a m e a su r ed v a lu e ( X o r [X wi t h b a r ab ov e ] ) a nd th e “t r ue” v a l u e ( µ ) . b . M e d ia n . Th e m e d ia n is t he m i dm os t v al ue o f a d a ta di s tr i bu t io n . W hen a l l t h e val u es a r e a r r an g ed i n in c r e as in g (o r de c re asi n g ) o r de r , t h e m e d ia n i s t h e m id d le v a lu e f o r a n od d nu m be r o f ob se r va t ion s . F o r a n e ve n nu m b e r o f o b se r va t io ns , th e m ed ian is t he ar i th m e t ic m e an o f t he t wo m i dd l e va l ue s . F o r a n o r ma l d i s t r ib u t ion , t h e m ed i an eq u a ls t he m ea n . Th e m e di a n i s l e ss a f f ec te d b y “ o ut l ie r s ” o r b y a s k e we d d is t r ib ut i o n. c . M o de . Th e m od e i s t he m o s t f r eq u en tl y o cc u r rin g v a lu e (o r v al u es ) i n a f r e q ue nc y d is t ri b ut io n . Th e m o de is u s ef ul f o r n on - n o rm al di s t r i bu t io ns , e s pe ci a ll y t ho s e th a t a r e b i m od a l. 2 . E s ti m a te s o f va r i ab i li t y. F o r a n in f i ni t e n um be r o f o bs e r vat i on s , t he 2
p o p u la t i on va r i a nc e ( σ ) c an be us ed t o d es c r i be t he v a r ia b il it y o r “ s p re a d ” o f o bs e r v a ti on s i n a da t a d is t ri b ut i on . Fo r a fi n i te nu m b e r o f 2
o b se r v a t io ns , th e s am p le va r i a n ce (s ) c an be us e d t o d es c ri be t he va r i a bi l it y o r s p re a d o f ob s e r v at i on s i n a d a ta di s t r i bu t io n . 2
a . S am p le va r i a nc e (s ) i s e s ti m a t ed b y
wh e r e [ X w i th ba r a b ov e ] i s t h e m e a n a nd ( n - 1) is t he nu m b e r o f d e gr e es o f f re e do m ( d f ). b . R a ng e . F o r a v e r y s m a l l n um be r o f o bs er va t ion s , t h e r a n ge ( w ) c an be u s ed to de s c r ib e th e v a ria b il i t y in th e d a ta se t : w = | Xlar gest - Xsmal l est| c . Th e s t a nd a r d d e vi a t io n ( s o r S D) , on e o f th e m os t c om m o n l y e n co u nt e re d es ti m a t es of v a r i ab il i t y, i s e qu a l t o th e s q ua r e ro o t o f t he va r i a nc e .
or
d . P r e ci s io n ( re p r od uc ibi l it y ) i s t he de g r ee to wh ic h re p li ca t e m e as u re m e n ts “m ad e i n e xa c t l y t h e sa m e wa y” a g r e e wi t h e ac h o th e r . P r e c i si o n i s o f te n e xp r e s s e d a s t h e r e l at i ve s tan d a r d d e vi a t io n ( R S D or %RSD):
3 . Th e st a n da r d d e vi a t io n o f th e m ea n (s m ) , o r s t an d a rd e rr o r o f th e m ea n ( S E M) , i s a n es t im a te of t h e va r i ab i l it y o r e r r o r in t h e m ea n o b t ai ne d fr om n o bs e r v at i on s . I t is o ft en us e d t o e s t a bl is h c on f id e nc e i n te r va ls fo r d e sc r ib in g th e m ea n o f a d a ta s e t o r wh e n c om par i n g t h e m e a ns o f t wo dat a s e ts .
P.23
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 30 : E a c h qu e st io n , st a t em en t , o r in co m p le t e s t a te m e n t i n t hi s s ec ti o n c an be co r r ec tl y a ns we r e d o r c o m p l et e d b y o ne o f t h e s ug g es t ed an s we r s or p h ra s e s . C h oo s e t he be s t an s we r . 1 . I f a vi t am i n s o l ut i o n c o n t ai n s 0 . 5 m g o f f l u or i d e io n in ea c h m i ll i l i te r , t h e n h ow ma n y m i l l i g r am s o f f l uo r i d e i o n w o u ld b e p r o vi d e d b y a d r o p p e r t h a t d e li ve r s 0.6 m L ? (A) 0.3 mg (B) 0.1 mg (C) 1 mg ( D ) 0 . 83 m g V i e w A n s we r 1 . T h e a n sw e r i s A [ se e] . 2 . How ma n y c h l o r am p he n ic o l c a ps ul e s , e ac h co n t ai n i ng 250 m g , a re ne e de d t o p r o vi d e 25 m g pe r kg pe r d a y f o r 7 d a ys f o r a p e r s o n w e i gh i n g 2 00 l b? ( A ) 9 0 c ap s u le s ( B ) 6 4 c ap s u le s ( C ) 1 3 c ap s u l es ( D ) 2 5 c ap s u l es
V i e w A n s we r 2 . T h e a n sw e r i s B [ se e] . 3 . I f 3. 1 7 k g o f a d ru g is u s e d t o m a ke 50 , 00 0 tab l e t s, h ow m a n y m i l l i g ra m s w il l 30 ta b l et s c o n t ai n ? (A) 1.9 mg ( B ) 1 90 0 m g ( C ) 0 . 00 1 9 m g (D) 3.2 mg V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . 4 . A c ap su l e co n t ai n s 1 /8 g r o f e ph e d r in e s u l fa t e , ¼ g r o f t h eo p h yl l i n e , a n d g r o f p h en o ba r b i ta l . W h a t i s th e t ot a l m as s o f t h e a c ti ve i n g re d ie n ts i n m i l li g r am s ? (A) 20 mg (B) 8 mg (C) 28 mg (D) 4 mg V i e w A n s we r 4 . T h e a n sw e r i s C [ se e] . 5 . I f 1 f l uid o u nc e o f a c o ug h s yr u p c o n t a i ns 10 g r o f s o d iu m c i t r a te , h ow ma n y m i l l i g r am s a r e c o n t ai n ed i n 1 0 m L? ( A ) 6 50 m g (B) 65 mg (C) 217 mg (D) 20 mg V i e w A n s we r 5 . T h e a n sw e r i s C [ se e] . 6 . How ma n y c a p s u l es , e a ch c o n t ai n i ng ¼ g r o f ph en o b a r bi t a l, ca n be ma nu f a c t u re d if a b o t t le c o n t ai n i ng 2 a vo i r d u poi s o un c es o f p he n o ba r bi t a l is a va il a bl e ? ( A ) 7 71 c a ps ul e s ( B ) 3 50 c a ps ul e s ( C ) 3 5 00 c a ps ul es ( D ) 1 2 50 c a ps ul es V i e w A n s we r 6 . T h e a n sw e r i s C [ se e] . 7 . Us i n g th e f o rm u l a f o r c a l am i ne l o ti o n, d e te r mi n e t he am o un t o f c al am i n e ( i n g r a ms ) n e c es s a r y t o p r e p a r e 24 0 m L of l o ti o n .
Calamine
80 g
Zinc oxide
80 g
Glycerin
20 mL
Bentonite magma
250 mL
Calcium hydroxide topical solution
sufficient quantity to make 1000 mL
( A ) 1 9 .2 g ( B ) 1 40 g (C) 100 g (D) 24 g V i e w A n s we r 7 . T h e a n sw e r i s A [ se e] . 8 . F r o m th e f o ll ow i ng f o r m u la , ca l cu l a te t he a m o un t o f w h i t e w ax r eq u i r e d t o m a ke 1 l b o f c o l d c r e am . De t e r mi n e t h e ma s s i n g r a ms .
Cetyl esters wax
12.5 parts
White wax
12.0 parts
Mineral oil
56.0 parts
Sodium borate
0.5 parts
Purified water
19.0 parts
( A ) 5 6 .7 5 g ( B ) 2 54 . 24 g ( C ) 5 4 .4 8 g ( D ) 8 6 .2 6 g V i e w A n s we r 8 . T h e a n sw e r i s C [ se e] . 9 . How ma n y g r a m s o f a s pi r i n s h o u ld be u se d to p r epa r e 1 .2 55 k g o f th e p ow d e r ?
ASA
6 parts
Phenacetin
3 parts
Caffeine
1 part
( A ) 1 25 g ( B ) 7 50 g (C) 175 g (D) 360 g V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . P . 24
1 0 . A s o lu t i o n c on t a in s 1 . 25 m g o f a d r u g pe r m i l l il i t e r . At w h a t r a t e s h o u ld t he s o l u t io n b e in f u se d (d ro p s /m i n ) i f t he d r ug is t o b e a dm i n is t e r ed a t a r a t e of 80 m g / h r? ( 1 m L = 3 0 d r o ps ) ( A ) 6 4 d r op s / m i n ( B ) 1 . 06 dr o ps /m in ( C ) 3 2 d r op s /m in ( D ) 2 0 d r op s /m in V i e w A n s we r 1 0 . T he a nsw e r i s C [ se e] . 1 1. T he re c o mm e nd e d m ai n t en an c e d o s e o f am i no p h yl l i n e f o r c h il d r e n i s 1 . 0 m g / k g/ h r b y i n j e c t i o n . I f 10 m L o f a 25 m g /m L s o lu t i o n o f a m ino p h yl l i n e i s a dd e d t o a 1 0 0 -m L b o t t le f o r d ex t ro s e , w ha t s h o u ld be t he r a te o f de l i ve r y i n m L / h r f o r a 40 - l b c h i ld ? ( A ) 2 . 30 m L /h r ( B ) 8 . 00 m L /h r ( C ) 1 8 .9 m L /h r ( D ) 1 8 .2 m L /h r V i e w A n s we r 1 1 . T he a nsw e r i s B [ se e] . 1 2. F o r ch i l d r en , st r e p t om yc i n i s t o b e ad m i ni s te r e d a t a d os e o f 3 0 m g / k g o f b o d y w e ig h t d a i l y i n d i vi d e d d o s es e ve r y 6 - 1 2 h r . Th e d r y p ow d e r is d is s ol ve d b y a d d in g w a te r f o r i n je c ti o n , U S P i n a n a mo u n t t o yi e l d t h e de s i r ed co n ce n t r a tio n as i nd i ca t e d i n th e fo l l ow i ng t a b l e ( f o r a 1 -g vi a l ) .
Approximate Concentration (mg/mL)
Volume (mL)
200
4.2
250
3.2
400
1.8
R e c o ns t i t u ti n g a t t he low e st p os s ib l e c o nc e n t ra t i o n , w h a t vo lu m e ( i n m L ) w ou l d b e w i t hd r aw n t o o b ta i n o n e da y' s d o s e f o r a 5 0- l b c hi l d? (A) 3.4 mL ( B ) 2 2 .7 3 m L ( C ) 2 . 50 m L ( D ) 2 . 27 m L V i e w A n s we r 1 2 . T he a nsw e r i s A [ se e] . 1 3. T he a tr o p i n e s u lf a t e i s a va i l a b le on l y i n t h e for m o f 1 / 1 50 gr t ab l e ts . H ow m a n y a t r o p i n e s ul fa t e ta b l et s w o ul d yo u u s e t o co m po u n d th e fo l l ow in g p res c r i p t io n ?
Atropine sulfate
1/200 gr
Codeine phosphate
1/4 gr
Aspirin
5 gr
d.t.d.
#24 capsules
Sig:
1 capsule p.r.n.
( A ) 3 ta bl e ts ( B ) 6 ta bl e ts ( C ) 1 2 t a bl e ts ( D ) 1 8 t a bl e ts V i e w A n s we r 1 3 . T he a nsw e r i s D [ se e] . 1 4. I n 2 5.0 m L o f a so l u ti o n fo r i n j e ct i o n, t he r e a re 4. 00 m g o f t h e d r u g . I f th e d o s e t o be ad m in i s te r ed t o a p a t i en t is 20 0 µ g, w h a t q u a n ti t y ( i n m L ) o f t hi s s o l u t io n s h o ul d be us ed ? ( A ) 1 . 25 m L
( B ) 1 25 m L ( C ) 1 2 .0 m L ( D ) N o n e o f t h e a bo v e V i e w A n s we r 1 4 . T he a nsw e r i s A [ se e] . 1 5. H ow m a n y m i l l i g r a m s o f p a p a ve r i ne w i l l t h e p a tie n t r ec e i ve e a ch d a y?
Rx
papaverine
1.0 g
hydrochloride aqua
30.0 mL
syrup tolu, qs ad
90.0 mL
Sig:
1 teaspoon t.i.d.
(A) 56 mg (B) 5.6 mg (C) 166 mg (D) 2.5 mg V i e w A n s we r 1 5 . T he a nsw e r i s C [ se e] . 1 6. C o ns id e r i n g t h e f o l low i n g f o r m u la , how m an y g r a m s o f s od i u m b r o mi d e s h o u ld be u se d i n f il l i ng t h i s p r e s c r ip t i on ?
Rx
sodium bromide
1.2 g
syrup tolu
2.0 mL
syrup wild cherry, qs ad
5.0 mL
d.t.d.
#24
(A) 1.2 g ( B ) 1 20 0 g ( C ) 2 8 .8 g (D) 220 g
V i e w A n s we r 1 6 . T he a nsw e r i s C [ se e] . 1 7. H ow m a n y m i l l i l i t e r s o f a 7 .5% s t o c k s ol u t i on o f K M n O 4 s h ou l d b e u s ed t o o b ta i n t he KM n O ne e de d ? KMnO4, qs D i s t i l le d w a te r , a d 1 0 00 S i g : 2 t e as p oo n s d i l ut ed t o 50 0 m L yi e l d a 1 :50 0 0 s o l ut i o n ( A ) 2 67 m L ( B ) 1 33 m L ( C ) 2 6 .7 m L ( D ) 1 3 .3 m L V i e w A n s we r 1 7 . T he a nsw e r i s B [ se e] . 1 8. T he fo r m u l a f o r R in g e r 's s o l u t io n fo l l ow s. H ow m u c h s o di u m c h lo r i de is n ee d ed t o m ak e 12 0 m L ?
Rx
sodium chloride
8.60 g
potassium chloride
0.30 g
calcium chloride
0.33 g
water for injection, qs ad
1000 mL
( A ) 1 20 g ( B ) 1 . 03 g ( C ) 0 . 12 g (D) 103 g V i e w A n s we r 1 8 . T he a nsw e r i s B [ se e] . P . 25
1 9 . H ow m a n y g r a m s o f t a l c s h ou l d b e a d de d to 1 lb o f a pow d e r c o n ta i n i ng 20 g o f z i nc u nd e c yl e n a t e p e r 10 0 g t o re d uc e t he c o nc e n t ra t i o n o f z i nc u n d ec yl e n a t e t o 3 %? ( A ) 3 02 6 .7 g ( B ) 2 57 2 .7 g (C) 17 g (D) 257 g V i e w A n s we r 1 9 . T he a nsw e r i s B [ se e] . 2 0. H ow m a n y m i l l i l i t e r s o f a 0 .9% a q u eo u s s o lu t i o n c an be m ad e f ro m 2 0 .0 g o f so d i u m c hl o r i de ? ( A ) 2 22 2 m L ( B ) 1 00 m L (C) 222 mL (D) 122 mL
V i e w A n s we r 2 0 . T he a nsw e r i s A [ se e] . 2 1. T he b lo o d o f a re c kl e ss d r i ver c o n t ai n s 0 . 1 % a l c o h o l . E x p r e ss t he co n ce n t r a ti o n o f a lc o h ol i n p a r ts p e r m i l l io n . ( A ) 1 00 pp m ( B ) 1 00 0 p pm ( C ) 1 pp m ( D ) 2 5 0 p pm V i e w A n s we r 2 1 . T he a nsw e r i s B [ se e] . 2 2. S yr u p i s an 85 % w / v so l u t io n o f s u c r os e in w a t e r. I t h a s a d en s i t y o f 1 . 3 1 3 g /m L . H ow ma n y m i l l i l i t e r s o f w a t e r s h o u ld be u se d to ma ke 1 25 m L of s yr u p ? ( A ) 1 06 . 25 m L ( B ) 1 64 . 1 m L ( C ) 5 7 .9 m L ( D ) 2 5 .0 m L V i e w A n s we r 2 2 . T he a nsw e r i s C [ se e] . 2 3. H ow m a n y g r a m s o f b e n ze t h on i um ch l o r i de s h o u ld be u se d i n p re pa r i n g 5 ga l . o f a 0 .0 2 5 % w / v s o l u t io n ? ( A ) 1 89 . 25 g ( B ) 1 8 .9 g ( C ) 4 . 73 g (D) 35 g V i e w A n s we r 2 3 . T he a nsw e r i s C [ se e] . 2 4. H ow m a n y g r a m s o f me n t h ol s h o u ld be u se d to p r epa r e t h is p re s c ri p t i on ?
Rx
menthol
0.8%
alcohol, qs ad
60.0 mL
( A ) 0 . 48 g (B) 0.8 g (C) 4.8 g ( D ) 1 . 48 g V i e w A n s we r 2 4 . T he a nsw e r i s A [ se e] . 2 5. H ow m a n y m i l l i l i t e r s o f a 1 :1 5 0 0 s o l u t io n c a n b e m a de by d i s s o l vi n g 4 .8 g o f c et yl p yr i d i n i u m c h lo r i d e in w a t e r ? ( A ) 7 20 0 m L (B) 7.2 mL
(C) 48 mL (D) 4.8 mL V i e w A n s we r 2 5 . T he a nsw e r i s A [ se e] . 2 6. T he ma n u f ac t u r e r s pe c i f ie s th a t o n e D om e bo r o t ab l e t d is s o l ve d i n 1 p in t o f w a te r m ak e s a m o d if i e d B ur ow 's s o l u t io n a p p r ox i ma t e l y e q u i va le n t to a 1 :4 0 di lu t i o n . H ow ma n y t a b l e ts s ho u l d b e us e d i n p re p a r in g ½ g a l o f a 1 :1 0 di l u t io n ? ( A ) 1 6 t a bl et s ( B ) 1 89 t ab le t s ( C ) 1 2 t a bl e ts ( D ) 4 5 t a bl e ts V i e w A n s we r 2 6 . T he a nsw e r i s A [ se e] . 2 7. H ow m a n y m i l l i o s m ol e s o f c a l ci u m c h lo r i d e ( C a C l 2 · 2 H 2 O - m o l w t = 14 7 ) ar e r e p r es e n te d i n 14 7 m L o f a 1 0 % w / v ca l ci u m c h lo r id e so l u t io n ? ( A ) 1 00 m Os m o l ( B ) 2 00 m Os m o l ( C ) 3 0 0 m Os m o l (D) 3 mOsmol V i e w A n s we r 2 7 . T he a nsw e r i s C [ se e] . 2 8. H ow m a n y g r a m s o f b o r ic aci d s h o u ld be u se d i n co mp o u n di n g th e fo l l ow in g p r e sc r i p t io n ? P h e n ac a in e H C l 1 . 0 % ( N a C l e q = 0. 1 7) C h l o r o b u ta n ol 0 .5 % ( N a C l e q = 0 .1 8 ) B o r i c ac i d , q s ( N a C l e q = 0 .5 2 ) P u r i f i e d H 2 O , ad 30 m L M a ke is o t o ni c s o l ut i o n S i g : 1 d r o p i n e a ch e ye ( A ) 0 . 37 g ( B ) 0 . 74 g ( C ) 0 . 27 g ( D ) 0 . 47 g V i e w A n s we r 2 8 . T he a nsw e r i s A [ se e] . 2 9. A p h ar m a c is t p re p a r es 1 g al o f K C l s o l ut i o n b y m i x i n g 5 6 5 g o f K C l ( va l en c e = 1 ) i n a n a p p ro p r i at e veh i c l e. +
H ow m a n y m i l l i e q u i va len t s o f K a r e i n 1 5 m L of t h i s s o lu t i on ? (a t o mi c w ei g h ts : K = 30 ; C l = 35 . 5 ) ( A ) 7 . 5 m Eq ( B ) 1 0 m Eq (C) 20 mEq (D) 30 mEq ( E ) 4 0 m Eq V i e w A n s we r 2 9 . T he a nsw e r i s D [ se e] . P . 26
3 0 . A va n c o m yc i n s o l u ti o n co n t ai n i ng 10 0 0 m g o f va n c om yc i n h yd r o c h l o r i de d i l u t ed t o 2 50 m L w i th D 5W i s t o b e in f u se d a t a c on s ta n t r at e w i th an i n f us i on p u m p i n 2 h r. W ha t is th e r a te o f d r u g a d mi n ist r a t i o n? ( A ) 2 . 08 m g /m in
( B ) 8 . 33 m g /m in ( C ) 4 . 17 m g /m in ( D ) 1 6 .7 m g /m in ( E ) 5 . 21 m g /m in V i e w A n s we r 3 0 . T he a nsw e r i s B [ se e] . F o r q u es ti o n s 3 1 -3 4 : F i v e i b up r o fe n t a b le ts we r e as s a y e d f o r d r u g c o n te n t , a nd th e f ol l o wi n g r es u lt s we r e o b tai n ed b y h i gh - p r es s u r e li q ui d c h rom a to g r ap h y ( H P L C ) a na lys i s : 1 98 . 2 m g , 19 9 .7 m g , 20 2 .5 m g , 2 01 . 3 m g, 19 6 .4 m g . 3 1 . W h a t i s th e m e an i bu p r o f e n c on t e n t? ( A ) 1 96 . 9 m g ( B ) 2 00 . 2 m g ( C ) 1 9 9. 6 m g ( D ) 2 4 9. 5 m g ( E ) 2 02 . 5 m g V i e w A n s we r 3 1 . T he a nsw e r i s C [ se e] . 3 2. W ha t i s t he s ta n da r d de vi a t io n o f i b up r o f en c on t e nt i n t h e a n a l yz e d t a b le t s ? ( A ) 2 . 17 m g ( B ) 3 . 35 m g ( C ) 2 . 42 m g ( D ) 3 . 00 m g ( E ) - 2 .1 7 m g V i e w A n s we r 3 2 . T he a nsw e r i s C [ se e] . 3 3. W ha t i s t he p e rc e n t r e la t i ve s t a n da r d de vi a t i on ( %R S D ) f o r t h is ib u p r o fe n ta b l e t a na l ys i s ? ( A ) 1 . 69 % ( B ) 1 . 21 % ( C ) 8 . 25 % ( D ) 3 . 35 % ( E ) 1 . 50 % V i e w A n s we r 3 3 . T he a nsw e r i s B [ se e V I I I. B . 4] .34 . W ha t is t he s ta n da r d d e vi a t i o n o f th e m e an dr u g c on t e n t o f th i s s amp l e ? ( A ) 0 . 48 0 m g ( B ) 0 . 60 5 m g ( C ) 1 . 21 m g ( D ) 1 . 08 m g ( E ) 0 . 82 5 m g V i e w A n s we r 3 4 . T he a nsw e r i s D [ se e V I I I. C] . P . 27
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is A [ s ee I . A . 2] . 2 . T he an sw e r is B [ s ee I I ] . 3 . T he an sw e r is B [ s ee I I ] . 4 . T he an sw e r is C [ s ee I I ] . 5 . T he an sw e r is C [ s ee I . A . 2] .
6 . T he an sw e r is C [ s ee I I ] . 7 . T he an sw e r is A [ s ee I I I ] . 8 . T he an sw e r is C [ s ee I I ; II I . A ]. Th e f o rm u la te l ls th e p har m ac is t th a t wh i t e wa x ( W .W .) r e p re s e n ts 12 pa rt s ou t o f t h e to t al 10 0 p a rt s i n t h e p r es c ri p ti on . W ha t we w i s h t o d e te rm i ne is th e m a s s o f wh i t e wa x r e q u i re d t o p re p a re 45 4 g ( 1 l b ) o f t h e r e c i p e. Th is ca n b e e as il y s ol v e d b y p r o po r ti o n:
9 . T he an sw e r is B [ s ee I I I . A] . 1 0 . Th e a n sw e r i s C [ s ee I V . E ]. 1 1 . Th e a n sw e r i s B [ s ee I I ; I V ] . 1 2 . Th e a n sw e r i s A [ s ee I V ] . 1 3 . Th e a n sw e r i s D [ s ee I I ; I I I. B ] . 1 4 . Th e a n sw e r i s A [ s ee I . A .2 ; I I ] . D i m en si o na l a na l y s i s i s o f t en us e fu l f o r c al c u l at in g do s e s . C o ns id e ri n g t ha t 4 m g o f t h e d r u g is p re s e n t i n e ac h 2 5 m L o f s ol u ti o n, we c an ea si l y c a lc ul a te t he n u m b e r o f m i ll il i te r s t o b e u s e d t o gi v e a d os e o f 0. 2 00 m g (2 0 0 µg ) . Al wa y s i nc l ud e u n i ts i n yo u r ca lc u la t io ns .
1 5 . Th e a n sw e r i s C [ s ee I I I. B ] . 1 6 . Th e a n sw e r i s C [ s ee I I I. B ] . 1 7 . Th e a n sw e r i s B [ s ee V . A ; V I ] . F i r st , de t er m i n e t he m a s s o f d ru g i n th e f i na l d il ut e d s ol u ti o n.
N o w, i f 0 .1 g o f d r ug is pr e s en t i n 5 0 0 m L o f 1 :5 00 0 s o lu t io n , 2 te as po o n fu l s ( 1 0 m L ) o f th e p r es c r i pt i on c o n t ai ns th e s am e a m o u nt o f d r ug ( 0. 1 g) be f o re di l u ti on . F r o m t hi s , t he am ou n t o f d r u g i n 1 00 0 m L ( t he to ta l v o lu m e ) of th e p r es c rip t i on c a n b e de t e rm in ed :
F i n al l y , t o o b ta i n t he c o rr e c t am o un t of d ru g t o f or m u la t e t he p re s c r ip ti o n ( 1 0 g) , we a r e to us e a 7. 5 % s t oc k s o lu t io n . R e c a ll i ng th e de f i ni t io n o f p e rc e nt a ge s tr e n g th w/ v:
P.28
1 8 . Th e a n sw e r i s B [ s ee I I I. B ] . 1 9 . Th e a n sw e r i s B [ s ee V . C ; VI . C ] . 2 0 . Th e a n sw e r i s A [ s ee I . A .2 ; V. A ] . U s i ng di m e ns i on al an a l ys is
2 1 . Th e a n sw e r i s B [ s ee V . D . 1] . 2 2 . Th e a n sw e r i s C [ s ee I . A ; V . A .1 ] . U s i ng th e de ns i t y , t he we i gh t of 12 5 m L o f s yr u p c a n b e c al cu la t ed : 1 2 5 m L × 1. 3 13 g /m L = 16 4 . 12 5 g U s i ng p ro p or t io n a n d t he s uc r os e c on ce n t ra t io n in w/ v, t h e we i gh t of su c ro s e i n 1 25 m L o f s y r u p c an be c a lc u l a te d :
F i n al l y , t h e we i g h t o f wat e r in 12 5 m L o f s yr u p c an b e ca lc u la t ed : 1 6 4 .1 2 5 g - 1 06 . 25 g = 57 . 8 75 g wh i c h ha s a v o lu m e of 57 . 9 m L . 2 3 . Th e a n sw e r i s C [ s ee I ; I I ; V] . 2 4 . Th e a n sw e r i s A [ s ee I ; V] . 2 5 . Th e a n sw e r i s A [ s ee I ; V] . Th e p r o bl em i s e as i l y s olv e d b y p ro p o rt i on . Th e qu e st i on to be an s we r e d is , If 1 g of d r u g i s p re s en t i n 1 5 00 m L o f s o lu t io n , wh a t vo lum e c an be m a d e wi t h 4. 8 g o f d r u g?
2 6 . Th e a n sw e r i s A [ s ee I ; V] . 2 7 . Th e a n sw e r i s C [ s ee V I I . B] . R e c al l in g t h e e xp r e s s i on f o r i d ea l o sm ol a r c on c en t r a ti o n:
2 8 . Th e a n sw e r i s A [ s ee V I I . C] . 2 9 . Th e a n sw e r i s D [ s ee V I I . A] . 3 0 . Th e a n sw e r i s B [ s ee I V . E ]. U s i ng di m e ns i on al an a y ls is :
3 1 . Th e a n sw e r i s C [ s ee V I I I. B . 1] . Th e m ea n i s c al c u la t ed d i r ec tl y f r om th e eq ua t ion :
P.29
3 2 . Th e a n sw e r i s C [ s ee V I I I. B . 3] . Th e s t an da r d d e v i at i on c a n be c a lc ul a te d wi t h t he m o s t co m m on l y us e d eq u a ti on :
3 3 . Th e a n sw e r i s B [ s ee V I I I. B . 4] .
3 4 . Th e a n sw e r i s D [ s ee V I I I. C ] .
3 Pharmaceutical Principles and Drug Dosage Forms L aw re n ce H . B lo c k
I. INTRODUCTION. P h a r m a c e u ti c a l p r in c i pl es a re th e u n de r l y in g ph y s ic oc h em ic al p ri nc ip l es t h a t a ll o w a d ru g t o be i nc o r po r at e d i nt o a p ha rm a c eu t ic al d os a ge f o rm ( e . g ., so lu t io n , c ap s u l e) . Th e s e p r in ci p le s a pp l y wh e t h e r th e d r u g is e xt e m p o r an e ou s l y c o m po u n de d b y t he ph a rm ac is t or m a n uf ac t u re d f o r c om m e r c i a l d is t ri bu t io n a s a d r u g p r o du c t . A. Th e f i n is h ed do s ag e f o r m c o n ta in s t h e ac t i ve d r u g i ng r ed i en t i n a ss o ci at i on wi t h no nd r u g ( u s u a ll y i ne r t ) i ng r ed i ent s (e x ci p i en t s ) t h at m ak e u p th e ve h ic l e, o r f o r mul a t i o n m at r i x . B . Th e d r u g d e li ve r y s ys t e m c on c e p t, wh i c h h as e vo l ve d si n ce th e 1 9 60 s , i s a m o r e h ol is t ic c on c ept . I t e m b r ac es no t o n l y th e d ru g ( o r p r o dr u g ) a nd i t s f o rm ul a ti o n m a t r i x, b ut a ls o t h e d y n am ic i n te r ac t io ns am on g th e d r ug , its f o r m u l at io n m a t ri x, i t s c on t a in e r , a nd th e p h y si o log i c m i l ie u x o f th e pa ti e n t. Th e s e d y n a m i c in t e ra c tio n s a r e t he s u bj ec t of b io p h a r ma ce u t ic s (s ee C h a p te r 4 ).
II. INTERMOLECULAR FORCES OF ATTRACTION A. I n t r o d u c t io n . Th e a pp l ic a ti on o f p ha r m a c e u tic a l p ri n c i pl es t o d ru g d o sa g e f o rm s is il lu s t r a te d wh e n d r u g d os ag e f o rm s a r e c a te g o r iz ed a cc o r di ng t o t he i r p h ys i c a l s t a te , de g r ee o f h e te r o g e ne i t y, a n d c h em i ca l c o m po s i ti o n . Th e us u al r e l e v an t s t at e s o f m a t t e r a r e g a se s , l i qu i d s, an d s o l i ds . In t er m o l ec ul a r f or c es o f a tt r ac t io n a r e wea k es t i n g as es an d s t r on g es t i n s ol id s . C o n ve r s io ns f ro m o ne ph y s ic a l s t a te to an o th e r c an i n vo l ve s im pl y o v e rc om in g in t e rm ol ec ul a r f o rc es o f a tt r ac t io n b y a dd i ng e n e rg y ( h ea t ) . Ch em ic a l c om p os it i on c a n h a ve a d r a m a t ic e f fe c t o n p h ys ic oc he m i c a l p r o pe r tie s a n d b eh a vi o r. Fo r th is r e as o n, it is ne ce s s a r y to d i st i ng ui s h b et we e n po lym e r s , o r m ac r o mo l ec ul e s , a nd m o r e c on ve n ti on a l ( i . e ., sm al le r ) m o le c u le s , o r mi c r om o l ec u le s . B . I n t e rm o le c u la r f o rc es o f a t t r a ct i o n. B ec au s e a t om s v a r y i n t he i r e l ec t r on eg a ti v i t y , el ec t r on s h a r in g b e t we e n d if f e re n t a t om s is li ke l y to be u n e qu al . Th is as y m m e t ric el ec t r on di s t r i bu t io n c au s es a s h i ft in t he o v er a ll e l ec t r on c l ou d i n t h e m o le c ul e . A s a re s u l t , t he m o l ec ul e te n ds t o b e ha ve a s a d i po l e ( i .e . , a s i f i t h ad a p os i ti v e an d a ne g a tive p o le ) . Th e d ip ol e a ss o ci at e d wi t h e ac h c ov a l e n t b on d h as a c or r es p o n d i ng d ip o le m om e nt ( µ ) d e fi n ed as t h e p r od uc t of th e d is t a nc e o f c ha rg e s e pa r a ti on ( d ) a nd the c h a rg e ( q ) : µ = q × d Th e m ol ec u la r di po l e m om e nt m a y b e vi e we d as th e vec t o r s um o f th e i n di vi d ua l b o nd m om e nt s .
1 . N o np o l a r m o l ec ul es th a t h a v e pe r f ec t s ym m e t r y ( e . g . , c a rb on t e t r ac hl o ri d e ) h a v e d ip ole m o m e n ts of z e r o ( F ig ur e 3 -1 ) . 2 . P o la r m o le c u l es a r e as ym m e t r i c a nd ha v e non z e r o di po l e m o m e n ts . 3 . W he n d i po l a r m ol ec u le s a p p ro ac h o n e a no t he r c lo s e en o ug h — “p os i ti v e t o po si t i v e ” o r “n e ga ti v e t o ne g at i v e ” —s o t h at t hei r el ec t r on c l ou ds i n t er p en e t ra t e, i n te r m ole c u la r r e pu l s i ve fo r c es a r is e . W hen th es e d ip o la r m o le cu l es a p pr o ac h o ne a n o th e r s o t ha t th e p os i ti v e P.31 p o le o f o ne is c lo s e t o t he n eg a ti v e po l e o f t he o th e r , m ol ec u la r a t t r a c ti on o cc u rs ( d ip o le d i po l e i n te r a c t io n ) . W hen th e i d en t ic a ll y ch a r ge d p ol es o f t h e t wo m o le c u l es a r e c lo s e r, r e pu l si o n o c c u rs .
Figure 3-1. The carbon tetrachloride molecule.
C . T yp e s o f i nt e r m ol e cu l a r f o rc e s o f a t t r a ct i on i nc lu d e t he f ol lo wi n g : 1 . N on p ol a r m ol ec ul e s do n ot ha v e pe r m a n en t d ip o le s . H o we v e r , t he i n st a nt a ne o us e l ec t ro n di s t ri bu t io n i n a m o le c u l e c a n b e a s ym m e t r ic . Th e r e s ul t an t t r a ns ie n t d ip ol e m om en t c a n i nd uc e a dip o le in an ad j ac en t m o le cu l e. Th is i nd u ce d d i p o le - i nd u ce d di p o le in t e r a c ti o n ( L o nd o n d i s pe r s i on f o r ce ) , wi t h a f o rc e o f 0 . 5 -1 k ca l /m ol, i s s u f fi ci e nt t o f ac il i ta t e o r d e r i n a m ol ec u la r ar r ay . Th e s e re la t i v el y we a k e l ec t r os ta t ic fo r c e s a r e r e s po ns ib l e f o r t he li q ue fa c ti o n o f n on p ol a r g as es . 2 . Th e t ra ns ie n t d ip o le in d uc e d b y a p e rm an e nt d i po l e , o r d i po l e -i n d uc ed d i p o le i nt e r ac t i o n ( D e bye i n d u c t i o n f o r ce ) , i s a s tr o ng e r i n te r ac t io n , wi t h a f o rc e o f 1 - 3 k c a l/ m o l . 3 . P e rm a ne n t di p o le in te r a c t io n s ( K e es o m o r i en t a t i on f o rc e s ), wi t h a f o r ce of 1 -7 k c al /m o l, tog e t he r wi t h De b y e an d Lo n d on fo r ce s , c o ns t it u te va n d e r Wa a ls f o rc e s. C o l l ec ti v e l y , th e y a re re s p o ns i bl e f o r t h e m o r e s u bs ta n ti v e s t r uc t u re and m o l ec ul a r o r de r in g fo un d in li qu i ds . 4 . H yd r o g e n b on d s . B ec a us e t h e y a r e sm a ll and h a ve a l a r ge el ec t r os tat i c f i e ld , h y d r o ge n a t om s c an a pp r oa ch hi g hl y e le c t ro n e ga ti ve a to m s (e . g ., f l u or i ne , o xy g e n , n i t ro gen , c h lo r i ne , s ul f u r) an d i n t e r ac t e le c t r os t a ti c a ll y to f o r m a h y d r o ge n b o nd . De p e nd in g o n th e e le c tr o ne g a ti v i t y o f t he se c o nd
a t om an d th e m ol ec ul a r e n v i r on m e n t i n wh ic h h y d r o ge n b o nd i ng oc c u rs , h yd r o ge n b o nd en e r g y va r i es f ro m a pp r o xi m a te l y 1 t o 8 k c a l/ m ol . 5 . I on - i on , io n - d ip o le , an d i on - i n du c ed d ip o le fo r c e s. P o si t i ve - ne g a t i ve i o n in t e r ac t i on s i n th e s o l id s t a te in vo l v e fo rc e s o f 10 0 - 20 0 kc a l/ m o l . I o nic i n t er a ct i on s a re r ed uc e d c o ns id e ra b l y i n l i qu id s ys t em s i n t he p re se nc e o f o t h e r e le c t r ol y t e s . I on - d ip o l e i n te r ac ti o n , o r d i p ol e i nd u c ti o n b y a n i o n , c a n a ls o a f fe c t m o le c u l ar a g gr e ga t io n , o r o r d er i ng , in a s y s te m .
III. STATES OF MATTER A. G a s e s . Mo l e c u le s i n th e ga s e o us s t at e c an be p ic t u re d a s m o v in g a lo ng s t r ai g ht pa t hs , i n a ll di r ec t io ns an d a t hi gh ve lo c it i es ( e. g . , m e a n ve l oc it y f o r H 2 O v a po r : 5 87 m / s ec ; fo r O 2 : 4 40 m / s e c ), unt i l t h e y c o ll id e wi t h o t he r m o le cu l es . A s a re s ul t o f t h es e r a nd om c o ll is i on s, m ol ec u la r ve lo ci t ie s a nd p a t hs c h an ge , an d t h e m o l ec ul e s c o n ti n ue to c o ll id e wi t h o t he r m o le c u l es a n d wi t h t he bo u nd a ri e s o f t he s y s t em (e . g. , th e wa l l s of a c on t ai ne r ho l di n g t h e g as ) . Th is p ro c e s s , re p e at e d i nc es s a nt l y , is re s po ns i bl e f o r t h e p r e s su r e e xh i bi t ed wi t h in t he c o n fi ne s o f th e s y s t e m . 1 . Th e i n te r r el a ti o n a m on g vo l um e ( V ), p r es s u re ( P ) , a n d t he ab s o lu t e t e m p e ra t u r e ( T ) i s g i v en b y t h e i de a l g a s l aw , wh i ch is th e e qu a ti o n o f s t a te fo r an id ea l g a s : PV = nRT P V = ( g/ M) R T wh e r e n is th e n um be r o f m ol es o f g as — eq ui v a l en t t o t he nu m b e r o f g r am s ( g ) o f g as d i v i de d b y t he m ol ec u la r we i gh t of t he g a s ( M) — a n d R is th e m o l a r g a s c on s t an t ( 0. 08 2 0 5 L a tm / m o le de g ) . 2 . P ha r m a c e u ti c a l g as es i nc l ud e t h e a ne s t he t i c g a s es ( e. g ., ni t r ou s o xi d e , h a lo t ha n e ). C o mp r e ss ed g as e s i nc lu d e o xy g e n ( f o r th e ra p y ) , ni t ro g en , an d c a r bo n d io xi d e . L iq u e fi ab l e ga s es , i nc lu d in g c e rta i n h a lo h yd r o c a r b o n s a n d h yd r o c a r b o n s , a re u s ed as pr o pe ll a nt s i n ae r o s o l p r o du c t s ( p r e s su r i z e d p a ck a g in g) , as a re co m p r es se d g as es , s uc h a s n i t ro us o xi de , n i t ro g en , an d c ar b on di oxi d e . E t h yl en e o xi d e is a g as us e d t o s te r il i z e o r d i si n fe ct he a t -l a bi le ob j ec t s . 3 . I n g en e ra l , as t he te m p e r a tu r e o f a s u bs ta n ce in c r ea se s , i ts h e a t c o n t en t , o r en t h al p y, i n c r e as es a s we ll . a . S ub s ta nc es c a n u nd e rg o a c h a ng e o f s t at e , o r p h as e c ha n ge , fr om t he s o li d t o t h e l iq u id s t at e (m e l t in g ) o r f ro m t h e li q ui d to th e ga se ou s s ta t e ( va p o r i z at i o n ). b . V o la t i le l iq u i ds (e . g ., e t he r , h a lo t ha n e, m e th ox y f l u r a n e) a re us ed as i n ha l at i on an es t he t ic s . Am y l ni t r it e i s a vo la ti l e l iq u id t ha t i s i nh a le d f o r i ts va s o di l at in g ef f ec t i n a c u t e a n gi n a. c . S ub l im a t io n oc c u rs wh e n a s o li d i s h ea t ed di re c tl y t o t h e g as eo us , o r va p o r , s t at e wi t ho u t p as s i ng th r o ug h t h e l iq ui d s ta t e (e . g. , c am p ho r , i o di n e ). Ic e s ub l im es a t p r e s s u re s b el o w P.32
3 t o r r. Th e p r oc es s o f f re e z e - d r yi n g , o r l yo p h i l i z a t io n , i s a fo r m o f v a c uu m d r y i n g i n wh ic h wa t e r is r e m o v ed b y s ub l im at i on f r o m t he f ro z e n pr o du c t. I t i s a n e sp e c i al l y us ef u l p ro c es s f o r d r y in g a q ue o us s o lu t io ns o r d is pe r s i o ns o f he a t - o r o xy g e n - s e ns iti v e d r ug s a nd bi ol o gi c a ls ( e . g. , pr o te i ns , p e pt id e s ) . d . Th e r e v er s e p ro c e s s (i . e ., di r ec t t ra ns i ti on f rom t he va po r s t at e to th e s o li d s ta t e ) is al s o r e fe r re d to as s u bl im a ti on , bu t t h e p r ef e r re d te r m is d e p os i t i on . So m e f or m s o f s u lf u r a nd c o ll o id al sil i c o n d io xi d e a r e p r ep a red i n th is wa y . 4 . Th e i n te r m o l ec ul a r f o rc es o f a t tr ac t io n i n g as es a re vi r tu a ll y n on e xi s t en t a t r oo m t em p er a tu r e . G as es di s p l a y l i t tl e o r n o o rd e r in g . B . L i q ui d s. Th e in t er m o le c ul a r f o rc es of a tt r ac t ion i n l iq ui ds ( va n de r W a a ls f o rc e s ) a r e s u f fi c i e n t t o im p os e s om e o r de r i ng , or r eg u la r a r r a ng em e nt , am on g t h e m ol ec u le s. H yd r o g e n bo n d i ng in c re as es t he l i ke li h oo d o f c oh e s i on in l i qu i ds a n d f u r th e r a f fe c ts t he i r p h y si co c h em ic al b e h a vio r . Ho we v e r , t he s e f o rc es ar e m uc h we ak er t h an co va l e n t o r i o n ic f o r ce s . Th e r e fo r e, li q ui ds t en d t o d is p la y sh o r t -ra n g e r a th e r t ha n l o ng - r an g e o r d e r. H y p o th e ti c a l l y , a lth o u gh m o le cu le s o f a li qu i d wo u ld te n d t o a g g re g at e i n l oc a li z e d c lu s te r s , n o d ef i ne d s t ru c tu r i ng wo u l d b e e v i de n t. 1 . S u r fa c e a n d i n te r f a cia l t en s i on a . Mo l e c u l es i n th e b ul k p h as e o f a li q ui d a r e s urr o u nd e d b y o th e r m o le cu l es o f th e s am e k in d ( Fi gu r e 3 - 2 A ) . Mo l e c ul e s a t t h e s u r f ac e o f a l i qu i d a r e n ot c o m p le t el y s u r ro un d ed b y li k e m o lec u le s ( F ig u re 3 -2 B ) . As a r e s ul t , m o l ec ul es at o r ne a r th e s u rf ac e o f a l iq uid e xp e r i en c e a n e t i n wa rd p u ll f ro m m ol ec ul e s i n t he i nt e ri o r o f th e l iq u id . Be c au s e o f t hi s n et in wa r d i n t er m ol ec ul a r a t t ra c t i on, t h e li q ui d s u rf ac e te nd s t o s p on t an eo u s l y c o nt r ac t . Th us l i qu id s t en d to as su m e a sp h e ri cal s h a pe ( i. e ., a v ol um e wi t h t h e m in im um s u r fa c e a rea ) . Th is c o n fi gu r a ti o n h as t he le as t f r e e e ne r g y . b . A n y e xp a ns i on of th e s u r fa c e in c re as es t he f ree e ne r g y of t he s y s t em . Th u s s u r fa ce f r ee e ne r gy c a n b e d e fi n ed b y th e wo r k r e q ui r ed to in c re as e t h e s u rf a c e ar e a A o f t he l i qu id b y 1 a r ea un it . Thi s v al u e is e xp r e s s ed as t h e n um b e r o f m i l li - N e wt o n s ( m N ) n ee d ed to e xp a n d a 1 -m 2 s u r f ac e b y 1 u n i t: wo r k = γ × ∆ A wh e r e ∆ A is th e i n c r e as e i n s u rf ac e a r e a a nd γ is t h e s u r f ac e te n si o n , o r -1
s u r f a ce f r ee en e r g y, i n m N m —e q ui va l en t t o ce n t im et e r -g r am - s e co n d -1
( C G S ) u n it s o f d y n es c m . A t 2 0° C . wa t e r h as a s u r fa ce t en si on o f 7 2 m N -1
-1
m , wh e r e as n- oc t an o l ha s a s u r f ac e t en si o n o f 27 m N m . Th us m o r e wo r k m us t be e xp e n de d t o e x p a n d t he s u r fa c e o f wa t er t h an to e xp a n d t h e s u r fa ce o f n -o c ta n ol (i . e., t o p r oc ee d f ro m a g i ven vo l um e o f b ul k l iq u id to t h e c o r re s p o nd in g v ol um e o f s m a ll dr o pl e ts ) . c . A t t he b ou n da r y, o r i n t e r f a ce , b e t we e n t wo im m i sc ib l e l iq ui ds t ha t a re i n c o nt ac t wi t h o n e a no t he r, t h e c o r r es po n di n g i n te rf a c i al t en s io n (i . e ., f re e e n e rg y, o r wo r k r e qu i re d t o e xp a nd t he in t e rf ac i al a r e a) r ef l ec ts th e e xt e n t o f t he i n t er m o l ec ul a r f o rc es o f a t tr ac t io n a n d r e pu l s i on a t t he in t e rf ac e .
W hen t he in t e rf ac e i s b et we e n t wo l i qu id s , su bs ta n t ia l m ol ec ul a r i n te r ac t io n o cc u rs ac r os s t he in t e rf ac e b e t we e n t h e t wo p ha s e s . Th is i n te r ac t io n P.33
r e d uc es th e i m b a la nc e in f o rc es of at t r ac ti o n wi t h i n e ac h p h as e. Th e i n t er f ac i al te ns i on be t we e n n -o c t a no l a nd wa t e r is r ed uc e d t o 8 . 5 m N m from 72 mN m
-1
-1
(γ ai r / wa t e r ) . Th is re d uc ti o n i nd ica t es , in pa r t , t he
i n t er f ac i al i n te r ac t io n b et we e n n - oc ta n ol an d wa te r .
Figure 3-2. A. Molecules in the bulk phase. B. Molecules at the surface of a liquid.
Figure 3-3. Liquid flow.
2 . Th e fl o w o f a li q ui d a c r o s s a s ol id s u r fa ce c a n b e e xa m in e d i n t e rm s o f t h e ve l oc i t y, o r r a t e of m o v em e nt , of t he li qu i d re l a ti v e to t he s u r fa c e a c r oss wh i c h i t f lo ws . M o r e i n s i gh t c a n b e g ai ned b y vi s u al i zi ng th e fl o w o f l i qu i d as in v o l v i ng th e m o v e m en t o f nu m e r ou s p ar a l l e l l a ye rs of li q ui d b e t we e n a n u p pe r , m o v ab l e p la t e a nd a l o we r , fi x e d pl a te ( Fi gu r e 3 - 3 ) . Th e a p pl ic a ti o n o f a c o ns ta n t f o rc e (F ) t o t he up p er pla t e c au s es b o th th is pl a te a n d t h e u pp e rm os t l a y e r o f li q ui d i n c on t ac t wi t h i t t o m o v e wi t h a v el oc i t y ∆ y / ∆ x . Th e i n te r ac t io n be t we e n t he fi xe d b o tt om p l a te an d t h e l iq ui d l a y e r c l os es t t o i t p r e v e nt s t h e m o v em en t of t he bo t to m l a y e r o f l i qu id . Th e
ve l o c i t y ( v ) o f t h e r em ain i ng la ye r s o f l i qu id be twe e n t h e t wo p l at es is p r o po r t io n al to th e i r di s ta n c e f ro m t h e im m o va b le p la t e ( i .e . , ∆y / ∆x ) . Th e ve l o c i t y g r a d i e n t l ea ds t o de f o rm at i on of t he li qu i d wi t h t im e . Th i s d e f o rm at i on is t h e r a t e of s h ea r , dv /d x , o r D. N ew t o n d ef i ne d f l o w i n t e rm s o f t he ra t io o f t he fo r c e F a pp l ie d t o a pl a te of a re a A — sh e a r s t r es s (τ ) — d i vi de d b y t h e v e l oc it y gr a d ie n t ( D ) in d uc ed b y τ :
or
Th e p r o po r ti o na li t y c o ns ta n t η is th e c oe f fi ci e nt o f vi s c o s it y. I t i n di c a t es t h e re si s t a nc e t o f l o w o f a d ja c en t l a y e rs of fl u id . Th e r e c i p ro c a l o f η is -2
-1
f l u i d i t y. U n i t s of v is c os ity i n t he C G S s ys t em a r e d y n es c m s , o r p o is e . -2
-1
I n t he S I s y s t em , th e u n it s ar e N e wt o ns m s , wh i ch c o r re s po nd s t o 1 0 p o is e . Th e v i s c os it y o f wa t e r a t 2 0 ° C i s a pp r o xi m a t e l y 0 . 01 po is e , o r 1 -2
-1
c e nt i po is e (c ps ) , wh i c h c o r r es p on ds t o 1 m N m s . a . S ub s ta nc es th a t f l o w in ac c o r d an ce wi t h th e eq u a ti on in I II . B . 2 ( N e wt on ' s l a w) a r e k n o wn as N ew to n i a n s ub s t an c es . L i qu id s th a t c o ns is t of s im p le m o le cu l es a n d d il u te di s p e r s i on s t e nd to be N ew t o n i an . Fo r a N e wt o n ia n f l u id , a pl o t o f s he a r s t res s a s a fu nc t io n o f s he a r r a t e ( a fl ow cu r ve o r r h e o g r am ) y i el ds a s tr a ig h t l i ne wi t h a sl op e o f η ( F i gu r e 3 - 4, C u rv e 1 ) . b . N o n - New to n ia n su b st a n c es do no t o b e y Ne w t o n ' s e qu a ti o n o f f lo w. Th e s e s ub s ta nc es t en d to e xh i b i t s he a r - de p en d en t o r ti m e- d e pe n de n t vi s c o s i t y. I n e i t he r c as e, v i s c os i t y i s m o re ap t l y t e r m e d a p pa r e n t vi s c o s i t y b e c a us e N e wto n ' s l a w i s n o t s t r ic t l y o be ye d . H et e ro g en e ou s l i qu i ds a n d s ol id s a r e m os t li k e l y no n - Ne wt o n i an . ( 1 ) S he a r - de p e nd e n t vi s c o si t y i n v o l v e s e i th e r an i nc r ea s e in ap pa r e nt vi s co si t y ( i .e . , s h ea r t hic k e ni n g , o r d i l at a nc y) ( F i g ur e 3 - 4 , Cu r ve 3) o r a d e c re as e i n a p pa r en t v is c os i t y (i . e ., sh e a r t h i nn in g , o r p se u do - p la s t ic i ty) ( F i gu r e 3 - 4 , C u rv e 2 ) wi t h a n i nc r ea se in th e ra t e o f s h ea r . Sh ea r th ic k en in g i s d is p la y e d b y s us pe ns io n s t ha t ha v e a h ig h s ol id s c on t e nt of s m al l , d e f lo cc ul a te d p a r ti c l es . S h e a r t hi n ni n g is di sp l a ye d b y p o l ym e r P.34 o r m a c ro m o le c ul e s ol u tio n s . P l as t ic , or B i n gh am b o d y, b e h a vi o r ( F ig u re 3 4 , C u rv e 4 ) i s e xe m p li f ied b y f lo cc ul a te d p a r ti cl es in c o nc e n t r a te d s us p en s i o ns th a t s h o w no a pp a re n t r e sp on s e t o lo w- l e v e l s t r es s . F lo w b e gi n s o nl y a ft e r a li m i t in g y i el d s t re s s ( yi e l d va l u e ) i s e xc e e d ed .
Figure 3-4. Non-Newtonian flow curves.
( 2 ) T im e - de p en d en t vi sc o s i t y ( a ) Th e y i el d v al ue o f p la s t i c s ys t em s m a y b e tim e d e pe n de n t ( i .e . , m a y d e p en d o n t h e t im e s c a le i n v ol v e d i n t h e a pp li c at i o n o f f o rc e ). T hi x o t r opi c s ys t em s di s p l a y s h ea r - thi n ni n g b eh a v i or b ut do no t im m e di a te l y r ec o v e r t h e ir hi g he r ap p ar e nt v i s c os i t y wh e n t h e r a te o f sh e a r i s l o we r ed . In a t h i xo t r o p ic s y s te m , s t r uc t u r al r ec o ve r y is re la t i v ely s l o w c om pa r e d wi t h s t r uc t ur a l b r ea k d o wn . ( b ) T h ix o t r op y o c c u rs wi t h h e te r o ge ne o us s y s t em s t h at in v o l v e a t hr e e d i m e ns i on al s t r uc t u re or n e t wo r k . W hen s uc h a s ys t em is a t re s t, it ap p ea rs t o ha ve a r e la t i v el y r i gi d c o ns is te n c y . U n de r s h ear , t he s t r uc t u re br e ak s d o wn a n d f lu i di t y in c re as e s (i . e. , ge l - so l tr a ns f orm a ti o n ). ( c ) R h eo p ex y ( n e g a t i ve t h i x ot r o p y, o r a n t i t h i xo t r o p y) o c c ur s wh e n t he a p p ar e nt v i s c os it y o f t h e s y s te m c on t in ue s t o i nc re a s e wi t h c o nt i nu ed a p pl ic a ti o n o f s he a r u p to s o m e eq u il ib r i um val u e a t a gi v e n s h ea r ra t e . Th e s e s y s te m s di s p la y a s o l - ge l t r a ns fo r m a t io n . O n e e xp l a na t io n fo r a n t it h i xo t r o pi c b eh a v io r is t ha t c on t in u ed s h ea r inc r e as es th e f r eq u en c y of p a r ti c l e or m a c ro m o le c u le i nt e r ac ti o ns a n d l ea ds t o in c re as e d s tr uc t u re in t h e s ys te m . C . S o l i ds . I n te r m o l ec ul ar f o rc es o f a tt r ac t io n a r e s t ro n ge r in s o li ds th a n in l i qu i ds o r ga s e s . Mo l e c ula r a r ra n ge m e n ts i n s ol i ds m a y b e ch a r ac te r i ze d a s e i t he r c r y s ta l li ne o r am or p h ou s . 1 . C r ys t a l l i n e s o li d s h av e t h e f o ll o wi n g a t tr i bu t es : a . Fi xe d m o l ec u la r o r der ( i . e. , m o le cu le s o c c up y s e t p os it i on s i n a s pe c i fi c array) b . A di st i nc t m el ti n g p oi nt c . An i s o t r op i ci t y ( i . e . , th e i r p r op e r ti es ar e n o t t he sa m e in al l d i re c ti on s ) , wi t h t h e e xc e p t io n o f c ubi c c r y s ta ls 2 . Am o r p h o us so l i ds hav e t h e f o ll o wi n g a t tr i bu t es : a . R an d om l y ar r a ng ed m o l ec ul e s wi t h th e s h or t - ra n g e o rd e r t y p i c a l o f l i qu i ds b . N o m el t in g p o in ts
c . Is o t r o pi c i t y ( i . e . , p rop e r ti e s a re t he s am e i n al l di r ec ti o ns ) P.35
d . L ess th e rm o d y na m i c s t a b il i t y t h an th e c o r re sp on d in g c r y s ta l li ne so li d a nd t h e r ef o re m o r e a p t t o e xh i bi t c h em ic al an d p h y sic a l i ns ta b il i t y, i nc r ea s e d d i ss ol u ti on r a te , e tc . 3 . P o l ym o r p h i s m i s t h e c o nd i ti on wh e r e in s u bs t an c es c a n e xi s t i n m o re t h a n o ne c r y s t al li n e f o rm . Th e s e p o l ym o r p h s h a ve d if f e re n t m o l ec ul a r a r r a ng em e nt s o r c r y s ta l la t t ic e s t ru ct u r es . A s a r es u lt , th e d i ff e r en t p o l ym o r ph s o f a d ru g s oli d c a n h a v e d if f e re n t p r op e r ti e s. Fo r e xa m pl e , t he m e lt i ng po in t , s ol u bi li t y , d i s s ol u ti on r a te , d e ns it y , a n d s ta bi l it y c an di f fe r c o ns id e ra b l y a m on g t h e p o l y m o r ph ic f or m s of a dr u g . Ma n y d r ug s e xh i b i t p o l ym o r ph ic be h a v io r . Fa t t y ( t ri g l yc e r id e ) e xc i p ien t s ( e .g . , th eo b r om a o il , c oc o a b u tt e r ) a r e r ec o gni z e d fo r th e i r p ol ym or p hic be h a vio r . 4 . Th e i n c o r po r a ti on o f s o l v e n t m o l ec ul es in t o t he c r ys ta l l a tt ic e o f a so li d r e s ul ts in a m o l ec ul a r a dd u c t k n o wn as a s o l va te o r h yd r a t e ( t h e l a t te r t e r m is us e d wh e n wa t e r i s t h e s o l v e nt ) . In ge ne ra l , s ol va t es or h y d ra t es e xh i b i t di f fe r e nt s o lu bi l it ie s a n d d is s o lu t io n ra t e s t h a n t he i r u n so l va te d /a n h y d ro us c ou n t e rp a rt s . 5 . M e l t in g po i n t a n d h ea t o f fu s io n . Th e m e l ti ng p oi n t o f a s o li d i s t he t e m p e r at u re a t wh i c h t h e s ol i d is t ra ns f o rm ed t o a l i qu id . W he n 1 g of a s o li d i s h ea t ed an d m el ts , t h e h ea t a bs o r be d i n t he p r oc es s is re f e r re d t o a s t h e la t en t he a t o f f us i on . D . P h a se di a g r am s a n d p h a se eq u i li b r i a. A ph as e d ia g r am r ep r es en t s th e s t a te s o f m at t e r ( i .e . , s oli d , l i qu id , an d g as ) th a t e xi s t a s t em pe r a tu r e a n d p r e ss u re ar e v a ri e d ( F igu r e 3- 5 ) . Th e da t a P.36
a r r a y s s ep a ra t in g th e p ha s es i n Fi gu r e 3 - 5 d el i nea t e th e t em p er a t ur es and p r e ss u re s a t wh i c h t h e ph a s e s c an c o e xi s t . Th u s g a s ( o r vap o r ) a nd li q ui d c o e xi s t a lo n g “ c u r v e ” B C, s ol id an d l i qu id c o e xi s t a l on g “c ur v e ” A B , a nd s o li d a nd g as (o r v a po r ) c o e xi s t a lo n g “ c u r v e ” D B. D e pe n di n g o n t he ch ang e i n te m p e r at u re an d p r es s u r e, e va po r a t i on o r c on d e ns a t io n oc c u r a l on g c u r ve B C , f u si o n o r m e lt i n g al on g c u r v e A B , and s ub l i ma t i on o r d e p os i t i on al o ng c u r v e D B . Th e t h re e “ c ur v e s ” in t e rs ec t at po i nt B . O n l y a t t h is un i qu e t em p e ra t ur e a n d p r es s u r e , k n o wn a s t h e t r ip l e p o in t , d o a l l t h r e e p ha s e s e xi s t in equ i li b ri u m . ( Th e t r i pl e p oin t f or wa t e r is 0 . 01 ° C and 6 . 0 4 × 10
-3
a tm . ) C o nt i nu i ng al o ng cu r v e B C , t o h i gh e r te m p e ra t u re s a nd
p r e ss u re s , on e u l ti m a t ely r e a c h es po i nt C , k no w n as t he c ri t i ca l po i n t, a b o ve wh ic h th e re is n o d i s t i nc ti o n b et we e n t he l iq u id an d th e g as ph as es. S u b st a nc es th a t e xi s t abo v e t hi s c ri t ic al po i nt a re k no wn a s s u pe r c r i t ic a l f l u i d s. S up e rc r it ic a l f lu id s s uc h a s c ar b on di o xi d e ( c ri t i c al po in t , 3 0 .9 8 ° C a n d 7 3 .8 at m ) o f te n e xh i b i t m a rk ed l y al t e re d p h ys ic oc h em ic al p ro p er t ie s ( e . g ., de ns i t y , d i ff u s i v i t y , o r s o lu b il it y c ha r ac t e ri s ti cs ) th a t r e nd e r t h em
u s ef u l as s o l v e nt s a nd pr o c es s i ng ai ds in th e p r od u c t i on of ph a rm ac e ut ic a l s a n d d r ug de l i v e r y s y s tem s .
Figure 3-5. Phase diagram for CO2 showing the variation of the state of matter as pressure and temperature are varied. The solid state exists in the region ABD; the liquid state, in the region ABC; and the gas state, in the region to the right of curve CD. B corresponds to the triple point, the pressure and temperature at which all three phases coexist. C corresponds to the critical point, the pressure and temperature above which the liquid and gas phases are indistinguishable.
IV. PHYSICOCHEMICAL BEHAVIOR A. H o m o g e ne o u s s ys t e m s 1 . A s o l u ti o n i s a h om og e n eo us s y s t em i n wh ic h a s ol u t e is m o le c u l ar l y d i sp e rs ed , o r di s s o l v ed , i n a s ol ve n t . Th e s ol v e nt i s t he p re do m i n an t s p ec ie s . S a tu r a t ed s ol ut i o n s a r e s o l ut i on s t ha t , a t a g i ven t em pe r a tu r e a n d p r es s u r e , c o n ta i n t he m a xi m u m a m o u nt of s ol u t e t ha t c a n b e a cc o m m od a te d b y t he s ol v e n t . I f th e s at u r at i on , or s ol u bi li t y, li m i t i s e xc e e d e d, a f r ac t io n o f th e s o lu t e ca n s e pa r at e fro m th e s ol u ti on an d e xi s t i n eq ui l ib r iu m wi t h i t. a . S o lu t es c a n b e g as es , l iq u id s, o r s o l id s , an d no n el e c t r ol y t e s o r e l ec t r ol y t es . ( 1 ) N o ne l ec t r o l yt e s a r e s u bs ta n c e s t ha t do n ot fo r m i on s wh e n d is s o l v ed i n wa t e r . E xa m p l es ar e es t r ad i ol , g l yc e r in , ur e a, a n d s uc r os e. Th e i r a q u eo us s o lu t io ns do not c on du c t e le c t r ic c u r r en t. ( 2 ) E l ec t r o l yt e s a r e s u bs t an c e s t h at d o f o r m i on s in so lu t io n . E xa m p l es a r e s o di um c h lo r id e , h y dr o c hl o ri c ac i d, an d a t r op in e . As a r es ul t , t h ei r a q u eo us s o lu t io ns c o nd uc t el ec t ri c c u rr e nt . El e ct ro l y t es a re c h a ra c t e r i z ed a s s t r o n g o r w ea k . S t r on g el ec t r ol y t es ( e. g . , s o di u m c h l o ri de , h y dr o c h lo r ic a c id ) ar e c o m pl e te l y i o n i z ed in wa t e r a t al l co nc e nt r a ti o ns . W eak e l ec t r ol y t es ( e. g . , as p ir in , a tr o pi n e) a re pa r t i a ll y i o n iz e d in wa t e r . b . Th e co l l ig a t i ve p r o pe r t i e s o f a s ol u t io n de pe n d o n t h e t o ta l n u mb e r o f i o n i c a nd n on i o ni c s o l ut e m ol e cu l es i n t h e s o lu t i o n . Th e se p ro p er t ie s d e p en d o n i on i z a ti o n b ut a r e i n d ep e nd e n t o f o t he r c he m ic a l p r o p e r ti e s o f t h e so l u te . 2 . C o ll i g at i ve p r o pe r t i es i nc lu de t he fo l lo wi n g : a . L ow e ri n g o f va p o r p re s s u re . Th e p a r t ia l va po r p r e ss u r e o f e ac h vo l a t il e c om po n en t i n a s o l u ti on is eq ua l to th e p ro d uc t o f th e m ol f ra c ti on
o f t he c om p on e nt in th e s o lu t io n a n d t he va po r pr e s s u r e o f t he pu r e c om p on e nt . Th is is Ra o ul t ' s law :
wh e r e p A is th e p a r ti a l v a p o r p r es s u r e a bo ve a so l u ti on in wh i c h t he m o l f r a ct i on of t he s o lu t e A is x A a n d is th e va p o r p re s s u re o f t he pu r e c om p on e nt A . Th e v a p o r p r es s u r e i s t he p re s s u re a t wh i c h an eq ui l ib r iu m i s e s ta b li sh e d b et we e n th e m o le c u l es o f A i n t h e li qu i d s ta t e a nd t he m o le cu l es o f A i n t h e g as e ou s ( va p o r) st a te in a c l os ed , e v a c ua t ed c o nt a in e r . Th e v a po r p res s u r e i s t em p er a tu r e d e pe n d en t , b ut in d ep e nd en t o f t he am ou n t o f l iq u id an d v a po r . Ra o ul t ' s l a w ho l ds fo r id e al s o lu ti o ns of n o n el ec t ro l y t es . F o r a b in a r y s o l u t i o n ( i .e . , a s o lu t i on of co m p on e nt B in c om p on e nt A )
Th e l o we r i ng o f t he v a por p r es s u r e o f t h e s ol ut i on r el a ti v e t o t he va p or p r e ss u re of th e p u r e s o l ve n t i s p r op o r ti on a l t o t h e n um b e r o f m ol ec ul es o f s o lu t e i n t he s o lu t io n . The ac t ua l l o we r i ng o f t he va p o r pr e s s ur e b y t h e s o lu t e, ∆ p A , i s g i v en b y
b . E l e va ti o n o f t he b oi l in g p oi n t . Th e b o il i n g po i n t i s t h e t em pe r a tu r e at wh i c h th e v a po r P.37
p r e ss u re of a l iq ui d e q ual s a n e xt e r n a l p r es s u r e of 7 60 m m Hg . A s ol u ti o n o f a n on v o l at i le s o lu t e ha s a hi g he r bo il i ng po in t t h a n a p u r e s o l v e nt b e ca us e th e s ol u te lo we r s t he v a po r pr es s ur e o f th e s o l ven t . Th e am o un t o f e l e va ti on o f t he bo i li ng po i n t ( ∆ T b ) d ep e nd s o n t he co nc e n tr a ti o n o f t h e s o lu t e:
wh e r e K b is th e m ol al bo il i ng po i nt el e v a ti o n c o n s t a n t , R is th e m ol a r g as c o ns ta n t , T i s a bs o lu t e te m pe r a tu r e ( d eg r ee s K) , M 1 i s t he m o le c u l a r we i g h t o f t he s o lu t e, m is th e m o l al i t y of th e s ol u ti o n, and ∆ H v a p i s t he m o la l e n t ha lp y o f v ap o r i z at i on o f t he s o l v en t . c . D ep r e ss i o n o f th e f ree z i ng po i n t . Th e f r ee z ing p o in t , o r m e lt i ng po i nt, o f a p u re c o m p ou n d is t he t em pe r a tu r e a t wh ic h th e s o li d a n d t he li qu i d p h as es a re in eq ui l ib r ium un d e r a p r es s u r e o f 1 a t m o sp h e re ( at m ). Th e f r e e zi ng po in t of a s ol ut io n is th e t em p er a t ur e a t wh i c h th e s o li d p ha s e o f t h e p u r e s o l v e nt an d th e l i qu id ph as e o f th e s ol u ti o n a r e i n e qu i li b ri um u n d er a p r es s u r e o f 1 atm . Th e a m o u nt of d ep r es s i on of t he f re e zin g po in t ( ∆ T f ) de p en ds on th e m ol a li t y o f t he s o lu t io n :
wh e r e K f is th e m ol al f r ee z i n g p oi n t c on s t a n t a nd ∆ H f u s i o n i s t he m o la l h e at o f f us io n . d . O s mo t i c p r e ss u r e. Os m o si s i s t h e p ro c e s s by wh i c h s o l v e nt m o le cu l es p a ss th r ou g h a s em ip e rm e ab l e m e m b r an e (a ba rr i e r th r ou g h wh i c h o nl y s o l ven t m ol ec u le s m a y pa s s ) f ro m a re g io n o f d i lu t e s ol u ti o n t o o ne o f m or e c o nc en t r at e d s o l ut i on . So l v e n t m o l ec ul es t ra ns f er b ec a us e o f t h e i ne qu a lit y i n c h em ic al po t en t ia l o n t h e t wo s i de s o f t h e m em b r an e . S ol v e n t m ol ec u le s i n a co nc e nt r a te d s ol u ti on h a v e a l o we r ch e m i ca l p o t en t ia l t h an s o l ven t m o le cu l es i n a m o r e d il ut e s o lu t io n . ( 1 ) O s mo t i c p r e ss u r e is t h e p r e ss u r e t h at m us t b e ap pl i ed to t he s o lu t ion t o p re ve n t t h e f lo w o f pur e s o l v e nt in t o t he c o nc en t r a te d s ol u ti o n. ( 2 ) S ol ve n t m ol ec ul es m o v e f r om a r eg i on wh e r e t h e ir e sc a pi n g t e nd e ncy i s h ig h to on e wh e r e t hei r es c ap i n g t e nd e nc y i s l ow . Th e p r es e nc e o f d i ss ol ve d s ol u te lo we r s th e es c a pi n g t en d en c y o f t h e s ol v e n t i n p ro p o rt i on t o t he s o lu t e c o nc e nt r a tio n . ( 3 ) Th e va n ' t H o f f e q ua ti o n de f in es th e o s m o ti c p r e ss u re π as a f u nc ti o n o f t h e n um b e r o f m ol es of s o l u te n 2 in th e s ol u ti o n of v o l um e V: πV = n2RT 3 . E le c t r o l yt e s o l u t i on s a n d i o n ic eq u i li b r i a a . Ac i d - b as e e q ui l i b r ia ( 1 ) A cc or d in g t o th e Ar r h e n i us di s so c ia t i o n t h eo r y, a n a c i d i s a +
s u bs ta n c e th a t l ib e ra t es H i n aq ue o us s o lu ti o n . A b a se is a su bs t an c e t ha t -
l i be r a te s h y d r o xy l i o ns (O H ) i n a qu e ou s s ol u ti on. Th i s d e fi ni t io n a p pl ie s o n l y un d er aq u eo us c o nd i t io ns . ( 2 ) Th e Low r y- B r ø n s t e d t h e o r y i s a m o r e p o we r fu l c o nc ep t th a t a pp li es to a q u eo us an d n o na qu e ous s ys t em s . I t is m o st com m o n l y u se d fo r p h a rm ac e ut ic al an d bi olo g ic s y s t em s b ec au s e the s e s ys t em s a r e p r im a ri ly a q u eo us . ( a ) A cc or d in g t o th is de f in i t io n , a n a ci d i s a s u bs ta n ce (c h a rg ed o r u n ch a rg e d ) t ha t i s c ap a bl e of do n at i ng a p r ot o n. A b a se is a su bs t an c e ( c h ar g ed o r u nc ha r g ed ) th a t i s c ap ab l e o f a c c ep t in g a p r ot o n f r om a n a c i d. -
Th e d is s o c i a ti o n o f a n ac i d ( H A ) al wa y s p r od uc es a b as e (A ) a c c o rd i ng to t h e fo ll o wi n g f o rm u la : +
HA ↔ H + A
-
( b ) H A an d A a re a c on ju g a t e a ci d - ba s e p a i r ( an ac i d a nd a b as e t h at e xi s t i n e qu i li b ri um an d d i f fe r in s t r uc tu r e b y a pro t o n ). Th e p r o to n o f an a c id do es no t e xi s t f r ee in s o l ut i on , b u t c om bi ne s wi t h t h e s o l v e nt . In wa t e r , +
t h is h yd r a t e d p r o t o n i s a h yd r o n i u m io n ( H 3 O ). ( c ) Th e re l at i v e s t r e n gt hs o f a c i ds an d b as es a re d e te r m i n ed b y t h ei r a b il i t y to do n at e o r ac c ep t p ro t on s . F o r e xa m p le , i n wa t e r, H C l d o na t es a p r o t on m o re r ea d il y t ha n d o es a c et ic ac id . Th us H C l i s a s t ro n ge r ac id . Ac i d s t r en g th is a ls o de t er m i ne d b y th e a f fi n it y o f t h e s o l v en t fo r p r o to ns . Fo r
e xa m p l e , H C l m a y di s s oc i at e c om pl e te l y in li q ui d a m m on i a, bu t on l y v e r y s l ig h tl y i n g la c i al ac e ti c a c id . Th us H C l is a s t ro ng ac i d i n l iq ui d a m m on i a a n d a we a k a c i d i n g la c ia l ac et ic ac id . P.38
( 3 ) Th e Lew i s th e o r y e x t e n ds th e a c i d -b as e c o nc e pt t o r ea c ti o ns t h at do n o t i n vo l v e p r ot o ns . I t d ef i n es a n a c i d as a m ol ecu l e o r i o n t h at acc e p ts an e l ec t r on pa i r f r om a n o the r a to m a nd a b as e as a s ub s ta nc e t h at do n at e s a n e l ec t r on pa i r t o b e s ha r ed wi t h an o th e r a t om . +
b . H c on c en t r a t io n v alu e s a r e v e r y s m a ll . Th ere f o r e, th e y a re e xp r e ss ed i n ex p on e n ti a l n o t at i o n a s p H . Th e p H i s t he lo ga r i th m o f th e r e ci p ro ca l o f +
t h e H c on c e n t ra t io n
+
+
wh e r e [ H ] is th e m ol a r c o n c e n t ra t io n o f H . B ec au s e t he lo g a ri t hm o f a r e c ip r oc al eq u al s t he neg a t i ve l og a r i th m o f th e n u m b e r , t hi s e qu a ti o n m a y b e r e wr i t te n a s : +
p H = -l o g [ H ] or +
[ H ] = 10
-pH +
Th u s t he p H v a l ue m a y be d ef i ne d a s t he ne g a ti v e l og a ri t hm of th e [ H ] +
-6
va l u e . F o r e xa m p le , i f the H c o nc e nt r a ti o n o f a s o l u ti on is 5 × 1 0 , th e pH va l u e m a y b e c a lc ul a te d a s fo ll o ws :
pH
=
-log (5 × 10-6)
log 5
=
0.699
log 10-6
=
-6.0
pH
=
-(-6 + 0.699)
=
-(-5.301)
=
5.301 +
c . As p H d ec r ea s e s , H c o n ce n t r a ti o n i n c re a ses e xp o ne n t ia l l y. W he n th e +
p H d ec r ea s e s f r om 6 t o 5 , t he H c o nc en t r at io n in c r ea s e s f r om 10
-6
-5
to 10 ,
o r 1 0 t im es i t s o ri g in a l v a l ue . W he n t he p H f a ll s fr o m 5 to 4 .7 , t h e H c o nc en t r at i on in c re as es f r o m 1 × 1 0
-5
+
-5
t o 2 × 1 0 , o r do u bl e i ts in i ti al va lue .
d . D i ss o ci a t io n co n s tan t s . Io n iz a ti o n i s t he com p le t e s e p a ra t io n o f t h e i o ns in a c r y s t al la t t ic e wh e n t h e sa l t i s d is s o l v ed . D i s s oc i a ti o n is t he s e pa r a ti on o f i on s i n s o lu t i on wh e n t h e i on s a r e a s s o c i at e d b y i nt e ri o ni c a t t r ac ti o n. ( 1 ) F or w e ak el e c t ro l yt e s , di s s oc ia t io n i s a re v e rs i bl e p r oc es s. Th e e q ui l ib r iu m o f t h is p r oc es s c an be e xp r e s s ed b y th e la w o f m a ss a c ti on . Th i s la w s t a te s t h at th e ra t e o f th e c he m i c a l re ac ti o n i s p r op o rt i on al t o t he p r o du c t o f t h e c o nc e nt r at i o n o f t h e r ea c ti ng su bs ta n c e s, e ac h r ai s e d to a p o we r o f th e n um be r o f m o le s o f t h e s u bs t an c e in s o l ut i on . ( 2 ) F or w e ak ac i ds , di s s o c ia t io n i n wa t e r is e xp r e ss e d a s: +
HA ↔ H + A
-
Th e d yn am ic eq u il ib r i um b e t we e n t h e s i m u l ta n eou s fo r wa r d an d re v e r se r e a ct i on s is in d ic at e d b y t h e a r r o ws . B y t h e l a w of m as s ac t io n , r a t e o f fo r wa r d r ea c t i on = K 1 [ H A ] +
-
r a t e o f re v e r s e r ea c t i on = K 2 [ H ] [ A ] A t e qu i li b ri um , t h e f o r wa r d a nd re v e r se r at e s a re e q u al . Th e re f or e , +
-
K1[HA] = K2[H ][A ] Th u s t he e qu i l ib r i um e xp r e s si o n fo r t he d is s oci a t i o n o f a w e ak ac i d is wr i t t e n as :
wh e r e K a r ep r es e nt s t h e a c id di s s oc ia t io n c on s tan t . Fo r a we a k a c i d , t h e a c i d d i ss o ci a t io n co n s ta n t is c on v e n ti o na l l y e xp r e s s e d as p K a , wh i c h is -5
l o g K a . Fo r e xa m p l e, t he K a o f a c e t ic a c i d a t 25 ° C i s 1 . 75 × 1 0 . Th e p K a is c a lc ul a te d a s f ol l o ws : P.39
pKa
=
-log (1.75 × 10-5)
log 1.75
=
0.243
log 10-5
=
-5
pH
=
-(-5 + 0.243)
=
-(-4.757)
=
4.76
( 3 ) F or w e ak ba s es , di s s oc i at i on m a y al s o b e e xp r e ss ed wi t h th e K a e xp r e s s io n f o r t h e c o nj ug a t e a c id o f t h e b a se . Th i s ac i d is f or m e d wh e n a p r o t on re a c t s wi t h t he bas e . F o r a ba se th a t d oe s n o t c on t ai n a h yd ro xy l g r o up , +
+
BH ↔ H + B Th e d i s so c ia t i on co n s ta n t fo r th is r ea c ti on is exp r e s s e d as :
H o we ve r , a b as e d i ss o ci a t i o n c on s t an t i s t r a di tio n al l y de f in e d f o r a we ak b a se wi t h th is e xp r e s s ion : -
B + H2O ↔ OH + BH
+
wh e r e K b r ep r es en t s t he d i s s oc ia t io n c on s ta n t o f a we a k ba s e . Th is d i s so c i at i o n c on s t an t c a n be e xp r e s s ed as p K b , a s f o ll o ws : p K b = - l og K b ( 4 ) C e r t ai n c o mp o u nd s ( a c id s o r b as es ) c a n ac ce p t o r do n at e m o re th a n o n e p r o to n . C o ns eq u en t ly , t h e y ha ve m o re t ha n o n e di s so c ia t i on c o n s ta n t . e . H e nd e r so n - H as s el b al c h eq u a ti o ns de s c r ib e th e r el a ti on be t we e n th e i o ni ze d a n d t h e u ni on i z ed s p ec i es of a we a k el ec t r o l y t e. ( 1 ) F or w e ak ac i ds , th e H e n d e rs on - H as s e lb a lc h e q u at io n i s o b ta i ne d f r o m t h e e q ui li b r iu m r el a ti o n de s c r i be d i n I V . A .3 d . (2 ) :
( 2 ) S im il a rl y , t he H en d e rs o n - Ha s s el b al c h eq u at ion f o r w e a k b as e s is as f o l lo ws :
+
wh e r e B is th e u n io n i z ed we a k b as e a nd B H i s th e p ro t on a te d b as e . f . Th e d eg r e e o f io n iz a ti o n ( α ) , t he f ra c ti on o f a we a k e le c tr o l yte t ha t i s i o ni ze d i n s ol u ti o n, is c a lc u la t ed f ro m t he f ol lo wi n g e qu a ti o n:
wh e r e [ I ] a n d [ U ] re p re s en t t he c o nc en t r at i on s o f t h e i o ni z e d a n d u ni on i zed s p ec ie s , r es pe c ti v e l y . The d eg r ee o f i on i za ti on dep e n ds s ol e l y o n t h e p H of t h e s ol u ti o n a nd th e p K a o f t he we a k e le c t r o l yte . W h e n p H = p K a , t h e H e n d e rs on - H as s e lb a lc h e q u at io n s a re , fo r a we a k ac i d an d a we a k b as e , r e s pe c t i v e l y :
t h us
P.40
t h us
I n e ff ec t , wh e n t he p H o f t h e s ol u ti on is nu m e r ic al l y e qu i val e nt t o t he p K a o f t h e we a k e le c t r ol y t e , whe t h e r a we ak ba s e o r a we a k a c i d , [ I ] = [ U] an d th e d e g re e o f io ni z a t io n α = 0 . 5 (i . e. , 50 % o f t h e s ol ut e is i o ni ze d ) . g . S o lu b i li t y o f a w e a k e l e c t ro l yt e v a r i e s as a fu n ct i on of p H . ( 1 ) F or a w ea k a c id , th e t o t al s ol u bi l it y C s is gi v e n b y th e e xp r e s si on : -
Cs = [HA] + [A ] wh e r e [ H A ] is t h e i nt r i ns ic s o lu b il i t y o f th e u n io niz e d we a k ac id an d i s -
-
d e n ot e d as C 0 , wh e r e as [ A ] i s t h e c o nc e nt r a ti o n o f it s a ni o n . B ec a us e [ A ] c a n b e e xp r e s s e d i n t e rm s o f C 0 a nd th e d is s o c ia t i on c o ns ta n t K a ,
Th u s t he so l u bi l i t y o f a w e ak ac i d i n c re a se s w it h i n c re a si n g p H ( i. e ., wi t h a n i nc r e as in g d e gr ee o f i on i z a ti o n, as th e a ni o n i s m o r e p o la r a n d t h e r ef o re m o r e wa t e r s o lu b le t ha n t h e u ni o ni z e d we a k a ci d ). ( 2 ) S im il a rl y , f o r w e ak ba s e s,
Th u s t he so l u bi l i t y d e c r e a s es w i t h i nc r e as i n g p H b ec a us e m o r e o f th e we a k b as e i s i n t he un p ro t o na t ed fo r m . Th i s f o rm i s l es s p ol a r a nd th e r ef or e l e ss wa t e r s ol ub l e. h . B u f fe r s an d b u f f e r ca p a ci t y ( 1 ) A bu f f e r i s a m i xt u r e o f s a lt wi t h a c i d or ba s e t h a t r es is ts ch an g es i n p H wh e n s m a ll qu a nt i ti es of a c id o r b as e a r e a dd ed . A b u ff e r c an be a c o m bi n a ti o n o f a we a k a c id an d i ts c o nj u ga t e ba s e ( s a l t ) o r a c om b in a tio n o f a we ak ba s e an d i t s c o n ju g at e ac id (s al t ) . Ho we v e r , bu f fe r so lu t io ns a re m o r e c om m on l y p r e p a re d f ro m we ak ac id s a nd t h e ir sa l ts . Th e y a r e n o t o r d in a ri l y p re p a re d f r om we a k b as es an d t h ei r s a lt s be c a us e we ak ba s es a r e of t en un s ta bl e a n d v o l a ti le . ( a ) F or a w ea k a c id an d i t s s a l t, t he fo l lo wi n g bu f f e r e qu a ti o n is s a ti s fa c t o r y fo r c a lc ul a tio n s wi t h a p H of 4 -1 0 . I t i s i m p o r ta n t i n t he p r e pa r a ti o n o f b uf f e re d ph a r m a ce u ti c a l s ol u ti on s :
( b ) F o r a w ea k b a se and i t s s a lt , th e b u f fe r e q ua t i on is s im il a r b u t a ls o d e p en ds on th e d is s o c i a ti o n c on st a nt o f wa t e r ( pK w ) . Th e e q u at i on b e co m e s :
( 2 ) B u f fe r a ct i o n is t he r e s is ta nc e to a ch a ng e in p H . ( 3 ) B u f fe r c ap a ci t y i s t he a bi li t y o f a b u f fe r s o lu ti o n t o re s i st c h a ng es in p H . Th e sm a ll e r th e p H c h a ng e c a us ed b y a d di t io n of a g i ven am ou n t o f a c id o r b as e, t he g re a t er t h e bu f f e r c a pa c i t y o f t h e s ol u ti o n. ( a ) B u ff e r c ap ac i t y i s t h e n um b e r o f g r am e q ui v a le n ts o f a n ac i d o r b as e t h a t c ha ng e s t he p H o f 1 L o f b uf f e r s o l ut i on b y 1 u n it . ( b ) B u ff e r c ap ac i t y i s a f fe c te d b y t h e c o n c e n tr a tio n of t he bu f fe r c o ns ti t ue n ts . A h ig h er c on c en t r at i on pr o v i de s a gre a t e r ac i d o r b as e r e s er ve . B uf f e r c a p ac it y ( β ) i s r el a te d to to t al c o nc e nt r a ti o n ( C ) as fo ll o ws : P.41
wh e r e C r e p re s e n ts th e m o la r c o nc en t r at i on s o f th e ac id an d t h e s al t .
( c ) Th u s b uf f e r c a p ac it y d e p en ds on th e val u e o f t h e ra t io of t he s a lt to t he a c id fo r m . I t i nc r ea s e s as t he ra t io ap p r oa c h es un i t y . Ma xi m u m bu f f er c a pa ci t y oc c u r s wh e n p H = p K a , an d i s r e p re s e n te d b y β = 0 .5 76 C . B . H e t e r og e ne o u s ( d is pe r s e ) s ys t e m s 1 . I n t ro d uc t i o n a . A s u s pe n si o n i s a t w o - p ha s e s ys t em th a t i s co m po s e d o f a s o li d m a ter i a l d i sp e rs ed in an oi l y o r aq u e ou s li q ui d . Th e pa r t icl e s i ze o f th e d is p er s ed s o li d i s us u al l y > 0 . 5 µ m . b . A n e m ul s io n i s a he te r o ge n eo us s ys t em th a t c o ns is ts of a t l ea s t on e i m m is ci b le li qu i d t ha t i s in t im a te l y di s p e rs e d i n a n o t he r in th e f o rm of d r o pl e ts . Th e d r op le t di am e te r us ua l l y e xc e e d s 0 .1 µ m . E m u ls i on s a r e i n h e r en t l y u n s t a b l e b e c a u s e th e d r o pl e ts o f th e d i s p e rs ed li q ui d t e nd to c o al es ce t o f o rm l a rg e d ro p le t s u nt i l a ll of th e d isp e r s e d d r op l et s h a v e c o al es ce d . Th e t hi r d c om p on e nt of t he s y s t em is an em u l si f yi n g a g e nt . Th i s ag e nt p re v e n ts c o ale s c e nc e a nd m a in t ai ns th e i n t eg r it y o f th e i n di vi d ua l d r op l et s . 2 . D i sp e r si o n s t a bi l i t y. I n an i de a l d i sp e r si o n , th e di s p e rs ed p ar t ic le s do n o t i n te r ac t . Th e p ar t ic les a re un i fo r m i n s i z e an d u n de r go no ch a ng e i n p o si t io n o t he r th a n t he ra n d om m o v em en t th a t r es u lt s f r om B ro wn i a n m o ti o n. I n c o n t ra s t , in a r e a l di s pe r s i on , th e p a rt i c l es a re no t u n if o rm l y s i z e d ( i .e . , t h e y a r e n o t m o n o di s pe r s e ). Th e p a rt i c l es a re s u bj ec t to p a r ti c ul a te ag g re g at i on , o r c l um p in g , a nd th e d is p e r s i on be co m es m o re h e t e ro ge n eo us wi t h ti m e. Th e r a t e o f s e t tl i n g ( se p a r a ti n g , o r c re a mi n g ) o f t h e d is p e rs ed ph as e i n th e di s p e rs io n m ed i um i s a f un c ti on o f t he pa r t ic le s i z e , d is pe r s i o n p ha s e v is c o s i t y , an d d i f fe r en c e in d en s i t y be t we e n th e d i sp e rs ed ph a s e an d t h e d is p e rs io n m ed iu m , i n ac co r d an c e wi t h S to k es ' s l aw :
wh e r e d is th e p a rt ic l e d ia m et e r , g i s t h e ac c e l e rat i o n o wi n g t o g r a v i t y , η is t h e vis c o s i t y o f t he di s p er s i on m e di um , a n d ( ρ 1 - ρ 2 ) is t h e d if f e re nc e b e t we e n th e d en s i t y o f th e pa r t ic le s ( ρ 1 ) an d th e d e ns i t y o f th e d is p e rs io n m e di um ( ρ 2 ) . Al t ho ug h St o k e s ' s la w wa s d e r i v e d t o de t e rm in e t h e s et t li ng, o r se d im en t at i on , o f n o nin t e r ac ti n g s p h e ri c a l p a rt i c l es , i t a ls o p r o v id e s g u id a nc e f o r d e te r m i ni n g t h e s ta b il i za ti on o f di s pe r s io n : a . P a r ti c le s iz e s h o ul d be as sm a l l as po ss ib l e. S m a ll e r p a rt ic l es y ie l d s l o we r s e di m e n ta t io n , o r f l ot a ti o n, r a te s . b . H i g h p a r ti c u la t e ( d isp e r s ed p ha s e) c on c en t ra t i o ns in c re as e t h e r a te o f p a r ti c l e - pa r t ic le c o ll is io ns an d i n te r ac t io n . A s a re s ul t , p a rt ic l e a gg r eg a ti on o cc u rs , an d i ns t ab il i t y i nc r e as es a s t h e a gg r eg a te s b e ha v e as la r ge r p a r ti c l e s . In t he c as e o f li q ui d - li qu i d d is pe r s i on s , p a r ti c l e - pa r t ic le c o ll is io ns c a n l ea d t o c oa l es c e nc e ( i . e ., la r g er pa r t ic le s ) a nd d ec r ea s e di sp e rs io n s t ab i li t y. c . Avo i d a n ce o f p a r t ic le - p a r t ic l e i n te r a c ti o n s
( 1 ) A gg r e ga t io n c an be pr e v e n t ed if th e p a r ti c l es h a v e a s i m i l a r e le c t r ic al c h a rg e . P a r ti c l es in an aq u e ou s s y s t em al wa ys ha ve so m e el e ct r ic al c h a rg e b e ca us e o f io n iz a t io n o f c he m i ca l g r o up s o n t he p a r ti c l e s u r fa ce o r a d s o r pt i o n o f c ha r ge d m o le c u l es o r io ns at t he i n t er f ac e . I f t h e a ds o rb ed s p ec ie s is a n i on i c s u r fa c t a nt ( e. g . , s o d iu m l au ry l s ul f a te ) , t h e c h a r ge a ss o ci at e d wi t h t he s u r fac t an t io n ( e .g . , l a ur y l su lf a t e a ni o n ) wi l l a cc u m u la t e a t t h e i nt e r fac e . Ho we ve r , i f a re l at i ve l y n on - s u r f ac e- a c t i v e e l ec t r ol y t e i s a ds o rb e d, th e s i gn of t he c h a rg e o f t h e a ds o r be d i on is le s s r e a di l y p re di c te d . ( 2 ) Th e ma g ni t u de o f t he c ha r g e i s t he di f fe r e nce i n e le ct r ic al p ot e nt ia l b e t we e n th e c ha r ge d s u rf a c e o f t he pa r t ic le an d th e bu lk of t he di s p e rs io n m e di um . Th is m a gn i tu de i s a pp r o xi m a te d b y t h e e l e c t ro k i ne t ic , or z e t a , p o t e n ti a l ( ζ ) . Th e z e ta po t e nt i al is m ea s u r e d f r om t he fi xe d , a vi dl y b ou nd l a ye r s o f i on s a nd s o l v ent m ol ec ul es on t he pa r ti cl e s u r fa c e . W hen ζ is h i gh ( e . g ., ≥ 25 m V ) , i n te r p ar ti c ul a te r ep u l si ve f o r ce s e xc e e d th e a t t ra ct i v e f o r ce s . A s a re s u l t, t he di s pe r s i on is de f l oc c ul a te d an d re l at i v el y s ta b le to c o ll is io n a n d s ub s e qu e nt a g g re ga t io n ( fl o cc u la t io n ) . W hen ζ is s o l o w t ha t i n t er p a rt ic u la t e a t t r ac t i ve f o r ce s p r e do m i na t e , l oo s e p a rt ic l e a gg r eg a te s , o r f l oc s , f o rm (i . e. , f lo cc u l a ti o n o c c u rs ) . d . D e ns i t y c a n b e m an i pu l a te d t o d ec r e as e t he ra t e o f di s p e rs io n i n st a bi li t y . Th e s e tt l in g P.42
r a t e d ec r e as es a s ( ρ 1 - ρ 2 ) a pp r oa ch e s z e r o . H o we ve r , th e d e ns i t y o f th e d i sp e rs io n m ed i um u s ua ll y c an n ot be al t e re d s u ff ic i en t l y to ha l t t he s e t tl ing ( o r f lo t at i on ) p r oc es s . I n t h e d is p e rs ed ph as e , t he d e ns it y o f s ol i d p ar t ic les i s n o t r e ad il y a l te r ed ; al te r i ng t he de ns i t y o f l i qu id p a rt ic l es wo u ld r eq ui r e t h e a d di t io n o f a m i s c ib le l iq ui d o f hi gh e r (o r l o we r ) de ns i t y . Al t e ri ng t he c om p os it i on of s u s p e ns io n s is al so p ro b le m a t ic be c a u se m o st s o li d p a r ti c l e s a re de n s e r th an t h e d is pe r s i o n m e d iu m . A d d i ti v e s o f h ig h er ( o r l o we r ) d en s i t y m i g ht al t er t h e b io p ha rm a ce u ti c a l c h a ra c t e ri s ti c s o f th e f o r m u l at io n (e . g ., r at e o f d r u g r el e as e, r es id e nc e t i m e a t t he s i te o f a d m i ni s t ra ti o n , o r a bs o rpt i o n) . e . Th e se d im e n ta t i on , or f l o t at i o n, r a te is in v e rs e l y p r o po r ti o na l t o th e vi s c o s i t y. A n i n c r e as e in t he vi s c os i t y o f t h e d is p e r si o n m e di u m d e c re as es th e ra t e o f s ett l i ng , o r fl o ta t io n . H o we v e r , al t ho u gh th e ra t e o f d e st a bi li z a t io n c a n b e s lo we d b y a n i nc r ea se in v i s c os i t y , i t c a nn o t b e h a l te d . 3 . E mu l s io n s t a bi l i t y. C o a l es c en c e oc c ur s i n em u ls io n s ys te m s wh e n t he l i qu i d p a rt ic l es o f th e d is p e r s e d p ha s e m e r ge t o fo r m l a rg e r p a r ti cl es . C o a l esc e nc e is la r g el y pr e v e n t ed b y th e i n t e r fa ci a l f il m o f s u r fa ct a nt a r o un d th e d r op l et s . Th is f ilm p re v e n ts di r ec t c on t ac t of th e l i qu i d p ha se o f t h e d r o pl e ts . C o al es c e n c e o f d r op l et s i n o il in wa te r ( o / w) em u ls io ns is a ls o i n hi b it e d b y t he el e c t ro st a t i c re p u ls i on o f s i m i lar l y c ha r ge d pa r ti c l es . C r e a m i ng is th e re ve r s ib l e s e pa r at i on of a l a y e r o f em ul s i fi e d p a rt ic l es .
B e c au se m i xi n g o r s h ak in g m a y be s u f fi ci e nt t o re c on s t i tu t e t h e em u ls io n s ys t em , c r ea m i ng is no t n e c e s s a ri l y un ac c e p ta b le . H o we v e r , c ra c ki n g , or i r r e ve r s i b le p ha s e s ep ar a t i o n , is ne v e r ac c e p tab l e . P h as e i n ve r s i on , or e m ul si o n- t y p e r e v e rs a l, in v o l v e s t h e r e ve rs io n o f a n em ul si o n f r om a n o / w t o a wa t e r in oi l ( w/ o ) fo rm , or v i ce v e rs a . P h as e in ve r s io n c an c h an g e t he c o ns is te n c y o r te xt u r e o f t h e e m u ls io n o r c a us e fu r t h er de t e ri o ra t io n i n i t s s t ab i li t y .
V. CHEMICAL KINETICS AND DRUG STABILITY A. I n t r o d u c t io n . Th e s tab i l i t y o f t h e ac t i ve co mp o n e nt o f a d r u g is a m a jo r c r i te r io n i n t h e r a tio n al de s i g n a nd e val u at i o n of d ru g d os a ge fo r m s. P r o b le m s wi t h s t a bi l i t y c a n d et e rm i ne wh e t he r a g i v e n f o rm ul a ti o n is a cc e pt e d o r re j ec te d . 1 . E xt e n s i v e c h em ic a l d eg r a da t io n o f th e a c ti v e i ng r e di e nt ca n c au s e s u b s ta n t ia l lo s s o f ac t i ve i ng r ed i en t fr om t he dos a ge fo r m . 2 . C he m i c al d e g ra d at i on c an p ro d uc e a to x ic p ro d u c t t h at ha s u nd es i r ab l e s i de ef f ec ts . 3 . I ns ta b il it y o f th e d r ug p r o du c t c a n c au s e d ec r ea s e d b i oa va i l ab i l i t y. A s a r e s ul t , t he t he r ap e ut ic e ff i c a c y of t he do sa ge f o rm m a y b e su bs t an t ia l l y r e d uc ed . B . R a t es a nd o r de r s of r e a c t io n s 1 . Th e r a te o f a re a c ti on , o r d eg r a da t io n r a te , is t h e v el oc i t y wi t h wh ic h th e r e a ct i on oc c u rs . Th is r ate is e xp r e ss ed as d C/ d t ( t h e c ha n ge in c o nc en t r at i on , o r C , wi t hi n a g i v en ti m e in t e r val , o r d t ). a . R ea c ti o n r a te s d ep e nd o n c e r t ai n c on d it i on s (e . g . , r e ac t a nt c o n ce n t r a ti o n , t em p e r at u r e , p H, p r es e nc e o f so l ve n t s o r a dd i t i ve s ). R a d i at i on an d c at a l y ti c ag e n ts (e . g. , po l y va l en t ca t i on s ) a ls o h a ve a n e f f ec t . b . Th e ef f ec t i v e s tu d y of r e ac t io n ra t es i n th e b od y r e q ui r es ap pl ic a ti o n of p h a r ma c ok i n et i c p r i n cip l e s ( s e e C ha p te r 6 ) . 2 . Th e o rd e r o f a re a c tio n is th e wa y i n wh ic h t he co nc e n tr a ti o n o f t h e d ru g o r r ea c ta n t i n a c he m i c a l r e ac t io n a f fe c ts th e r a t e. Th e r a te of a r e ac ti o n, d C / d t , is p ro p or t io n al to t h e c on c en t ra t io n to th e n t h p o we r , wh e r e n is the o r d e r o f t h e r e ac ti o n— t ha t is ,
Th e s t ud y o f r e ac ti o n o rd e r s is a c ru c i a l as p ec t o f ph a rm ac ok i ne t ic s ( s ee C h a p te r 6 ). U s u al l y , ph ar m a c eu t i ca l de g r ad a t ion c an be t re a te d a s a z e r o - o rd e r , fi r s t - o rd e r , o r h i gh e r - o rd e r r ea c t ion . Th e fi r s t t wo a r e s um m a r i z e d as f ol lo ws . a . I n a z e r o- o r d e r re a ct io n , th e ra t e is in d e pe nd e n t o f t he c on c en t r a t io n o f t h e r e ac t a n ts (i . e ., dC / d t
0
C ) (s e e C h ap t e r 6 ) . O th e r f a ct o rs , s uc h a s
a b so r p ti on o f l ig h t in c e rt a i n p ho t oc he m i c a l re ac ti o ns , d e te r m i n e t he r at e . P.43
Figure 3-6. Concentration (C) versus time (t) for a zero-order reaction. The slope of the line equals -k0. The slope of the line is not equal to the rate constant because it includes the minus sign.
( 1 ) A z e r o -o r d e r re a c ti on c an be e xp r e s s ed as : C = -k0t + C0 wh e r e C is t he d ru g c on c e n t r at i on , k 0 i s t he ze r o -o r d e r r a te co ns t an t i n u n i ts o f c o nc en t r at i on / tim e , t is th e t im e , a nd C 0 i s t h e in i ti a l c o nc e n tr a tio n . ( 2 ) W hen t h is e q ua t io n is pl o t te d wi t h C on t he ve r t ic al a xi s ( or d in a te ) a g ai n st t o n t h e h o ri z o n ta l a xi s (a bs ci ss a ), t he slo p e of t he l in e is eq u a l t o - k 0 ( F ig u re 3 -6 ) . Th e n e g at i v e s ig n i n di c a t es th a t th e s lo pe is d e c re as in g . b . I n a fi r s t - o r de r r ea c t io n , th e ra t e de p en d s o n t h e fi r s t pow e r o f t h e c o n ce n t r a ti o n o f a s in gl e r e ac t an t ( i. e ., d C /d t
1
C ).
( 1 ) I n a f i rs t - o rd e r r e ac tio n , d ru g c o n ce n t r at i o n d e c r ea s es ex p on e n ti a l ly w i t h t i me , i n a c c o rd a nc e wi t h t he eq ua t io n C = C0e
-k t 1
wh e r e C is t he c o nc en t r at i o n o f t h e r ea c ti ng m a t er i a l, C 0 i s t h e i ni ti a l c o nc en t r at i on , k 1 i s t he fi r s t -o r de r r at e c on s ta n t in u ni ts o f r ec ip r oc a l t im e, a n d t is ti m e . A p lo t o f the l og a ri t hm of c o nc en t r ati o n a ga i ns t t im e p r o du ces a s tr a ig h t l in e wi t h a s lop e of -k / 2 .3 0 3 ( Fi g u re 3 -7 ) . ( 2 ) Th e ha l f - li f e (t 1 / 2 ) o f a r e ac ti o n is th e ti m e req u i re d fo r th e c o nc en t r at i on of a d r ug to d ec r ea s e b y o n e h al f . F o r a f i rs t -o r de r r ea ct i on, h a l f- l if e i s e xp r e s s e d b y :
( 3 ) Th e t im e re q u i re d for a d r u g t o d e g r ad e t o 90 % of it s o r ig i na l c o nc en t r at i on ( t 9 0 % ) is als o i m p o r ta n t. Th i s t im e re p r es en t s a re as o na bl e l i m i t o f d e g ra da t io n fo r th e ac ti ve in g r ed ie n ts . The t 9 0 % c an be ca lc ul a te d as:
( a ) B ec au s e k 1 = 0 .6 9 3 / t ½ ( b ) Th e n
P.44
Figure 3-7. Logarithm of concentration (log C) versus time (t) for a first-order reaction. The slope of the line equals -k/2.303.
( 4 ) B o th t ½ an d t 9 0 % a re c o n ce n t r a ti o n i n de p e nd e n t . Th us , f o r t ½ , i t t ak e s t h e s am e a m o u nt of t im e t o re d uc e t h e c o nc e nt r at i o n o f t h e d ru g fr om 1 00 m M t o 5 0 m M a s it do es f r o m 5 0 m M t o 25 m M. C . F a ct o r s th a t a f f ec t re a c t io n r at e s. F ac to r s ot h e r t h an c o nc en t r at i on c a n a f f ec t t h e r e ac ti o n r a te an d s t ab i li t y o f a d r ug . The s e f ac t o rs i nc l ud e t e m p e r at u re , th e p r es e nc e o f a so l v e nt , p H, an d t h e p r es e nc e o f a dd i ti ves . 1 . T em pe r a t u r e. A n i n c re a s e i n t e mp e r a tu r e c au s es a n i n c r e as e i n r e a ct i on ra t e , as e xp r e s s e d in th e e q ua t io n f i rs t s u g g es te d b y A r r h en iu s : k = Ae
-Ea/RT
or
wh e r e k i s t h e s p ec i fi c re a c t i on r at e c on s ta n t, A i s a c o ns t an t k no wn a s th e f r e q ue nc y f ac t or , E a is th e en e rg y o f a c ti v a t io n , R i s t h e m o l a r g as c on s ta n t ( 1 . 9 87 c a l/ d eg r ee × m ol e) , a nd T i s t he ab so l ut e te m pe r a tu r e. a . Th e co n s ta n ts A an d E a a re o bt ai n ed b y de t erm i ni ng k a t s e ve ra l t e m p e r at u re s a n d t he n pl o t ti n g l og k ag a in st 1 /T . Th e s lo pe o f t he r es ul t in g l i ne eq u al s - E a / (2 . 30 3 × R ) . Th e in t e rc ep t on th e v e r t i c a l a xi s e qu a ls l o g A . b . Th e ac ti v a t io n e n e rg y ( E a ) is th e a m o u nt of ene r g y r eq u i re d t o p u t t h e m o le cu l es i n a n a c t i va ted s t a te . Mo l ec u le s m u s t b e ac ti v a t ed t o r e ac t. A s
t e m p e ra t u r e i nc r e as e s , m o re m o le c u l es a r e a c t iv a t e d , a nd t he r ea c t io n r a t e i nc r e as es . 2 . P r es e nc e of s ol ve n t . Ma n y d o s a ge fo r m s re qu i r e t h e in c or p o ra t io n o f a wa t e r - m is c i b le s o l v en t —f o r e xa m pl e , l o w m ol ec ula r we i g h t a lc oh ol s , su c h a s th e p ol y e t h y le n e g l y c o l s ( P E G s ) —t o s t ab il i ze t h e d r u g. a . A c h an ge in t he s o l ven t s ys t em al t e r s t he t ra ns i ti o n s ta t e a nd th e a c t i vi t y c o e f f i c ie n ts o f t h e re ac t an t m ol e cu le s . It c an al so c a us e s im u lt a ne o us c ha n ge s i n p h y s i c o c he m i c a l p a ra m e t e rs , s uc h a s p K a , su r f ac e t e ns i on , a n d v i s c os i t y . Th e s e c h an g es in d i r ec t l y a f f ec t t he r ea c t io n r a te. b . I n so m e c a s e s , a dd i t io n a l re a c ti o n p a thw a ys a r e g e ne r at e d. F o r e xa m p l e , wi t h a n in c re as i n g c on ce n t ra t io n o f e t han o l i n a n a qu e ou s s o lu t io n , as p i ri n d eg r a des b y an e xt r a r ou t e a nd fo r m s th e et h y l e st e r o f a c et yl sa l ic y l ic a c i d . Ho we v e r , a c ha n g e i n s o l ven t c an a ls o s t a bi l iz e the drug. P.45
3 . C h an g e i n p H . Th e m a g ni t ud e of th e ra t e o f a h y d r o l yt ic re ac t io n +
-
c a ta l yze d b y H a n d O H c an v a r y co ns i de r ab l y wi t h p H . +
-
a . H ca t a l ys i s p r e do m in a t es a t low e r p H , wh e re a s O H ca t a l ys i s o p e rat e s a t h ig h e r p H . A t i n te r me d i a te p H , t he r at e m a y b e p H i n de p e nd e n t o r m a y +
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b e c a ta l y z e d b y b o t h H a n d O H . R a te c o ns t an ts i n t h e i nt e rm e di a te p H r a n ge a re t y pi c al l y l es s th a n t h os e a t h ig h e r o r l owe r p H . b . To d et e rm i ne th e e f f ec t o f p H o n d e g ra d a ti on k i ne t i cs , d ec om p os it i on +
i s m ea s u r e d a t s e v e ra l H c o nc en t r at io n s. Th e p H o f o p ti m um st a b il i t y c a n b e de t e rm in ed b y pl o tt i ng t he lo g a ri t hm o f th e r a te c o ns t a nt (k ) as a f u nc t io n o f p H ( F ig u re 3 -8 ) . Th e po i n t o f in f l ec t io n o f t he pl o t is t he p H o f o p t im um s t ab il i t y . Th is va l ue is us ef u l i n t he de v e l op m en t o f a s t a bl e d r ug f o r m u l at io n . 4 . P r es e nc e of a dd i t i ves a . B u f fe r s al t s m us t b e a d d ed to m a n y dr u g so l ut i o ns to m a in t ai n t h e f o r m u l at io n at op t im um pH . Th e s e sa l ts ca n a f f ect t h e ra t e o f de g r a da t i on , p r i m a r il y as a r e s u lt o f s a l t i nc r e as in g t h e i on ic st r e n gt h . ( 1 ) I nc r ea s i ng s a l t c o nc en t r a ti o ns , p a rt ic u la r l y f rom po l y e le c t r o l y te s ( e .g . , c i t ra t e, ph os p ha t e ), c a n s u b s ta n t ia l l y a f f e c t t h e m a gn i t u de o f p K a . I n t hi s wa y, t h e y c h an ge t he ra te c o ns t a nt . ( 2 ) B u ff e r s al ts c a n a ls o p r o m o te d r u g d eg r a da t io n t h ro ug h g e ne r al ac id o r b as e c a t al y s is . b . Th e ad d i t io n o f su r f ac t a n ts m a y ac c e l e ra t e or d ec e le r at e d r u g d e g ra d at i on . ( 1 ) Ac c e l e ra t i on o f d e gr a d a t io n is c om m o n a nd i s c au s e d b y m i ce l la r c a ta l ysi s . ( 2 ) S t ab i l iz a ti o n o f a d ru g t h ro ug h th e a dd i ti o n o f a s ur f ac t an t i s l es s c om m o n .
c . C om p le x i ng ag e n ts c a n im p ro v e dr u g s ta b il it y. A r om a ti c e s t e rs ( e. g ., b e n zoc a in e , p r oc ai ne , tet r a c a i ne ) in c r ea s e i n h al f - l i f e i n t he p re s e nc e o f c a f fe in e . Thi s i nc r ea s ed s t ab i li t y ap p ea r s t o r es u l t f r om th e f o rm a ti o n o f a l e ss re ac t i v e c om pl e x b et we e n t h e a ro m a t ic es te r a n d t he c a f fe i ne . D . M od e s o f ph a r ma c eut i c a l d e g ra d a ti o n. Th e d e c o m p os i ti o n o f a c t i v e i n g re d ie n ts i n a do s a g e fo r m o c c u rs th r ou g h s e v e r a l p a t h wa ys (e . g. , h yd r o l ys i s , o xi d a ti o n, pho t o l ys is ; s e e C h ap t e r 1 2, I I . A ) . 1 . H yd r o l ys i s i s t he m o s t c om m o n t yp e o f d e g ra da t i on be c a us e m an y m e di ci n al c om p ou nd s a re es t e rs , a m i d es , o r l ac ta m s . +
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a . H an d O H a r e t h e m o s t c om m o n c a t al y s ts o f h yd r o l y t ic d e g ra da t io n i n s o lu t io n . b . E s te r s u s ua ll y u nd e r go h y d r ol y t ic r ea c t i on s t ha t c a us e d r ug in s ta bi l it y . B e c au se es t er s a r e r a pid l y d eg r ad e d i n a qu e ou s s ol u ti o n, f or m u l at o rs a re r e l uc t an t t o i nc o r po r a te d r u gs th a t h a v e e s t e r f un c ti o na l g r ou ps in t o l iq u id d o sa g e f o rm s .
Figure 3-8. Semilogarithmic plot of the rate constant (k) versus pH. This plot is used to determine the pH of optimum stability.
P.46
2 . O x i da t i on is u s u a ll y m e di a te d t h r ou gh r ea c ti on wi t h a tm os ph e ri c o xyg e n u n d er am bi e nt c o n di ti o ns ( au t o -o xi d a t io n ) . a . Me d i c i n al c om p ou n ds t h a t u nd e r go au t o -o xi d a ti o n a t ro om te m p e r at u r e a r e af f ec te d b y o x yg e n d i s so l ve d in t he s ol ve nt a n d i n t he he a d sp ac e o f t h e ir p ac k a ge s . Th e s e c o m po u nd s sh o ul d b e p ack e d i n a n i n e r t a t m o sp h e re ( e. g . , ni t r oge n ) to e xc l ud e a i r f r om th e i r c on t ai ne r s. b . Mo s t o xi d a ti o n r e ac ti on s i n v o l ve a f re e r ad i ca l m e ch a ni s m a nd a c h ain r e a c t io n . F r e e r ad ic a ls te n d t o ta k e el ec t r on s f r om o th e r c om po un ds . ( 1 ) An t i o x id a n ts in t he fo r m ul a ti on r ea ct wi t h th e f r e e r a di ca ls b y p r o vi di ng e l ec t r on s a nd ea s i l y a v ail a bl e h yd r o ge n a t om s . In t h is wa y , t h e y p r e v e nt th e p r o pa g at i on of c h ai n re ac t io ns .
( 2 ) C o mm o nl y u s e d a n ti o x i da n t s in cl u de as co rb i c ac i d, bu t y l a te d h yd r o xya n i s o le ( B H A ), bu t y l a te d h y d r o xy t o l u e ne ( B H T) , p r o p y l g al l at e , s o di um bi s u l fi t e, s o di um s u lf i te , a n d t h e t oc op h e ro l s . 3 . P h ot o l ys i s i s th e de gr a d a ti on o f d ru g m ol ec u le s b y n o rm al su nl i gh t o r r o o m li g ht . a . Mo l e c u l es m a y ab s o r b t h e p r op e r wa v e l en g th of l ig h t a nd ac q u i re s u f f i ci e n t e ne r g y t o u nd e r g o re a c ti o n . U su a ll y, p h ot o l y ti c d eg r a da t io n o cc u rs on e xp o s ur e to lig h t o f wa v e l e ng t hs < 400 nm . b . A n a m be r g la ss b o tt le o r a n o p a qu e c o n ta i ne r a c t s a s a b a r ri e r t o t hi s l i gh t , t h e re b y p re v e n ti ng o r r et a rd i ng ph o to l ys i s . F o r e xa m pl e , s od iu m n i t ro p r us s i de in aq u eo us s ol u ti o n h as a s h el f li f e o f on l y 4 h r i f e xp o s e d t o n o r m a l r o om l i gh t . W hen p r o te c t e d f r om li gh t , t h e s ol u ti o n is st a bl e f o r a t l e as t 1 y e a r. E . D e t e rm i n at i o n o f s h el f l i fe . Th e s he l f l if e o f a d r u g p re p a ra t io n i s t he a m ou n t o f t im e t h at t he p r o du c t ca n b e s t o re d b ef o r e i t b ec om e s u nf i t f o r u s e, t hr o ug h e i th e r c he m i c al de co m p os i ti o n o r p hy s i ca l d e te r i or a ti o n. 1 . S t o ra g e t e mp e r a tu r e a f f ec ts s h el f l i fe . It is gen e r al l y un d e rs to o d t o b e a m bi e nt te m p e r at u r e u nle s s s p ec i al s t o ra ge c o n di t i o n s a r e s p ec i fi e d. 2 . I n g en e r a l, a p r e pa r at i o n is co n s id e r ed f i t f or u s e i f i t va r i e s f r o m th e n o m i na l c o nc e n t ra t i o n o r d o se b y n o m o r e t h an 1 0 %, p r o vi d e d t h at t he d e co m p os i ti o n p ro d uc ts a r e no t m o re to xi c o r h a rm f ul t ha n t h e o ri g in al m a te r i al . 3 . S he l f - l if e te s t in g a i ds in de t e rm in i ng th e s ta nd a r d s he l f li f e o f a f o r m u l at io n . a . Sa m p l es a r e s t o re d a t 3 - 5 ° C a n d a t r oo m t em p er a tu r e (2 02 5 ° C ) . Th e s a m p l es ar e t h e n a na l yz e d a t v a ri o us i n te r va ls to de t e rm in e th e r a t e o f d ec o mp o s it i o n. S h e l f li f e i s c a lc u la t ed f ro m th is ra t e . b . B ec a us e s t o r ag e t im e a t th es e t e m p e ra t u re s ca n r es ul t i n a n e xt e n d e d t e s ti ng ti m e, ac c el e r a ted t e s ti n g i s c o n du ct e d as we l l , wi t h a ra n ge of h i gh e r te m p e ra t u re s . Th e r a t e c o ns t an t s o b ta i ne d f ro m t he s e s a m p l es ar e u s ed to p re d ic t s he l f li f e a t am bi e nt o r r e f ri ge r a ti on t em pe r a tu r es . T e m pe r a t u re - a cc e le r a t ed s t ab i l i t y t e s t i n g is n o t u se f ul if t em pe r a tu r e c h an g es a r e a c c om pa n ied b y c h a ng es in th e re act i o n m e c h a ni s m o r b y p h ys ic al c h an g es i n th e s y s t em (e . g. , c h an g e f r om t he s o li d t o t h e l iq ui d p h as e ) . c . S ta b i li t y a t r o o m te mp e r a t u re c a n b e p r ed ic te d f ro m a cc el e ra t ed te s tin g d a t a b y t he A r rh e ni us equ a t io n :
wh e r e k T 2 an d k T 1 a re the r a te c o ns t an ts at t he ab s ol u te te m p e r at u r es T 2 a n d T 1 , re s p ec t i v el y ; R is t he m o la r g a s co ns t an t; a nd E a is t he en e rg y o f a c ti va t io n . d . A l te r na t i v el y , an e xp r e s s i on of co nc e nt r a ti on c a n b e p lo t te d a s a li ne ar f u nc t io n o f ti m e . R at e c on s ta n ts (k ) fo r de g ra d at io n at se v e r al t em pe r at u re s a r e ob t ai ne d . Th e l og a ri th m o f th e ra t e co ns t an t (l o g k ) i s p lo t te d a g ai ns t
t h e re ci p ro c al o f ab s o l ute t em pe r a tu r e (1 / T ) t o ob t a in , b y e xt r a p o la t io n , th e r a t e c on s ta n t f o r d eg r ada t i on at r oo m t em pe r a tu re ( F ig u re 3 -9 ) . e . Th e le n g th o f t i me t ha t t h e d r u g w i l l m a in t a in i t s re q ui r e d p o t en c y c a n a ls o b e p r ed ic t ed b y c al c u l at i on of t he t 9 0 % ( se e V . B. 2 .b . ( 3 ) ). Th is m e th o d a pp li e s t o c h e m ic a l r e ac ti o ns wi t h a c t i v a ti o n e ne r g ie s o f 1 0 -3 0 k ca l /m ol , th e m ag n it u de o f t he ac ti v a t io n e n e rg y fo r m a n y ph a rm ac e ut ic a l d e g ra d at i on s t ha t oc c u r in s o l ut i on . P.47
Figure 3-9. Semilogarithmic plot of the rate constant (k) versus the reciprocal of absolute temperature (1/T), showing the temperature dependency of degradation rates.
VI. DRUG DOSAGE FORMS AND DELIVERY SYSTEMS A. O r a l s o l u t io n s. Th e U n i t e d St a t es P ha r m aco p e ia ( U S P ) 3 1 / Na t i o nal F o r m u la r y ( N F) 26 c a t eg o r i z es o ra l so l u ti o n s as “ li qu i d p r ep a ra t io ns , i n t en de d fo r or a l a dm in is t r a t io n , t ha t c o nt a in on e o r m o r e s ub s t a nc es wi t h o r wi t h o ut fl a v o r in g , s we e t e ni ng , o r co l or i ng ag en t s d is so l ve d in wa t e r o r c os o l ven t - wa t e r m i xt u r e s . ” O r a l s ol u ti on s c an c o nt a i n c e r t ai n p o l yol s ( e .g ., s o r bi t ol , g l y c e r in ) to in h ib i t c r y s ta ll i za ti o n a nd to m o di f y so lu b il i t y, t as t e, m o ut h fe el , an d o t he r v eh i c l e p r op e r ti es . Th e y c an b e “ f o rm ul a te d f o r d i rec t o r a l a dm in is t r at i on to t he p at i en t o r th e y m a y b e d i s p e ns ed in a m o r e c o nc en t r at e d f o rm th a t m us t be di lu t ed p ri o r t o a d m i ni s t ra ti o n .” D r u gs in s o l u t io n a r e m o re ho m og e n eo us an d e as i er t o s wa l l o w t h a n d r u gs i n s ol id f o r m . F or d ru gs t ha t h a ve a s lo w d i s s o lu ti o n r a te, o ns e t o f a c t i on an d b i oa va i la b il it y a r e a ls o im p r o v ed . Ho we ve r , d r ugs i n s o lu t io n a r e b u lk ie r d o sa g e f o rm s , de g ra d e m o r e r ap i dl y , an d a r e m o r e l i k e l y to in t e ra c t wi t h c o ns ti t ue n ts th a n t ho s e in s o l id fo r m . 1 . Wa t e r i s t h e m os t com m o nl y u s e d ve h i cl e for d r ug s o lu t io ns . Th e U SP r e c og ni z e s s e v en t y p es o f wa t e r fo r th e p r ep a r at io n of do s a g e f o rm s :
a . P u r i fi e d w a t e r U S P is wa t e r o b ta in e d b y di s ti lla t i on , i o n e xc h a ng e , r e v e r s e os m o s i s , o r o t her s ui t ab l e t r ea tm e nt . It c a n n ot c o nt a in m o r e t ha n 1 0 pa r ts pe r m i ll io n (p pm ) o f to t al s o li d a nd s h ou l d h a ve a p H b et we e n 5 a n d 7 . Pu r i fi ed wa t e r is u s ed in p re s c r ip ti o ns and f in is h ed m a nu f ac tu r e d p r o du c ts e xc e p t pa r en t e ra l an d o p ht h al m i c p ro d uc t s . b . W at e r f o r i n je c t io n US P i s wa t e r ob t ai n ed b y d i st i ll a ti on o r b y r e ve rs e o sm o si s . I t c o n fo r m s to th e s t an d a rd s o f p u ri f ie d wa t e r b u t i s al s o f r ee of p yr o g en . W at e r f o r i nj ec ti o n i s us e d as a s ol v e n t f o r th e p r e pa r a ti on o f p a r en t e ra l s ol u ti o ns . c . S te r i l e w a t e r fo r i nj ec t i o n U SP is wa t e r fo r i nj e ct i on th a t i s s t e r il i z ed a n d p ac k a g ed in s i ng le -d o s e c o n ta in e rs of t y p e I a n d I I g l as s . Th es e c o nt a in e rs do no t e xc e e d a c ap a c i t y of 1 L . Th e li m it a ti o ns f o r to t al s o li ds d e p en d o n t h e s i z e o f t he c o n ta i ne r . d . B a ct e r i os t a t ic w a te r f o r i n je c t io n U S P i s s te ri l e wa t e r f o r i nj ec t io n t h at c o nt a in s o ne o r m o r e s uit a b le an t im ic r ob ia l a g en ts . It is al s o pa c k ag e d i n s i ng le - o r m u l ti p le - do s e c o nt a in e rs of t y p e I o r I I g l as s . Th e s e c o nt a in e rs d o n o t e xc e e d th e c ap ac i t y o f 30 m L . e . S t e ri l e w at e r f o r i n hal a t i o n U S P is wa t e r t h at i s p u ri f ie d b y d is t il la t io n o r b y r e v e rs e os m o s i s (i .e . , wa t e r f o r i nj e c t i on ) an d r en de r e d s te r il e . I t c o nt a in s n o a nt im ic r o bi al a g en ts , e xc e pt wh e n us e d in hu m i di f ie r s o r s im ila r d e vi ce s. Th i s t y p e o f wa te r s h o ul d n o t b e us e d f or p a re n te r a l a dm in is t ra t io n o r f o r o th e r s te r il e do s a ge f o rm s . f . S t e r il e w a te r f o r i r r i ga t i o n U SP is wa t e r fo r i nj e c t i on th a t i s s t e r il i zed a n d s ui t ab l y pa c k ag e d. It c on t ai ns no an t im ic r ob ia l ag en t s o r o t he r ad d ed s u bs ta n c e . P.48
g . S t e r il e p u r i f ie d w a ter U S P i s p u ri fi e d wa t e r st e r il i ze d a nd s u i ta bl y p a ck ag e d. I t c o n ta i ns n o a n ti m i c ro bi a l a ge n t. I t i s n o t i nt e nd e d f o r u s e i n p a r en t e ra ls . 2 . O r a l d r u g s o l ut i o ns in c lu d e s yr u p s a nd e li x i rs as we l l a s o t he r le s s wi d e l y p r es c ri be d c la s s ic ( g a le n i ca l ) f o rm ul a ti o ns, s uc h as a r om a t ic w a te r s , ti n c tu r e s, f l ui de x t r a ct s , a nd s pi r i t s. a . S yr u p s a r e t r a di ti o na ll y p e r or a l so l ut i on s t ha t c o nt a in hi g h c o nc en t r at i on s o f s uc r os e o r o t he r s u ga r s . Th r o ug h c om m o n us ag e , t he t e r m s y r up ha s a ls o c om e t o i nc lu d e a n y o t he r li qu i d d os a ge fo r m p r ep a red i n a s we e t , v i s c ou s v eh ic l e , i nc l ud in g p e r or a l s us p e ns i on s. ( 1 ) S yr u p N F ( s i mp l e s yr u p ) is a co nc e nt r a te d o r n e a rl y s a t u ra t ed aq u eo us s o lu t io n o f s ug a r (8 5% ; 6 5 % w/ w) . ( 2 ) S yr u ps ha v e a l ow so l ve n t ca p ac i t y f o r w a te r - s o lu b l e d r u gs be c a us e t h e h yd r o ge n b o nd in g b et we e n s uc ro s e a nd wa t e r i s v er y s t ro n g. Fo r t hi s r e a so n , i t c a n be di f fi c u l t o r im po s s ib l e t o d iss o l ve a d r u g i n a s yr u p. O f t en , t h e d r u g is be s t di s s o l v ed i n a s m a ll qu a nt i t y of wa t e r , a nd t he fl a v o ri n g s yr u p i s a dd e d.
( 3 ) Th e su c r os e c o n ce nt r a t i o n o f s yr u p p la y s a c r uc i al ro l e i n t he co n tr ol o f m i cr o bi al g ro wt h . D i lut e s u c ro s e s o lu t io ns a re e xc e l l e nt m e di a f o r m ic r o or g an is m s . As th e c o nc en t r at i on of s u c ro s e a p p ro ac he s s at u r at i on , th e s yr u p b ec om e s s e l f -p r es e r v i n g ( i .e . , re qu i r es n o a d di t io n al p re s e r v a t i v e) . H o we ve r , a s a t u ra t ed s o lu t i on is u n de s i r ab l e b ec a u s e te m p e r at u r e f l uc t ua t io ns m a y c a us e c r y s t a ll i za ti o n. S yr u p N F i s a s e l fp r es e r ved s o lu t io n wi t h a m i ni m a l te nd e nc y t o un d e rg o c r y st a ll i z a ti on . b . E l ix i r s a r e t r ad i ti o na lly p e r o ra l s ol u ti o ns th a t c o n t ai n a lc o ho l a s a c os o l ven t . Ma n y p e ro r al s o lu t io ns a re no t d es c ri be d as e l i xi r s b u t c on t ai n a l co h ol . ( 1 ) To b e c o ns i de r ed an e l i xi r , t he s o lu t io n m u st c o n t ai n al c oh o l . Tr a d i t io n al l y , th e a lc oh o l c on t en t of el i xi r s ha s v ar i e d f r om 5% to 40 % . Mo s t e l i xi r s b e c o m e tu r bi d wh e n m o de r a te l y di lu t ed b y a q ue o us l i qu id s . E li xi r s a r e no t t h e p r ef e r re d v ehi c le fo r s a lt s b ec a us e a lc o h ol ac c e n tu a te s s al in e t a s te . Sa l ts a ls o h a v e l im i te d s ol u bi li t y i n a lc oh ol . Th e r ef o r e, th e a lc o ho l ic c o nt e nt o f s a l t -c on t ai n ing e li xi r s m u s t be lo w. ( 2 ) Ar o m a t i c e l ix i r N F, p r e pa r e d i n p ar t f ro m s y ru p , c on t ai ns ap p r o xi m ate l y 2 2 % a lc o ho l. Th e li m i t ed u s e f ul n es s o f t hi s e li xi r a s a s o l v e nt fo r d ru gs wa s o f f se t b y t h e d e v el op m en t o f i so - a lc o h ol i c e l ix ir . I t i s a c om b in a ti o n o f l ow -a l co h o li c e l i xi r , an e l i xi r wi t h lo w a l c oh ol ic c o nt e nt ( 8% - 1 0% al c o h o l) , a n d h i g h -a l co h ol i c e l ix ir , a n e li xi r wi t h h i gh al c oh o li c c on t en t (7 3 %- 7 8% a l co h ol ) . Mi xi n g a pp r o pr ia t e v ol um es o f t he t wo el i xi r s p ro v i d es a n a lc o ho li c c o nt e nt s u f fi c i e nt t o di s s o l v e th e d r u gs . B . M is c el l a ne o us so l u t io n s 1 . Ar o m a t i c w a t e rs a re c l ea r , s a t u ra t e d a qu e o us s o lu t i on s o f vo l a t il e o i l s o r ot h er a ro m a t ic or v o l a ti l e s u bs t an ce s . A r om a ti c wa t e rs m a y be us ed a s p l ea s a n tl y f la v o r e d v eh i c l es fo r a wa t e r - s o l ub le d r ug or as an aq u eo us p h as e i n a n e m u ls i on or s us p en s i o n. I f a l a r ge am o u n t o f wa t e r -s ol u bl e dr u g i s a d de d t o a n a r om a ti c wa t e r , t h en an in s o lu b le l a y e r m a y f or m a t t h e t op . Th i s “s a lt i n g o u t” is a c o m pe t it i v e p r oc es s . Th e m o le cu l es o f wa t e r -s ol u bl e d r u gs ha v e m o r e a tt r ac t io n fo r th e s ol ve n t m ol ec u l es of wa t e r th a n t he “ oi l ” m o le cu l es . Th e as s o c i a te d wa t e r m ol ec u le s a r e p u ll e d a wa y f r o m t he oi l m o le cu l es , wh i c h a r e n o l o ng e r h e ld in s o lu t io n . A r o m at ic wa t e rs s h ou l d b e s t o re d i n t i gh t , l ig h t - re s is t an t bo t tl es t o r ed uc e vo l a ti li z a t io n a n d d e g ra d at i on f ro m s un li g ht . A r om a ti c wa t e r s a r e us u al l y p re pa r e d b y on e of t h e fo ll o wi n g m et h od s : a . D i s ti l la t i o n is a u ni v er s a l m e t ho d b u t is n ot p ra c ti ca l o r ec on om ic a l f o r m os t pr o du c ts . I t i s t h e on l y m e t ho d , h o we v e r , fo r p r e pa r in g s t ro n g r os e wa t e r a n d o r an ge f lo we r wa t e r . b . W ith t h e s o lu t i on me th o d , t h e v o l a ti le , o r a rom a ti c , su bs t an c e is a d m i xe d wi t h wa t e r , wi t h o r wi t h ou t th e u s e of a d i s p e rs an t ( e. g ., t al c) . 2 . S p i ri t s , o r e s se n ce s , a r e al c o ho l ic o r h yd ro al c o h ol ic s o lu t io n s o f vo l at i le s u bs ta n c e s , th a t c on t ai n 5 0 % -9 0% al c o h ol . Th is h i g h a l co h o li c c o n te n t m a in t ai ns th e wa t e r -i ns ol u bl e v ol a ti l e o il s i n so l u t i o n. I f wa t e r is ad de d to a s p i ri t , t he oi ls s e pa r a te . S o m e sp i ri t s a r e m ed i cin a l (e . g ., a ro m a t ic
a m m o ni a s pi r i t) . Ma n y s p i r it s (e . g. , c om p ou nd o ra n g e s p i ri t , c om po u nd c a r da m o m s p i ri t ) ar e u s ed as f la v o r in g a g en ts . Spi r i ts s h ou l d b e st o r ed in t i g ht co n ta in e rs to r ed uc e l os s b y e v ap o ra t io n . 3 . T in c t u re s a r e a lc o ho lic o r h y d r oa lc o ho li c s ol u ti o ns of ch em i c al s o r s o lu bl e c o ns ti t ue n ts of ve g e ta bl e dr u gs . Al t ho ugh t in c tu r es v a r y in dr u g c o nc en t r at i on ( ≤ 5 0 % ), th o s e p re pa r e d f r om p o ten t d ru gs a re us ua ll y 1 0 % i n s t r en g th ( i. e ., 1 00 m L o f t h e ti nc t ur e h a s t he ac ti vi t y o f 1 0 g of t he d ru g ). Ti n c t u re s a r e us u al l y c on s id e re d s t ab le . Th e a lc o h o l c o n te n t o f t h e o f fi cia l t i nc t u re s v a r i es fr om 1 7% t o 2 1% f or op i um ti nc tu r e U S P a n d f r om 7 4 % to 8 0 % f o r c om po u nd be n zo i n t i nc tu r e U S P. Mo s t tin c tu r es a re p re pa r e d b y a n e x t r a ct i o n p r o ce ss o f P.49 m ac e r at i on or p er c o l at i on . Th e s e le c t i on of a s o lve n t , o r m en s tr u um , i s b a se d o n t h e s ol ub i li t y of t h e ac t i v e a nd in e r t c o ns t i tu en t s o f t h e c ru de d r u gs . Ag i ng c a n c a us e p r e c i pi t a ti on o f t he in ac t iv e c on s ti t ue n ts o f t i nc t u re s . G l y c er i n m a y be a dd e d t o t he h yd ro a lc oh o li c s ol v e n t t o i nc r ea se t h e s ol u bi li t y o f t h e ac t i ve c o ns t i tu en t an d re du ce p r ec i pi t at io n on s t o ra ge. Ti n c t u re s m u s t b e t ig h tl y s t op pe r e d a nd k e pt f rom e xc e s s i ve t em p er a tu r es . B e c au se m a n y of th e i r c o n s t i tu e nt s u nd e r go a p ho t oc h em ic al c h an g e wh e n e xp o s e d to l i gh t , t i nc tu r es m u s t be s t o re d i n l i gh t -r e s is ta n t c on t ai ne r s . 4 . F lu i de x t r ac t s a r e l iq ui d e xt r a ct s o f v eg e ta b le d r u gs th a t c on t ai n a lc oho l a s a so l v e nt , p r es e r v a ti v e , o r b ot h . F l ui de xt r a c t s a r e pr e pa r ed b y p e r co la t io n s o t h at ea c h m i ll il i te r c o nt a in s t he t her a p eu t ic c o ns ti t ue n ts of 1 g o f t h e s t a nd a r d d ru g . B e c au s e of t he i r h ig h d ru g c o nt e nt , fl u id e xt r a c ts a r e s om e ti m e s re f er r e d t o a s “ 1 0 0% ti nc t u re s . ” Fl u id ext r a c t s of po t en t d ru gs ar e u s ua ll y 1 0 t im es as c o nc e n t r at e d, o r p ot e nt , as t he co r r es p on di n g t in c tu r e. F o r e xa m pl e , t he us u al do s e o f t i nc tu r e b el l ad o nna is 0 .6 m L ; t he e q ui va l en t do s e of th e m o r e po t en t f l ui d e xt r a ct is 0 . 06 m L . Ma n y f l u id e xt r a c ts a r e c on s i d er e d to o p o te n t f o r s el f -a dm i ni s t r a ti on b y pa t ie n ts , s o th e y a re al m o s t ne v e r p r es c ri be d . I n a d di t io n , m a n y fl ui d e xt r a c ts a r e s im p l y to o b i tt e r . To d a y , m os t fl u id e xt r a c ts a r e m o d i fi ed b y ei t he r fl a v o ri ng o r s we e te n in g a g en ts . 5 . N as a l , o p ht h a lm i c, ot i c , a n d p a r en t e r al so l ut i o n s a r e c l as si f ie d s e pa r a te l y be c a us e o f the i r s p ec if ic us e a nd m e th o d o f p r e pa r at i on . 6 . M o u t hw as h es ar e s olu t i on s t ha t ar e u s ed to c le a ns e t h e m ou t h o r t r ea t d i se as es o f t he o ra l m uc o u s m e m b r a ne . Th e y of te n c o nt a in al co h ol or g l yc e ri n t o a i d i n di s s o l v in g th e v ol a ti l e i ng r ed i e n ts . Mo u t h wa s he s a r e m o re o f t en us ed c o s m et ic a ll y th a n t h e ra pe u ti c a l l y. 7 . As t r i n g en t s a r e l oc al ly a p p li ed so l ut io n s t ha t p r e ci pi t a te pr o te i n. Th e y r e d uc e c el l p e rm ea b il i t y wi t h o u t c a us in g i nj u r y . As t r in g en ts c a us e c o n s t ri c t i on , wi t h wr i nk li n g a nd bl a nc hi n g o f t h e s k i n . Be ca us e a s t r i ng en ts r e d u ce se c r e t io n s, t he y c an be us e d as an t ip e rs p i r an t s .
a . Al u m i n um ac e ta t e a nd a l um i nu m s u ba c e ta t e s o l u ti o ns a re us ed as we t d r e ss in gs in c o nt ac t de rm a ti t is . Th e p r ec ip i ta ti o n i s m i n im i z ed b y th e a d di t io n o f bo r ic ac id . b . C a lc i um h yd r o x i d e so l u t i on is a m i ld s t r in g en t t ha t i s us e d i n l ot i on s a s a r e ac ta n t a nd an al k a l i ze r . 8 . An t i b a c te r i al t o pi c al s o l u t io n s ( e .g . , b en za lko n iu m c hl o ri d e, st r on g i o di n e, po v i d on e io di n e ) k i ll ba c t e ri a wh e n a pp l ied t o t h e s k in o r m u co u s m em b r an e i n t h e p r op e r s t r en g th an d u n de r ap p ro p r ia t e c on di t io ns . C . S u s pe n si o ns 1 . L o ti o ns , m a gm a s ( i .e. , s u s p e ns io ns of f in el y d i v i de d m a te r ia l i n a s m a l l a m ou n t o f wa t e r) , an d mi x t u r es a re al l s us pe ns io n s t ha t ha v e ha d o f fi c i al f o r m u l as f o r s om e t im e (e . g . , c a l am in e l o ti on U SP , k ao li n m i xt u r e wi t h p e ct i n N F ) . O ff ic i al fo r m u l as a re gi v e n i n t h e U SP / N F . a . A c o m pl e te f o r mu l a a n d a de t a il e d m e th o d o f p r e pa r a t io n a r e a va i la b le fo r s o m e of f ic ia l s us p en s i o ns . F o r o t her s , o n l y th e c o nc e n t ra t io n o f t he ac ti v e in g re d ie n ts i s g i v e n, an d th e m an u fac t u re r ha s c o n si de r a bl e l a t it u de in th e f o rm u la t ion . b . S om e d r ug s a r e p ac k a g e d in a d r y f o r m t o c i rc um ve n t t h e i ns ta b il i t y of a q u eo us di s p e rs io ns . W a t e r i s a dd e d a t t h e t im e o f di s p en s i n g t o r e c on s t i tu t e t h e s u s p e ns i o n . 2 . P u r po s es o f s us p e nsi o n a . S us t a in i n g e f fe c t . F or a s u s t ai n ed - r el e as e p re p a ra t io n , a s us p en si o n n e ce ss it a t es d r ug di s s olu t i on be f o re ab s o r p ti on . b . S t ab i l i t y. D r u g d e g rad a t io n i n s us pe ns i on or s o li d d os a ge fo r m s o cc ur s m uc h m o re s l o wl y t h an de g r ad a ti o n i n s o l ut i on for m . c . Ta s te . A d r ug wi t h an u n pl e as an t ta st e c a n b e c o n v e rt e d i nt o a n i n so lu b le fo r m a nd t he n p r e pa r e d as a s us pe ns i on . d . B a si c s o l ub i l it y. W he n s u it a bl e s ol ve n ts ar e n o t a va i la bl e , t h e s us p en s i o n p r o v id es an a l t er n a ti ve . F o r e xa m p l e, o n l y wa t e r c an be us ed a s a so l ve nt f or o ph t ha lm ic p r e pa r a ti o ns b ec a us e o f t h e p os si b il i t y o f c o rn e al d a m a g e. O p ht h al m i c s u s p e ns i on s p ro vi d e a n a lt er n a ti v e t o o ph t ha lm ic s o lu t io ns . 3 . S us p e nd i n g a ge n t s in c lu d e h y d ro p hi li c c ol l oid s , c la y s , a nd a f e w o t h er a g e nt s. S om e a r e a ls o us e d as em u l si f yi n g a g en t s (s e e V I . D .3 ) . a . H yd r o p h i l i c c o ll o i ds ( i . e ., h yd r o c o l l o i d s ) i nc r e a s e th e v is co s i t y o f wa t e r b y b in d in g wa t e r m o le c u l es , t hu s l im i ti ng th e i r m ob il i t y , o r fl ui d it y. V i sc os i t y is p r op o r ti o na l t o t he c o nc en t r at i on of th e h yd ro c o ll o id . Th es e a g e nt s s u pp o r t th e g row t h o f mi c r o o rg a n is ms a n d re qu i r e a p r es e r va tive . Th e y a r e m o s t l y an i o ni c, wi t h t he e xc e p ti on o f m e t h yl c el l ul os e P.50
( n e u tr a l ) a nd c h it os a n ( c a t i on ic ) . Th us th e a ni o nic h yd ro c o l lo id s a r e i n co m p a ti bl e wi t h q u at e rn a r y a nt i ba c t e ri a l a ge n ts a n d o th e r p os i ti ve l y c h a rg ed d ru gs . C hi t os an i s i nc om pa t ib l e wi t h ne ga t i ve l y c ha r g ed d ru gs and e xc i p i e nt s . Mo s t h y d ro c ol l oi ds a re i ns o lu b l e i n al c o h ol i c s o lu t i on s .
( 1 ) Ac a c i a is us ua l l y u s ed as a 3 5% di s p e rs i on in wa t e r ( m u ci l ag e ) . I ts vi s co si t y is g re a te s t b etwe e n p H 5 a nd p H 9 . Ac a c ia is s us c e p ti bl e to m ic r o bi al de c o m p os i ti o n. ( 2 ) T r ag a ca n t h is us ua l ly u s ed as a 6 % d is pe r s io n in wa t e r (m uc il a ge ) . O n e a d va n ta g e o f t r ag ac a nt h o v e r ac ac i a is t ha t l es s is ne e de d . A ls o , t r a g ac an t h d oe s n ot c o n ta i n t h e o xi d a s e th a t i s p re s en t i n a ca c i a . Th is o xi d a s e c a ta l y z e s t he dec om p os it i on of o rg a ni c ch e m i c a ls . Th e vis c os i t y o f t r a g ac an t h is g re a te s t a t p H 5 . ( 3 ) M e t h yl c e l l u l o se is a p ol y m e r t ha t i s n o ni on ic an d s t ab le t o h ea t a n d l i gh t . I t is a v a i la bl e i n s ev e r a l v is c o si t y g ra d es . Be c au s e it is s o lu bl e i n c ol d wa t e r , b u t n ot in ho t wa te r , di s p e rs io n s a re p re pa r e d b y a dd in g m e th y l c e ll ul os e to bo il i ng wa t e r a n d t he n c oo l in g t h e p re p a ra t io n u n ti l t h e m at e ri a l d i ss ol ve s . ( 4 ) C a r bo x ym e t h yl c e l l ul o s e i s a n a ni on ic m a t er ia l th a t is so l ub le in wa t er . P r o l on g ed e xp o s u r e t o he a t c au s es l os s o f vis c os i t y . b . C l a ys ( e . g . , be n to ni t e, V e eg um ) a re s i li c a t es th a t a r e a n io ni c i n a qu e ou s d i sp e rs io ns . Th e y a re s t ro n gl y h y d r a te d a n d e xh i b i t th i xo t r o p y ( t h e p r o pe r t y o f f o rm in g a ge l- l ik e s t r uc tu r e o n s ta n di ng a nd be c o m i n g f lu i d o n a g i ta t io n ). ( 1 ) Th e of f ic ia l f o rm of be n t o ni t e i s t h e 5 % m a gm a . ( 2 ) V ee g um is h y d ra t ed t o a g r ea t e r d eg r ee t ha n b e nt o ni t e. Th u s i t is m or e vi s co u s a t t he s a m e c o nc e nt r a ti o n. c . O t he r a ge n t s i nc lu de a g a r , c h o nd r us (c a r ra g ee n a n) , ge la t in , pe c t i n, an d g e la t in i z e d s ta r c h . Th ei r u s e is li m i t ed b y th e ir s us c e p ti b il i t y to ba ct e ri a l a t t ac k, t he i r i nc om pa t ib ili t i es , a nd t he i r co s t. Xa nt h a n g um i s u se d i n m any m o de r n s us pe ns i on fo r m u l a ti on s b ec a us e o f i ts c o s ol ve n t c om pa t ib il i t y, i ts s t ab i li t y, an d i ts s o lu t io n' s h ig h v is c o s i t y r el a ti v e t o c o nc e nt r a ti on . 4 . P r e pa r a t io n a . S o li d s a r e w et t e d i n it i a l l y t o s e p a ra t e i nd i vidu a l p a r ti c l es an d c oa t the m wi t h a la y e r of di s pe rs i on m e d iu m . W ett in g i s acc om p li sh e d b y l e vi ga t i on ( i . e ., ad d it i on of a s ui t abl e no ns ol v e n t , o r l e vi g a ti n g ag e n t, t o t he s o li d m a te r i al , f o ll o we d b y b l en d in g to fo r m a p a s t e ) , us i ng a g la s s m o r ta r a n d p e st l e o r a n o i nt m e n t s l ab . A s u r f ac t a n t c a n a ls o b e u s e d . b . S u sp e nd i n g a ge n t s ar e t he n a d de d a s d r y powd e r a l on g wi t h t h e ac t i ve i n g re d ie n t. Fo r be s t r es ul t s , t he s u s p en d in g a g ent i s a dd ed in t he fo r m o f i t s a q ue o us d is p e rs i o n. ( 1 ) Th e aq ue o us di s p e rs io n is a d de d t o th e s ol id (o r t he le vi g at e d s o l id ) b y g e o me t r i c d i lu t i o n. ( 2 ) Th e pr e pa r a ti on is b ro u g ht to t he de s i r ed v o lum e b y s ti r r in g i n t h e a p p ro p r ia t e v e h ic le . D . E m u ls i on s 1 . P u r po s es o f e mu l s ion s a . I nc r e as e d d r u g s o lub i l i t y. Ma n y d r u g s h a v e l i m i t ed aq ue o us s o lu bi l ity b u t h a ve m a xi m um s o lu bi l it y i n t h e o il ph as e o f an em u ls io n . D r u g
p a r ti t io n in g f r om t he oi l p h as e t o th e wa t e r p ha s e ca n m ai n ta i n o r e n ha nc e a c ti vi t y. b . I nc r e as e d d r u g s t ab il i t y. Ma n y d r u g s a r e m o re s ta bl e wh e n i n co r po r a te d i n to an em ul s io n r a t he r th an an aq ue o u s s o lu t io n . c . P r ol o n ge d d ru g a c t i on . I nc o rp o ra t io n o f a d rug i nt o a n e m u ls i on c a n p r o lo n g b io a v ai l ab i li t y , as wi t h c e r ta i n in t r am us c u l a r i n je ct i on p re pa r a ti o ns . d . I mp r o ve d ta s t e. D r ugs wi t h an un pl e as an t ta ste a r e m o r e p al a ta b le and t h us m o r e c on v e ni e nt l y a d m i ni s te r ed in em ul si o n f o rm . e . I mp r o ve d a p p ea r a nce . O i l y m a te r ia ls in t en d ed f o r t op ic a l a pp li c at io n a r e m o r e a pp ea l in g i n a n e m u l s i f ie d f o rm . 2 . P ha s es o f e mu l s io n s. Mo s t e m u ls io ns a re c on s id e re d tw o -p h as e s ys t e m s . a . Th e li q u id d r op l e t is k n o wn as th e d i s pe r s ed , i n t e r na l , o r d i s co n t i nu o us p ha s e. Th e ot h e r li q ui d i s k no wn a s th e d i sp e r s io n m e d iu m , e x te r n a l p ha se , o r c o nt i n uo u s p h as e . b . I n p ha r m a c e u ti c a l a p pl i c a t io ns , o n e p ha s e is us u al l y an aq u e ou s s o l u t io n . Th e o th e r p has e i s u s u al l y l ip i d o r oi ly. Th e l i pi ds r an ge f r om ve g e t ab l e o r h y d r oc a rb on o il s t o s em is ol id h yd roc a r bo ns an d wa xe s . E m u ls io ns a re us ua ll y de s c r i be d i n t e rm s o f wa te r a nd oi l. O i l is t he li pi d, o r n o n aq ue o us , p h as e, r ega r d le s s of it s c om po s i t ion . P.51
( 1 ) I f wa t e r is th e i n t e r na l p ha s e, th e e m u ls i on is cl as s i f ie d a s w / o . ( 2 ) I f wa t e r is th e e x t e rna l p ha s e, th e e m u ls i on is cl as s i f ie d a s o /w . c . Th e t yp e o f e m ul s i on f o rm e d is p ri m a r il y d e ter m i ne d b y t he r e la t i ve p h a se vo l u me s a nd t he e m u ls i f yi n g a g e n t us ed. ( 1 ) F or an id e al em ul s i on , t he m a xi m um c o nc en tr a t io n of in t e rn al ph as e is 7 4 % (i .e . , th eo r e ti c a ll y , a n o/ w e m ul si o n c an be p r e pa r e d c o n ta i ni ng ≤ 74% o i l ). ( 2 ) Th e c h oi c e of an em u l s i f y i ng ag e nt is m o re im p o rt a nt th a n t h e r el a ti v e p h as e v ol um es in de t e rm i n in g th e f i na l e m u ls io n ty p e . Mo s t ag e nt s p r e f er e nt i al l y fo r m o ne ty p e o f e m u ls io n o r t he oth e r i f th e p h as e v o l um e p e r m i ts . 3 . E mu l s if yi n g a g e n ts . A n y c om po u nd t ha t l o we r s th e i n te r f ac ia l t e ns io n a n d f o rm s a fi lm at th e in t e r fa c e c a n p o te n ti al l y fu n c t i on as a n e m ul s i f y ing a g e nt . Th e e f fe c t i v e ne s s o f th e e m u ls i f yin g a g en t d e pe n ds o n i ts ch em ic a l s t r uc t ur e , c on c e n t ra t io n , s ol u bi li t y, p H , p h ys ic a l p r o pe r t ie s , an d e l ec t r os ta t ic e f f ec t . T r u e e m ul s i f yi n g a g e n t s ( p rim a r y ag e nt s ) c an fo r m a n d s ta b il i z e e m u ls i on s b y t h em s e l v es . S ta b i li z er s ( a u xi l ia r y a ge n ts ) d o n o t f o r m ac c ep t ab le em ul s i on s wh e n u s e d a lo n e, bu t a ss i s t p r im a r y ag en t s i n s t ab i li zi ng t he p ro du c t ( e. g . , i nc r ea se v i s c os it y) . E m u ls if y i n g a ge n ts a r e e i t he r na t u r al o r s yn t h e t i c . a . N a tu r a l e m ul s i f yi n g a g e n ts :
( 1 ) Ac a c i a f o rm s a g oo d, s ta b le em ul si on o f l o w v i s co s i t y. I t t en ds t o c rea m e a si l y, i s a c i di c , a nd is s t a b le at a p H r an ge o f 2 -1 0 . L ik e o t he r gu m s , i t i s n e g at i vel y c ha r g ed , d e hy d r a t es ea si l y , an d u su all y r e q ui r es a p re s e r va t i ve . I t is in co m p a ti bl e wi t h Pe r u v i an ba ls am , bi sm ut h s al t s , an d c a rb o na t es . ( 2 ) T r ag a ca n t h f o rm s a s t ab l e em u ls io n t h at is co a r s e r th a n ac ac i a e m ul si o n. I t is an i on ic , is di f fi c ul t t o h y d r a te , and is us ed m a in l y f or i ts e f f ec ts on v i s c os it y . L es s t ha n o f t h e a m o un t us ed f o r ac a ci a is n ee de d . ( 3 ) Ag a r is a n a ni on ic gum t ha t i s p r im ar i l y u s e d to i nc r ea s e vis c o si t y. I ts s t ab i li t y is af f ec te d b y he a t in g , d eh y d r a ti on , an d d es t r uc ti o n o f c ha r ge . I t i s a l so s us c ep t ib le to m i c rob i al de g r ad a ti on . ( 4 ) P ec t i n i s a q u as i- em u l s i f ie r th a t is us ed in t he sa m e p ro p o rt i on as t r a g ac an t h. ( 5 ) G e la t i n p r o v id es go od em u ls io n s ta b il i za ti on in a c on c en t ra t io n o f 0. 5% 1 . 0 %. I t m a y b e a ni o ni c o r c a t io n ic , d ep e nd in g on i ts i s oe le c tr ic po i nt . Ty p e A g e la t in ( +) , pr e pa r ed f ro m a n a ci d - t re a te d p r ecu r s or , is u se d i n a c i d ic m e di a . Ty p e B g el at i n ( - ), p r ep a re d fr o m a n a lk al i- t r e a te d p r ec u rs o r, is us e d i n ba si c m e d ia . ( 6 ) M e t h yl c e l l u l o se is n o ni o ni c a nd in d uc es vis c os i t y . I t is u s e d a s a p r i m a r y em ul s i f ie r wi t h m i ne r al oi l a n d c o d l i ve r o i l , a nd y i el ds an o/ w e m ul si o n. I t is us ua l l y u s e d in 2% c o nc en t r at i on . ( 7 ) C a r bo x ym e t h yl c e l l ul o s e i s a ni on ic an d i s u s u a ll y u s e d t o i nc r e as e vi s co si t y . I t t ol e r at es al c o h ol up t o 4 0% , fo rm s a b a si c s o l ut i on , a n d p r e ci pi t a te s i n t he p re s en c e o f f r ee ac i ds . b . S yn t h e t i c e m u ls i f yi n g a ge n t s a r e a ni o ni c , c at i o ni c , o r n on i on ic . A l t h ou gh t he s e s u r fa c ta nt s ar e a m ph ip h il ic m o le cu l e s , th ei r li po p hi li c a n d h yd r o ph i li c r e gi on s a r e s e l do m i n ve rs e e qu a ls of e a c h ot h e r: S om e s u r fa c ta n t m o l ec ul es te nd t o b e p r ed om i na n tl y l ipo p hi l ic , wh e re as o th e rs a r e pr e do m i n an t l y h y d r op h il ic . Th is im ba l an c e is r e f le c te d i n t h e h yd r o ph i li c -l ip o ph il ic ba la n c e ( H L B ) s c al e : Th e lar g e r th e HL B v a lu e , t he m o r e h y d r op hi l ic t h e m ole c ul e . Ta b l e 3 - 1 li s ts H LB va l u es fo r s u r fa c t a nt s a n d t h ei r c o r re s p o nd i ng u s es .
Table 3-1. Hydrophilic-Lipophilic Balance (HLB)
HLB Value RangeSurfactant Application 0-3
Antifoaming agents
4-6
Water-in-oil emulsifying agents
7-9
Wetting agents
8-18
Oil-in-water emulsifying agents
13-15
Detergents
10-18
Solubilizing agents
P.52
( 1 ) An i o n i c s y n th e ti c a ge n ts in cl u de su l f u r ic ac id e s te r s (e . g. , s o di um l a u r yl s ul f at e ) , s ul f o n ic a c i d d e r i va t i ve s ( e .g . , di o c t y l s o di um s u lf os uc c i n a te ) , a nd s oap s . So a ps ar e fo r e xt e r n a l us e. Th e y h a v e a h i gh p H a nd a re , th e re f o re , s e n s i t i v e t o t h e a dd i ti on of a c i ds an d e le c t ro l yt es . ( a ) Al k a l i s o ap s a r e h y dr o p hi l ic a n d f o rm a n o / w e m ul s i o n. ( b ) M e t a ll i c s oa p s a r e wa t e r i ns o lu bl e a n d f o rm a w/ o em u ls io n . ( c ) M o n o va le n t s o a ps fo r m a n o / w e m ul s i on . ( d ) P o l yva l e n t s oa p s f or m a w/ o e m u ls i on . ( 2 ) C a t io n ic s y nt h et ic ag e n ts (e . g. , be n z a lk on ium c h lo r i de ) a r e u se d a s s u r fa ce - ac t i v e a ge n ts in 1 % c o nc en t r at i on . Th e y a r e i n c o m p a ti bl e wi t h s o ap s. ( 3 ) N o ni o n ic s y nt h et ic ag e n ts a r e re si st a nt t o t he a dd i ti on o f ac i ds a n d e l ec t r ol y t es . ( a ) Th e so r b i ta n es t e rs k n o wn as S pa n s a r e h y dr o p ho b ic i n n a tu r e a n d f o r m w/ o e m u ls i on s . Th ey h a v e lo w h y d r o p hi l ic -l ip o p hi li c b al a nc e v a l ue s (1 9 ) ( Ta b le 3 -2 ) . ( b ) Th e po l ys o r b a t e s k no wn a s Tw ee n s a re h y d ro p hi l ic a n d t en d to fo r m o / w e m ul s i o ns . Th e y m ay f o r m c om pl e xe s wi t h ph e n ol i c c om p ou nd s . Th ey h a ve hi g h h y d r op hi l ic -l i po p hi l ic b a la nc e v al u es (11 - 2 0 ). 4 . P r e pa r a t io n . Va r io us m e th o ds a r e u se d to p rep a r e e m u ls io ns , de p en din g o n th e t y pe of em ul s i f y i ng a ge n t. a . C la ss ic al , ac ac ia - s t a bi l i z ed em ul s i o ns a r e p r ep a r e d b y on e o f th e f o l lo wi n g fo u r m et h od s :
( 1 ) W et g um ( E ng l is h ) m e t h od . A p r im a r y e m u ls i on of fi xe d o i l, wa t e r , an d a c ac ia ( in a 4 :2 : 1 r a ti o ) is p re p ar e d a s f ol lo ws : ( a ) Two p a r t s o f wa t e r a re a dd e d a ll a t on c e to one p a rt of ac ac i a. Th e m i xt u r e is tr i tu r a te d u n ti l a s m oo t h m u c i l ag e i s f or m e d. ( b ) O i l is ad d ed in s m al l i n c re m e n ts (1 - 5 m L) , wi th c o n ti n uo us t ri t u ra t io n , u n t il th e p r im a r y em ul s i on is f or m e d . ( c ) Th e m i xt u r e ( an o/ w e m ul s i o n) is t ri t ur a te d for a n ot h er 5 m in . ( d ) Th e o/ w m i xt u r e c a n t h e n b e b r ou gh t to vo lu m e wi t h wa t e r an d m i xe d to a c hi e v e h om o ge n ei t y . ( 2 ) D r y g u m ( c o nt i n en ta l ) me t h od . A p r im a r y em u ls io n o f th e f i xe d o il , wa t e r , a nd ac ac ia ( in a 4: 2 : 1 r a ti o ) i s p r ep a re d a s f o ll o ws :
Table 3-2. Commonly Used Surfactants and Their Hydrophilic-Lipophilic Balance (HLB) Values Agent
HLB Value
Sorbitan trioleate (Span 85, Arlacel 85)
1.8
Sorbitan tristearate (Span 65)
2.1
Propylene glycol monostearate (pure)
3.4
Sorbitan sesquioleate (Arlacel C)
3.7
Sorbitan monooleate (Span 80y)
4.3
Sorbitan monostearate (Arlacel 60)
4.7
Sorbitan monopalmitate (Span 40, Arlacel 40)
6.7
Sorbitan monolaurate (Span 20, Arlacel 20)
8.6
Glyceryl monostearate (Aldo 28, Tegin)
5.5
Gelatin
9.8
Triethanolamine oleate (Trolamine)
12.0
Polyoxyethylene alkyl phenol (Igepal CA-630)
12.8
Tragacanth
13.2
Polyoxyethylene sorbitan monolaurate (Tween 21)
13.3
Polyoxyethylene castor oil (Atlas G-1794)
13.3
Polyoxyethylene sorbitan monooleate (Tween 80)
15.0
Polyoxyethylene sorbitan monopalmitate (Tween 40)
15.6
Polyoxyethylene sorbitan monolaurate (Tween 20)
16.7
Polyoxyethylene lauryl ether (Brij 35)
16.9
Sodium oleate
18
Sodium lauryl sulfate
40
P.53
( a ) O i l is ad d ed to t he ac a c ia , a n d t he m i xt u r e is tr i t u ra t ed un t il th e po wd er i s d is t r ib u te d u n if o rm l y th r o ug h ou t th e o il . W at e r i s a d de d a ll a t o nc e, f o l lo we d b y r ap id t ri t u ra ti o n t o f o rm t he pr im a r y em u ls io n . ( b ) A n y r em ai ni n g wa t e r a n d o t he r in g re d ie n ts a re a dd e d t o f in is h th e p r o du c t. ( i ) E l ec t r o l yt e s i n h i g h c o n ce n t r a ti o n t e nd to cra c k an em ul s i o n . Th e y s h ou l d b e a dd ed la s t a nd i n as di l ut e a f or m a s po s s i bl e . ( i i ) Al c o h ol i c s o lu t i o ns t e n d t o d eh yd r a te an d p re c ip i ta t e h y d r oc ol lo i ds . Th e y s h ou l d b e a dd e d i n a s d il u te a c on c e n t ra t ion a s po ss i bl e. ( 3 ) B o t t le me t h od ( a v a ri a t io n o f t h e d r y gu m m eth o d u s e d f o r v ol a ti l e o il s ) . O i l is ad de d to th e a c a c ia i n a b o t tl e. Th e r at io o f o i l, wa t e r , a nd ac ac i a s h ou l d b e 3 :2 : 1 o r 2 : 1 : 1. Th e lo w v i s c os i t y o f th e vo l a ti l e o il re q ui r es a h i gh e r p r o po r ti o n o f a c ac i a. ( 4 ) N a sc e nt s oa p m e t hod . A s o ap is fo rm e d b y m i xi n g r el at i ve l y eq ua l vo l u m e s o f a n o il an d a n a q ue o us s ol u ti o n t ha t c o n t ai ns a su f f ic ie n t am ou n t o f al ka l i. Th e s o ap ac ts a s a n e m u ls i f yin g a g en t .
( a ) Th i s m e t ho d i s u s e d to f o rm a n o / w o r a w/ o em u ls io n , d ep e nd in g o n th e s o ap fo r m e d . F o r e xa m p le , ol i v e o i l, wh i c h co n ta in s o l ei c ac i d, is m i xe d wi t h l i m e wa t e r d u ri n g t he p rep a r a ti on o f ca l am in e l o tio n to ca lc iu m o le a te , an e m ul si f y i ng ag e nt . ( b ) A 50 : 50 r at i o o f o il to wa t e r e ns u re s s uf f ic ie n t e m u ls i on , p r o v i de d t h at t h e o i l c o n ta i ns a n a d equ a t e am o un t o f f re e f a t t y a c i d . Ol i v e o i l us u al l y d o es . C ot t on s e e d o il , p ea n u t o il , a n d s o m e o th e r v e g e t ab l e o il s d o n ot . ( c ) Th e ad di t io n o f an ac i d de s t r o ys t h e em u ls if y in g s o ap an d c au se s t h e e m ul si o n t o s e p a ra t e. b . E m u ls io ns s t a bi li z e d b y s y n t he t ic e m u ls i f y in g a g e n t s a r e r e ad il y p r e pa r e d b y a t wo - p h as e p r oc e du r e : ( 1 ) O i l- m i s c i bl e i ng r ed i en t s a nd wa t e r - m i sc ib le ing r e d i e nt s a r e s ep a ra t el y a d m i xe d , us i ng he a t i f ne c es s a r y t o e ns u re li qu ef a c ti on an d e as e of m i xi n g o f ea ch ph a s e . ( a ) H ig h m el t in g p o in t o i l- m is c i b le i n g re di e nt s (e .g . , wa xe s ) a r e m el t ed b e f o re lo we r m el ti n g p oin t in g r ed ie n ts (e . g ., oi ls ) a r e a d de d . ( 2 ) Th e t wo ph as e s a re h e a te d t o 7 0 ° - 80 ° a n d t he n c om b in e d wi t h st i r ri ng u n t il th e re s u l ta n t em u ls io n ha s c oo le d . ( a ) I n g en e ra l , h ea t - la bi le o r v ol a ti le in g r ed ie n ts s h ou l d n ot be in c o r po r a te d i n th e s ep a r at e p h as es bu t in th e re s u l ta n t e m u ls io n af t e r i t h as c o ol e d t o a b o ut 40 ° C . o r le s s . ( 3 ) F ur t he r m e c h an ic a l pr o c es s i ng of t he em ul s i on b y a h an d h o m o ge n i zer , i m m e rs i on bl en d e r, o r o th e r eq ui pm e nt m a y b e w a r r a n t e d t o i m p r o v e t h e h o m o g en ei t y a nd s t ab i li ty o f t he p ro d uc t. 5 . I nc o r p o ra t i on o f m e di c i n al ag e n ts . Me d ic i na l a g en ts ca n b e i n co r po r a te d i n to an em ul s io n e i th e r d u ri ng o r a f te r i ts fo rm a ti o n. a . Ad d i t i o n o f a d r ug du r i n g e m u ls i on f o r ma t io n . It is be s t t o i nc or p o ra t e a d r ug in t o a v eh ic l e d ur in g em ul s i o n f o rm at i on , wh e n i t c a n b e i n co r po r a te d i n m ol ec u lar f o rm . So l ub le d ru gs s ho u l d be di s s o l v ed in th e a p p ro p r ia t e p ha s e ( e. g ., d r u gs th a t a r e s o l ub l e in t h e e xt e r n a l p ha s e o f t he e m ul si o n s h o ul d b e a dd ed as a s ol u ti on t o t he p rim a r y em ul si o n) . b . Ad d i t i o n o f a d r u g t o a p r e fo r m ed em u ls i o n c a n p r es en t s om e d i f fi cu l t y , d e pe nd i ng on th e t y pe o f em u ls io n a n d t h e n a tu r e o f th e e m ul si f ie r ( Ta bl e 3 - 3 ) . ( 1 ) Ad d i t i o n o f o l ea g i no u s m a t e ri a l s t o a w / o e m u ls i o n p re s en ts no p r o bl em be c a u s e of th e m is c i b il i t y o f th e a d di ti v e wi t h t h e e xt e r n a l p ha se . H o we ve r , a d d i ti o n o f ole a g in o u s m at e r i al s to an o /w em u ls i o n c a n b e d i f fi cu l t a f te r em ul s i on f or m a ti o n. ( a ) O cc as i on al l y , a s m al l a m o u nt o f o il y m a t e ri al is ad d ed if e xc e ss e m ul si f ie r wa s u s e d i n the o ri g in a l f o rm at i on . ( b ) A s m a l l am o un t o f an o i l- s o l ub l e d ru g c a n b e a d d ed i f it is d is s ol v e d in a ve r y s m al l q ua n ti t y o f o il wi t h g eo m e t r ic di lu t io n te c hn i qu es . ( 2 ) Ad d i t i o n o f w a te r o r a n aq u eo u s m a te r i al t o a w / o e m ul s io n is e xt r e m e l y di f fi c u l t , u nl es s en o ug h e m u ls i fi e r h as b e e n in c or p o ra t ed in t o th e e m ul si o n. H o we v e r , ad d it i o n o f a qu e ou s m a t e ria l s to a n o /w e m u ls i on
u s ua ll y p r es en t s n o p r obl e m s i f th e a d de d m at e ria l do es no t i n te r ac t wi t h t h e e m u ls i f y in g a g en t . Po t e nt i al in t er a ct io n s s h ou l d b e e xp e c t ed wi t h c a ti o ni c c o m p o un ds an d s a lt s o f we ak ba s es . ( 3 ) Ad d i t i o n o f s m al l qua n t i t ie s o f al c o ho l ic s ol u t i o ns t o a n o /w e m u ls i o n is po s s ib l e i f th e s o lu t e is c o m p a ti bl e or d is p er s i b le in th e a q u eo us ph as e o f th e em u ls io n . I f P.54
a c ac ia o r a no t he r gu m is u s e d a s t h e em u ls if yi n g a g e nt , th e a lc oh o li c s o lu t io n s ho u ld be di lu t ed wi t h wa t e r be f or e i t is a d d ed . Ta bl e 3 - 3 l is ts s om e c om m e r c i al em ul s io n ba s e s a nd t he i r g en e ra l c o m p os it i on .
Table 3-3. Selected Commercial Emulsion Bases: Emulsion Type and Emulsifier Used Commercial Base
Emulsion TypeEmulsifier Type
Allercreme skin lotion
o/w
Triethanolamine stearate
Almay emulsion base
o/w
Fatty acid glycol esters
Cetaphil
o/w
Sodium lauryl sulfate
Dermovan
o/w
Fatty acid amides
Eucerin
w/o
Wool wax alcohol
HEB base
o/w
Sodium lauryl sulfate
Keri lotion
o/w
Nonionic emulsifiers
Lubriderm
o/w
Triethanolamine stearate
Neobase
o/w
Polyhydric alcohol esters
Neutrogena lotion
o/w
Triethanolamine lactate
Nivea cream
w/o
Wool wax alcohols
pHorsix
o/w
Polyoxyethylene emulsifiers
Polysorb hydrate
w/o
Sodium sesquioleate
Velvachol
o/w
Sodium lauryl sulfate
o/w, oil in water; w/o, water in oil.
( 4 ) Ad d i t i o n o f c r ys t a l l i n e d r ug s to a w /o em u ls i o n o c c u rs m o re ea si l y i f t h e d r u gs a r e d is s o l v e d o r di s pe rs e d i n a s m a ll qu a n ti t y o f o il b e f or e th e y a r e ad de d . E . O i n t me n t s 1 . I n t ro d uc t i o n. O i n tm en t s a re se m is o li d p re p ar a t i o ns i n te n de d fo r e x t e r na l us e . Th e y a r e e a s i l y s p r ea d . Mo d i f yi n g t h e fo rm u la t io n c on t r ol s t h e ir pl a s t ic v is c o s i t y . O in t m e n ts a re t ypi c a ll y u s ed as : a . E mo l l ie n t s t o m ak e th e s k i n m o re pl i ab le b . P r o t ec t i ve ba r r i e r s to p r e v en t h a rm f ul s u bs t an c es f ro m co m i n g i n c o nt ac t wi t h th e s k i n c . V eh i cl e s i n wh i c h t o in c o rp o ra t e m ed ic a ti on 2 . O i n tm e n t b as e s a . O l ea g i no u s b as e s a re a nh y d r ou s a n d i ns ol ubl e in wa t e r . Th e y c an n ot a b so r b o r c o nt a in wa t e r a n d a r e n o t wa s h ab l e i n wa t e r . ( 1 ) P e t ro l a t um i s a go o d b as e fo r o i l -i ns ol u bl e i ng r e di e nt s . I t f o rm s a n o cc l us i ve f il m o n t h e s k in , ab s o r bs < 5 % wa t e r un d e r n o rm al c o nd i ti o ns , a n d d o es n o t b ec om e r an c id . W a x c a n b e i nc o r po r a t ed to s t i ff e n t he ba s e . ( 2 ) S yn t h e t i c e s t e rs a re u s e d a s c on s t i tu e nt s o f o l ea g in o us b as es . Th es e e s te r s i nc lu d e g l yc e r y l m o n os t ea r a te , i so p r op y l m yr i s t at e , i s o p ro p yl p a lm i ta t e, bu t y l s t ea r a te , a n d b ut y l pa lm i ta t e . L ong - c ha in al c o h ol s ( e .g . , c e t yl a lc oh o l, s t e a r y l al c o h ol , P E G ) c an al s o b e u s ed . ( 3 ) L an o l in de r i va t i ve s a r e of t en us ed in t op ic al a n d c os m e ti c p r e pa r a ti o ns . E xa m p l es a r e l a no l in oi l a nd h yd rog e n at e d l an ol i n. b . Ab s o r p t i on b as es a re a nh y d r ou s a n d wa t e r in s ol u bl e. Th e r e fo r e, t hey a r e no t wa s h a bl e i n wa t er , a lt h ou g h t he y c an ab so r b wa t e r . Th e s e ba s es p e r m i t wa t e r -s ol ub l e m ed i c a m e n ts to be in cl ud e d t h r ou g h p ri o r s ol u ti o n an d u p t ak e a s t he in t e rn al pha s e. ( 1 ) W oo l fa t ( an h y d ro us l a no l in ) c o nt a in s a h i gh p e r c e n ta ge o f ch o le s t e r ol a s we l l as es t e rs a n d a lc o h ol t ha t c on t ai n fa t t y ac i d s. I t a bs o rb s t wi c e i ts we i g h t in wa t e r a n d m e l ts be t we e n 36 ° C an d 4 2 °C .
( 2 ) H yd r o p h i l i c p e t r ol a tu m is a wh i t e p e t ro la t um c om bi n ed wi t h 8% b e es wa x, 3 % s t ea r y l al c o h ol , an d 3 % c ho l es te r ol. Th e s e c o m p o ne n ts a r e a d d ed to a w/ o e m u ls i fi er . P r e pa r ed fo r m s i n c l ude A q ua ph o r , wh ic h u s e s wo o l a lc o ho l t o re nd e r wh i t e p et r ol a t um e m u ls i fi ab l e . A q ua ph o r i s s up e ri or i n it s a bi li t y t o a bs o rb wa t e r . c . Em u l si o n b a se s m a y b e w/ o em ul si o ns , wh ic h a r e wa t e r i ns ol u bl e a n d a r e no t wa s h a bl e i n wa t er . Th e se em ul si o ns c a n a b s o r b wa t e r b ec au se of t h e ir a qu eo us in t e rn a l ph a s e . Em ul s i o n b as es m a y a l s o b e o / w e m ul si o ns , wh i c h a re wa t e r i ns o lu ble b ut wa s h ab le in wa t e r . Th e y c a n a bs o rb wa t e r in t h e ir a qu eo us e xt e r n al ph a s e . P.55
( 1 ) H yd r o u s w oo l fa t (l an o li n ) i s a w/ o em ul s i o n t h a t c on t ai ns a p p ro xi m a t el y 2 5% wa t er . I t a c t s a s a n e m o ll i en t a n d oc cl u si ve fi lm on the s ki n , e f fe c ti v e l y pr e v e nt in g ep id e rm a l wa t e r lo s s . ( 2 ) C o ld c r ea m i s a w/ o e m ul s i o n t ha t i s p r ep a red b y m e l ti ng wh i t e wa x, s p e rm ac et i , a nd e xp r e s s e d al m o n d oi l to ge t he r ; a d di n g a ho t a q ue ou s s o lu t io n o f s od i um b o r ate ; an d s t ir r i ng un t il th e m i xt u r e is c o ol . ( a ) Th e us e o f m i n e ra l o il r a th e r t h an al m o nd oi l m ak e s a m o re s t ab l e co ld c r e am . H o we v e r , c o l d c re a m p r ep a re d wi t h a lm on d oi l m ak es a be t t e r e m ol li e nt ba s e . ( b ) Th i s o in tm e nt s h ou l d b e fr es h l y p r e pa r ed . ( 3 ) H yd r o p h i l i c o i n tm e nt i s a n o / w e m u ls i on th a t u s e s s od i um l a ur y l s u lf a te as an em ul s i f y i ng a g en t . I t a b s o r bs 3 0 % -50 % w/ w wi t h o u t l os in g i ts c o ns is te n c y . I t i s r e ad il y m is c i bl e wi t h wa t e r a nd i s re m o v e d fr om t he s k i n e a si l y. ( 4 ) V an i s hi n g c r e am is a n o/ w e m ul s i o n t h at c o nt a i ns a la r g e p er c e n t ag e o f wa t e r a s we ll as hu m e c ta n t (e . g. , gl y c e ri n , p ro p yl e ne gl y c ol ) t ha t re t ar d s m o is tu r e l os s . A n e xc e s s o f s t ea r ic ac id in th e fo rm u la he lp s f o rm a t hi n f i lm wh e n th e wa t e r e v a po r a t es . ( 5 ) O t h e r e m ul s io n ba se s in c l ud e D er m o van , a h y p o a ll e rg e ni c , g re as el es s e m ul si o n b as e, an d Un i ba s e, a n on g r ea s y e m ul sio n ba s e th a t a bs o rb s a p p ro xi m a t el y 3 0% o f i ts we i g h t i n wa t e r a nd ha s a p H c lo s e to t ha t o f th e s ki n . d . W at e r - so l u bl e ba se s m a y be an h yd r ou s o r m ay c o n ta in s o m e wa t e r . Th e y a r e wa s ha b le in wa t e r an d a bs o r b wa t e r to th e po in t of s o lu b il i t y . ( 1 ) P E G o in t me n t i s a ble n d o f wa t e r -s ol u bl e p oly e t h yl e ne gl yc ol s t h at for m a se m i s o l id ba s e . Th is ba s e c a n s o lu bi l i z e wa t e r -s o lu bl e d r u gs a n d s om e wa t e r - i n s o lu b le dr u gs . I t i s c om pa t ib l e wi t h a wi de r a ng e o f d r ug s . ( a ) Th i s b as e c o n ta i ns 40 % P E G 33 50 an d 6 0 % P E G 4 0 0 . I t i s p re p a re d b y t h e fu si on m e t ho d (s ee V I . E . 3 .b ) . ( b ) O n l y a s m al l a m o u nt o f li q ui d ( < 5% ) c an be in c o rp o ra t ed wi t h ou t lo ss o f vi s co si t y . Th i s b as e c a n b e m a de s t i ff e r b y i nc r eas i ng th e a m o u nt o f P E G 3 3 5 0 t o 6 0% .
( c ) I f 6 % t o 2 5% o f a n aq u e ou s s o l ut i on is t o b e i n c o r po r a te d , 5 g o f t he 4 0 g o f P E G 3 35 0 c an be r ep l ac e d wi t h an eq u al am o u n t o f s te a r y l a lc o ho l . ( 2 ) P r o p yl e n e g l yc o l a nd p r o p yl e n e g l yc o l - e t h an o l fo r m a c le a r g e l wh e n m i xe d wi t h 2% h y d ro xy p r o p y l c e ll ul os e . Th is b as e i s a po pu l a r d er m a t ol o gic ve h i cl e . 3 . I nc o r p o ra t i on o f m e di c i n al ag e n ts . Me d ic i na l s ub s ta nc es m a y b e i n co r po r a te d i n to an oi n tm e nt ba se b y le vi g a t i on o r b y th e fu s io n m e t hod . I n so l ub le s u bs t an c e s s ho u ld be r ed uc e d t o t h e f in e s t po ss i bl e f o rm an d l e vi ga t ed b ef o re in c o r p ora t i on wi t h a s m al l a m o unt o f c om pa t ib l e l e vig a ti ng a g e nt o r wi t h t he ba s e its e lf . a . L e vi ga t i on . Th e s ub s ta n c e is i nc o r po r a te d i n to t h e o in t m e n t b y l e vi ga t io n o n a n oi nt m e nt s la b . ( 1 ) A s t ai nl e s s -s t ee l s pat u l a wi t h a l on g , b r oa d , fl e xi b l e b l ad e s ho u ld be u s ed . If th e s u bs ta nc e m a y i n te r ac t wi t h a m e ta l s p at u la ( e. g ., wh e n i n co r po r a ti n g i od in e a n d m e rc u ri c s al ts ) , th en a ha r d ru b be r s p at u la c a n be u s ed . ( 2 ) I ns ol ub l e s u b s t a nc es s ho u ld be po wd e r e d f i ne l y i n a m o rt a r a n d m i xe d wi t h a n e q ua l q u an t it y o f b as e u n ti l a sm oo t h, g ri t- f r e e m i xt u r e i s o bt a in e d. Th e r e st o f t he ba s e is ad d e d in in c re m e n ts . ( 3 ) Le vi g at i on of po wd e r s in t o a s m a l l p or t io n o f b a se is fa ci li t a te d b y t he u s e o f a m e lt e d b as e o r a s m al l q u an t it y o f c om pa t i bl e l e v ig a ti o n a id ( e. g ., m i ne r al oi l , g l yc e r in ) . ( 4 ) W ate r -s ol u bl e s al ts ar e in c or p o ra t ed b y d is s o lv i n g th em in t he s m a l le s t p o ss ib l e am o un t o f wa t er a n d i nc or p o ra t in g t h e aq u e ou s s o l ut i on di r ec tl y i n t o a c om pa t ib l e b as e. ( a ) U su a ll y , o rg an ic s o l ve n ts ( e. g . , e th e r , c h l o ro fo r m , a lc oh o l) a re no t use d t o di ss ol v e t he d ru g b ec a u s e th e d r u g m a y c r y s ta l li z e as th e s ol ve n t e va p o ra t es . ( b ) S ol v e n ts a re us ed as l e v i ga t in g a id s o nl y i f t he s o l id wi l l b ec om e a fi ne p o wd e r a ft e r t h e s ol v e n t e v a p o ra t es . b . F us i o n m et h o d. Th i s m e th o d is us e d wh e n th e b as e c o nt ai n s s o li d s t hat h a ve hi g he r m el t in g p o int s (e . g ., wa xe s , c e t y l a lc o h ol , gl y c e r y l m o no st e a ra t e ). Th is m e th o d i s a ls o us e fu l fo r s o li d m e di c a m e n ts , wh ic h ar e r e a di l y s o lu b le in th e m el t e d b as e. ( 1 ) Th e oi l p ha s e s h ou l d b e m e lt e d s e p a ra t el y , s ta r t in g wi t h m at e r ia ls th a t h a ve th e h i gh es t m el t in g p o in t . A l l o th e r o il - s o l ub l e in g re d ie n ts a r e a d de d i n d e c re as in g o r d e r o f m e l tin g po in t . ( 2 ) Th e in g re d ie n ts i n t he wa t e r ph as e a r e c om bin e d a n d h ea t ed s e pa r a tel y t o a t em p er a tu r e th a t is e q u al to o r s e v e r al d eg re e s a bo v e t ha t o f th e m e lt e d o il ph as e . P.56
( 3 ) Th e t wo ph as e s a re c o m bi n ed . I f a w/ o s y s te m i s d es i re d , t he n th e h o t a q u eo us ph as e i s i nc o rpo r a t ed in t o t he ho t o i l p ha s e wi t h a gi ta t io n . I f a n
o / w s ys t em is p r e fe r r ed , t h e n t he ho t oi l p ha s e is i n c o r po r a te d i n to th e h o t a q u eo us ph as e . ( 4 ) V ol a ti l e m a t e ri al s ( e .g . , m e nt h ol , c am ph o r , i od i ne , al c o h ol , p e r fu m e s ) a r e ad de d a f t er t he m e lte d m i xt u r e c o ol s t o 4 0 ° C o r le ss . F . S u pp o s it o r i es 1 . I n t ro d uc t i o n. A s up po s it o r y is a s ol i d o r se mi s o l id ma s s i n te n de d t o b e i ns e r t ed in t o a b od y o r i f i ce (i . e ., r ec tu m , v ag i na , u re t hr a ) . A f t er i t is i n se r t ed , a s u pp os i to r y ei t h er m e l ts a t bo d y te m pe r a t ur e o r di ss ol v e s ( o r d i sp e rs es ) i n t o t he aq u eo u s s e c re t io ns o f t he bod y c a vi t y. a . S up p os it o ri e s a re o ft en us e d f o r l oc al ef f ec ts (e . g . , r el i ef o f h em or r h oi ds o r in f ec t io n ) . b . W hen u s e d re c t a ll y , s u p p os it o ri es c a n p r o vid e s ys te m i c m ed ic a ti on . The a b so r p ti on o f a d r u g f r om a s up po s i t o r y th r ou g h t h e re c t a l m u c os a i nt o t he c i rc u la ti o n i n v ol v e s t wo s t ep s : ( 1 ) Th e dr u g is r el e as ed f r o m a v e hi c l e a nd pa r t it io n s / d if f us es th r o ug h t h e m uc o sa . ( 2 ) Th e dr u g is t r an s p o rte d th r o ug h t h e v e i ns o r lym p h v es s e ls in t o s ys t em ic fl ui ds o r t is s u es . Th e f i rs t - pa s s e f f ec t is a voi d ed be ca us e th e r e c ta l vei ns “ b y pa s s ” th e l i v e r . c . R ec ta l s up p os it o r ie s ar e us e fu l wh e n o r al ad m in i s t r a ti o n is in a pp r op r ia te , a s wi t h i n fa n ts , d eb i li t ate d o r c o m a t os e p a ti en t s, a n d p at i en ts wh o h a ve n a us e a, v o m i ti n g, o r g as t r o in t es t in al di s tu r ba nc es . S om e d ru g s ca n c au s e d i st u r ba nc es of t he ga s t ro i n te s t i na l t r ac t . 2 . T yp e s o f s u pp o s it o r ie s a . R ec t a l s u pp o si t o r i es a r e u s u a ll y c yli n dr ic a l an d ta p e re d t o a po i nt , f o r m i n g a b u ll et - l ik e s h ap e . As th e re c t um c o n tr ac t s , a s up po s i t o r y of th is s h ap e m o v es in wa r d r at he r t ha n o u t wa r d . S u pp osi t o ri es f o r a du l ts we i gh a p p ro xi m a t el y 2 g. S up po s it o ri e s f o r i nf a nt s a nd c h il d re n a r e sm a ll e r . b . V a gi n al s up p os i t o r ies a r e o v a l a nd t ypi c a l l y we i g h a pp r o xi m a te l y 5 g . D r u g s a dm in is t e re d b y th i s r o ut e a r e i n te nd e d t o h a v e a lo c a l e f f ec t , b ut s ys t em ic a bs o r pt i on c a n o c c u r . A n ti s e p ti cs , c on t ra c ep t i v e a ge n ts , a n d d rug s u s ed to t re a t t r ic h om on al, m on il i al , o r ba ct e ri a l i nf e c ti on s a r e o f te n f o r m u l at e d as v a gi n al s up p os i to r ie s . c . U r e th r a l s u pp o s it o r ie s a re t y pi c a l l y l o ng an d t a pe r e d. Th e y a re a p p ro xi m a t el y 6 0 m m lo ng a nd 4 -5 m m i n d ia m e t er . Th e y a r e a dm in is t e re d f o r a l oc al ef f ec t a n d a r e m os t o f te n us ed fo r an t i- i n fe c ti v e ag e nt s . A l p r os ta d il , o r p ro s t a gl an d in E 1 (P G E 1 ) , wh e n u s e d to t re a t e r ec t il e d ys f un c ti o n, is a v a i la bl e f o r u re t hr a l i ns e rt i on in th e fo r m o f a m ic r o pe ll e t, o r m i c ro s u p po s i t or y , t ha t i s o nl y 3 - 6 m m lo ng an d 1 . 4 m m in di am e te r . 3 . S u pp o si t o r y b a s e s a . C r i t e ri a fo r s a ti s fa c to r y s u p p o s i t o r y b a s e s . S u p po s i t o r y b as es s h oul d ( 1 ) R em a in fi r m a t r o om t e m p e r at u re t o a ll o w i nse r t io n . Th e s u p po si t o r y s h ou l d n ot s o f te n < 30 ° C t o a v oi d m el ti n g d u ri n g s t o ra g e. ( 2 ) H a ve a na r r o w, o r s ha r p , m el t in g ra ng e
( 3 ) Yi e l d a c le a r m el t j us t b el o w b o d y te m p e ra t u re o r d is so l ve ra pi d l y i n th e c a vi t y fl u id ( 4 ) B e i ne r t a n d c o m p a tib l e wi t h a v a ri e t y of d ru gs ( 5 ) B e n on i r ri t at i ng an d n o ns e ns it i z i ng ( 6 ) H a ve we t t in g a nd em u l s i f y i ng p ro pe r t ie s ( 7 ) H a ve a n a c i d v al u e of < 0. 2 , a s a po ni f ic a ti on v a l u e o f 2 0 0 -2 45 , an d a n i o di n e v a l ue of < 7 if t he b as e i s f a tt y b . S e le c ti n g a su p p os i to r y b a s e . L ip id - wa t e r s ol u bi l it y m us t b e c on si de re d b e ca us e o f i t s r e la ti o n t o t h e d r ug - r el e as e r a te . ( 1 ) I f a n o il - s o lu b le d ru g i s i nc o r po r at e d i nt o a n o il y b as e , t h en th e ra t e o f a b so r p ti on is s om e wh a t le s s t ha n t h at ac hi e ve d w i t h a wa t e r -s o lu bl e b a se . Th e l i pi d -s ol u bl e d r ug ten d s t o r e m a in di s s ol ve d in t he oi l y po o l f r om th e s u pp os i to r y . I t is le s s li k e l y t o e sc ap e i n to th e m u c ou s s ec re t io n s f r om wh i c h it is ul t im at el y a bs o r b ed . ( 2 ) C o n v er s el y , a wa t e r -s o lu bl e d r u g t en ds t o p as s m o re ra p id l y f ro m t he o i l p h as e t o th e a q ue ou s p ha s e. Th e r ef o r e, if r ap i d on s et o f ac t io n i s d es i re d , t h e wa t e r -s ol u bl e d r ug s h o ul d b e i n co r po r a te d i nt o t he oi l y ba se . c . B as e s t h at me l t i nc l ud e co c oa b ut t e r , o t he r co m b i na t i on s o f f a ts and w a xe s , W i te p so l ba s es , a n d W ec o be e ba se s ( Ta b le 3 -4 ) . ( 1 ) C o co a b u t t e r ( t he o br o m a o il ) i s t h e m o s t wi d e l y us e d s up po si t o r y b a se . I t is fi r m a nd s o li d u p t o a t em pe r a tu r e o f 3 2 ° C , at wh i c h p oi n t i t b e gi ns to s o f te n . A t 3 4 - 35 ° C , i t m el t s t o p r od uc e a t hi n , b lan d , o i l y l i qu id . P.57
Table 3-4. Composition, Melting Range, and Congealing Range of Selected Bases That Melt Base
Composition
Melting Congealing Range (°C) Range (°C)
Cocoa butter
Mixed triglycerides of oleic, palmitic, and stearic acids
34-35
28 or less
Cotmar
Partially hydrogenated cottonseed oil
34-75
—
33-36
32-33
37-39
36-37
Dehydag Base I Base
Hydrogenated fatty alcohols and esters
II Base III
9 ranges
9 ranges
Wecobee R
Glycerides of saturated fatty acids C12-C18
33-35
31-32
Wecobee SS
Triglycerides derived from coconut oil
40-43
33-35
32-33
29-32
H-15
33-35
32-34
H-85
42-44
36-38
Witepsol H-12
Triglycerides of saturated fatty acids C12-C18, with varied portions of the corresponding partial glycerides
( a ) C oc o a b ut t e r is a g ood b as e f o r a r ec t a l s up po s i t o r y, b u t i t i s l es s t han i d ea l fo r a v a g in al o r u r et h r al s u p po s i t or y . ( b ) A m i xt u r e of t ri g l yc e ri d es , c oc o a b ut t e r e xh i b it s po l y m o r ph is m . D e p e nd in g o n th e f us i on t e m p e ra t u re , i t c a n c r ys t a l li ze in t o a n y o n e o f f ou r c r ys t al fo r m s . ( c ) M a j o r l i mi t a t io n s o f c o c oa b ut t e r . Be c a us e o f t he fo ll o wi n g l im i ta t ion s , m a n y c om bi n a ti on s o f f at s an d wa xe s a r e us e d as s u bs t it u te s ( Ta b l e 3 - 4): ( i ) An i n a bi l i t y t o a b s o rb a q ue o us so l u t io n s. Th e ad di t io n o f no ni o ni c s u r fa c ta n ts t o th e b as e am e li o ra t es th is p ro bl em to s o m e e xt e n t . Ho we v e r , t h e re su l ta n t s up po s i t o rie s h a v e po o r s ta bi l it y a nd m a y t u r n r an c i d ra p id l y. ( i i ) T he low e r i n g o f th e m e l t in g po i n t p r o d uc e d b y c e r t a i n d r ug s (e . g. , c h lo r al h y d ra t e ). ( 2 ) W i te p so l b as e s c o n ta i n n a tu r al sa t ur a te d fa t ty a c id c h ai n s b et we e n C1 2 a n d C1 8 . L au r ic ac id is th e m a jo r c om p on e nt . Al l 1 2 ba s e s o f t h is s e ri es ar e c o lo r le ss an d a lm os t o d or l e s s . Th e d ru g - re l ea se c h a ra ct e ri s ti c s o f W it ep so l H 1 5 a re s im i la r to th os e o f c o c o a b u tt e r . ( a ) U nl ik e c oc o a b ut t e r, W itep s o l b as es do no t exh i b i t p ol ym o rp hi s m wh en h e a te d a n d c o o le d . ( b ) Th e in t e r v al be t we e n s o ft e ni ng an d m el t in g tem p e ra t ur e s is v e r y s m al l. B e c au se W it ep s o l b as e s s ol i di f y r ap id l y in t he m o l d , l ub r ic at i on of t he m ol d i s n o t n ec es s a r y .
( 3 ) W ec o be e b as es a re d e r i v ed f ro m c oc on u t o il . Th e i r ac ti o n is si m i la r to t h a t o f W ite ps o l b as es . In c o rp o ra t io n o f g l y c er y l m o no s t e a ra t e a nd p r o p yle n e g l yc o l m o n os te a r a te m ak es t he s e ba s e s e m u ls i fi a bl e . d . B a se s th a t d i ss o l ve in c lu d e P E G po l ym e r s wi th a m ol ec u la r we i gh t of 4 0 0 -6 0 00 . ( 1 ) A t ro om te m p e r at u re , P E G 4 0 0 is a l iq ui d , PEG 1 0 0 0 is a s e m i s ol id , P E G 1 5 00 an d 1 6 00 a re f a i rl y f i rm s em is o li ds , a nd P E G 3 35 0 a nd 60 0 0 a re f i r m wa x- l i k e s o l id s . ( 2 ) Th e s e ba s e s a r e wa t e r s o l ub le , bu t t h e d is s o lu t i on p ro c e ss i s ver y s low. I n t he re c tu m a nd v a gi n a, wh e r e t he am ou n t o f f lui d is v e r y s m a ll , th e y d i ss ol ve v e r y s l o wl y , b ut t h e y s o f te n a nd s p r ea d . ( 3 ) P E G s c om pl e x wi t h s e v e r a l d r ug s a nd a ff ec t dr u g re l ea se an d a b so r p ti on . ( 4 ) Mi xt u r e s o f P E G p o l ym e rs in va r yi ng p ro po r t ion s p r o v i de a b as e o f d i f fe r e nt p ro pe r t ie s ( Ta b le 3 - 5) . 4 . P r e pa r a t io n . Su pp os it o r ie s a r e p r ep a r ed b y t he f ol l o wi ng t h re e m et h ods : a . H a nd - r o l li n g i n v ol v e s m ol d in g t h e s u p po si t o r y wi t h t h e f in g er s a f te r a p l as t ic m as s is f or m e d . ( 1 ) A fi ne l y po wd e r e d d ru g is m i xe d wi t h th e g r a te d ba s e in a m o r t a r a nd p e st l e, us in g l e v i ga t io n a n d g e om et r ic di lu t io n tec h ni q ue s . A s m a ll qu a nt it y o f fi xe d o i l m a y b e a d ded t o f ac il i ta t e p r ep a r at i on . P.58
Table 3-5. Mixtures of Polyethylene Glycol (PEG) Bases Providing Satisfactory Room Temperature Stability and Dissolution Characteristics Base Comments 1
2
Provides a good general-purpose, watersoluble suppository
Provides a good general-purpose base that is slightly softer than base 1 and dissolves
Proportion Components (%) PEG 6000
50
PEG 1540
30
PEG 400
20
PEG 4000
60
more rapidly
3
Has a higher melting point than the other bases, which is usually sufficient to compensate for the melting-point lowering effect of such drugs as chloral hydrate and camphor
PEG 1500
30
PEG 400
10
PEG 6000
30
PEG 1540
70
( 2 ) Th e un i fo rm l y m i xe d s em i pl as t ic m as s is k n e ad e d f u r th e r , r ol l ed in t o a c yl i nd e r , a nd di v i de d i n to t he r eq u is it e n um b er of s up po s i t o ri es . Ea c h s m a l l c yl i nd e r i s r ol l ed b y h a nd u nt i l a s up p os it o r y sh ap e is fa s h io n ed . b . C o mp r e ss i o n is ge n er a l l y u s ed wh e n c oc oa bu t t e r is us ed as a b as e . ( 1 ) A un if o rm m i xt u r e o f d r u g a nd ba s e is p re pa re d as fo r th e h a nd - r ol li ng m e th o d. ( 2 ) Th e m i xt u r e is p l ac ed i n to a s up po s i t o r y c om pr e s s i on de v i c e . P re s s u re i s a p pl ie d , a nd t he m i xt u r e is fo r c e d i n to lu b ri c a te d c om p r es s i on m o ld c a vi ti es . Th e m ol d i s t hen c o o le d a n d t he s u pp os i t o ri es ej e ct e d. ( 3 ) Th i s p ro c ed u re ge n era l l y pr o du c e s a 2 -g s u ppo s it o r y. H o we ve r , a la r ge vo l u m e of t he ac ti v e in g re d ie n ts c a n a f fe c t t he am o un t o f c oc o a b ut t e r r e q ui r e d f o r a n i nd i v id u al f o rm ul a . ( a ) Th e am ou n t o f c oc oa b u t te r n e ed e d is de t e rm i n ed b y c a lc ul a ti n g t he t o t al am ou n t o f a c t i v e i ng r e di e nt t o b e us e d, di vid i ng t hi s n um be r b y th e c oc o a b u tt e r d en s i t y f ac to r ( Ta b le 3 -6 ) , a n d s u b t ra c ti n g t he r es ul t in g n u m b e r f r om th e to t al am o un t o f c oc o a b ut t e r r eq u i re d fo r th e d es i re d n u m b e r o f s up p os it o r ie s . ( b ) F o r e xa m p le , s up p os e 1 2 s u p po si t o ri es , e ac h c on t ai n in g 3 0 0 m g as pi ri n , a r e re q ui r ed . E ac h m o l d c a v i t y ha s a 2 - g c ap ac i t y. F o r 1 3 s up po si t o ri es ( c a lc ul a te d t o p r o v id e one e xt r a ) , 3 .9 g as p ir i n ( 13 × 0 . 3 g = 3 . 9 g ) i s r e q ui r e d. Th is nu m b e r i s d i v i de d b y t he de n s i t y fa c to r of as pi r i n ( 1 .1 ) ( Tab l e 3 - 6 ) . Th us 3 . 9 g of as pi r in r e pl ac es 3. 5 5 g o f c oc o a bu t te r . Th e t o ta l a m ou n t o f c oc oa bu t te r ne e d ed fo r 13 s u pp os i to r ie s o f 2 g e ac h e q ua ls 26 g . Th e am ou n t o f c oc oa b u t te r r eq ui r e d is 26 g - 3 . 5 5 g , o r 2 2 .4 5 g. c . Th e fu s io n me t h od is t h e p r in c i p al wa y t h a t s u p p os it o ri es a re m a de c om m e r c i a ll y . Th is m e t ho d is u s e d p r im a ri l y f or su p p os it o ri es t ha t c on t ai n c oc o a b u tt e r , P E G , an d g l y c e ri ng e la t in P.59
b a se s. Mo l d s m ad e o f a lu m in um , b r as s , o r n ic k e l- c o pp e r a ll o ys a r e us e d a n d c an m a k e 6- 5 0 s up po s it o ri e s a t o ne ti m e .
Table 3-6. Cocoa Butter Density Factors of Drugs Commonly Used in Suppositories Drug
Cocoa Butter Density Factor Drug
Cocoa Butter Density Factor
Aloin
1.3
Dimenhydrinate
1.3
Aminophylline
1.1
Diphenhydramine hydrochloride
1.3
Aminopyrine
1.3
Gallic acid
2.0
Aspirin
1.1
Morphine hydrochloride
1.6
Barbital sodium
1.2
Pentobarbital
1.2
Belladonna extract
1.3
Phenobarbital sodium
1.2
Bismuth subgallate
2.7
Salicylic acid
1.3
Chloral hydrate
1.3
Secobarbital sodium
1.2
Codeine phosphate
1.1
Tannic acid
1.6
Digitalis leaf
1.6
( 1 ) Th e ca p ac i t y o f t h e m o l ds is de t e rm i n ed b y m e lt i ng a s u f fi c i e n t q u a nt i t y o f ba s e o v e r a s t e am ba t h , p ou r in g i t i n to t he m o ld s , a nd al lo wi n g i t to co n ge al . Th e “b la nk ” s up p os it o ri e s a re t ri m m e d , re m o ve d , a nd we i g h e d . O n c e th e we i gh t is k n o wn , th e d r ug - c on t a in in g s u pp os i to r ie s a re p r e pa r e d.
( a ) To p re p a re s u pp os i tor i e s , th e d r u g is r ed uc e d t o a f in e p o wd e r . A sm all a m ou n t o f g r at e d c oc oa b u t te r is l i qu e fi ed in a s ui t a bl e c on t ai ne r pl ac e d in a wa t e r ba t h a t 3 3 ° C o r le s s . ( b ) Th e fi n el y p o wd e r ed d r u g i s m i xe d wi t h m el t ed c o c o a bu t te r wi t h c o nt i nu o us s ti r r in g . ( c ) Th e re m a i nd e r o f th e g r a te d c oc oa bu t t er is ad d e d wi t h st i r ri ng . Th e t e m p e r at u re is m a in t ai ned a t o r b e lo w 3 3 ° C . Th e l i qu i d sh o ul d a p pe a r c r e am y r at h e r t ha n c le a r. ( d ) Th e m o ld is v e r y l i ght l y l ub r ic a te d wi t h m i n e ra l oi l , a nd th e c r ea m y m e l t i s p o u re d i n to th e m ol d at r o om te m p e ra t u re . Th e m e lt is po u re d c o nt i nu o us l y t o a v o i d l a ye r i ng . ( e ) A f te r th e s up p os it o rie s c on g ea l , t he y a r e p lac e d i n a re f r ig e ra t o r t o h a r de n . Af t e r 3 0 m i n , t hey a r e r em o v ed f ro m t h e re f r ig e r at o r , t r im m e d, a nd u n m o l de d . ( 2 ) Th e fu s i o n p ro c es s s h o ul d b e us ed c a r ef ul l y wi t h t h e r m ol a bi l e d r u gs a n d i n s ol u bl e pow d e r s. ( a ) I ns ol ub l e p o wd e rs in t h e m el t m a y se t tl e o r fl oa t du r i ng po u ri n g, d e p en di n g o n t he i r d e ns it y . Th e y m a y al so c o ll ec t a t on e e nd o f t he s u pp os i to r y b ef o r e t he m e l t c on g ea ls , a n d c au se a n on u ni f or m d r ug d i st r ib u ti o n. ( b ) H a r d c r ys t al l in e m at er i a ls (e . g ., io di n e, m e r b ro m i n ) c a n b e i nc o rp o ra t ed b y d is so l v i ng th e c r y s ta ls in a m in im um vo lu m e of s ui t ab le so l ven t be f o re t h e y a re in c o r p or a te d i n to t he ba se . ( c ) V eg e ta b le e xt r a c ts c a n be in c o r po r a te d b y m o i s t e ni ng wi t h a f e w d r ops o f al co h ol an d l e v i ga ti n g wi t h a s m a l l am o un t o f m e lt e d c o co a bu t te r . G . P ow d e r s 1 . I n t ro d uc t i o n. A p h a rm ac e ut ic a l p o wd e r i s a m i xt u r e of f in el y d i v id e d d r u gs or c h em ic a ls i n d ry f o r m . Th e po wd e r m a y b e us ed in t e rn al l y o r e xt e r n a l l y . a . Ad va n t a g es o f p o wd er s ( 1 ) Fl e xi b i li t y o f c om po un d in g ( 2 ) G o od c h em ic al s t a bi lit y ( 3 ) R a pi d d is pe r s i o n o f in g r ed i en ts be c au s e of the s m al l p a r ti cl e s i z e b . D i sa d va n t ag e s o f p owd e r s ( 1 ) Ti m e- c o n s u m i ng p re pa r a ti o n ( 2 ) I na cc u ra c y o f do s e ( 3 ) U ns u it a bi li t y f or m a ny u n p le as a nt - t as ti n g, h yg r o s c op ic , a n d d el iq u es c e n t d r u gs c . M i l li n g i s t he m e c h an ic a l p r oc ess o f r ed u c i ng th e pa r t ic le s i ze o f s ol i ds ( c o mm i n u ti o n ) b ef o r e m i xi n g wi t h o th e r c om po n en t s , f u rt h e r p ro c e ss i ng , o r i n co r po r a ti o n i nt o a fi n al p r o du ct ( Ta b le s 3 - 7 a nd 3 - 8 ) . Th e pa r t ic le s i z e of a p o wd e r i s r e la t ed to the p r op o rt i on of t he po wd e r t ha t c an p as s th r o ug h t h e o p en i ng of s t an d a rd s i e v es o f v a r io us di m e nsi o n s in a sp ec i fi e d am o un t o f ti m e. M i c r om e r i ti c s is t he s t ud y o f p a r ti c l es .
Table 3-7. United States Pharmacopeia Standards for Powders of Animal and Vegetable Drugs Type of Powder
Sieve Size All Particles Sieve Size Percentage of Pass Through Particles Pass Through
Very coarse (#8)
#20 sieve
20% through a #60 sieve
Coarse (#20)
#20 sieve
40% through a #60 sieve
Moderately coarse (#40)
#40 sieve
40% through a #80 sieve
Fine (#60)
#60 sieve
40% through a #100 sieve
Very fine (#80)
#80 sieve
No limit
P.60
Table 3-8. United States Pharmacopeia Standards for Powders of Chemicals Type of Powder
Sieve Size All Particles Sieve Size Percentage of Pass Through Particles Pass Through
Coarse (#20)
#20 sieve
60% through a #40 sieve
Moderately coarse (#40)
#40 sieve
60% through a #60 sieve
Fine (#80)
#80 sieve
No limit
Very fine (#120)
#120 sieve
No limit
( 1 ) Ad va n t a g e s o f m i l li ng ( a ) I nc r ea s e s t he s u r fa c e a r ea , wh ic h m a y in c rea s e t he di s s ol u ti o n r a te a s we l l a s b io a v a il ab i li t y ( e.g . , gr is e of u l vin ) ( b ) I nc r ea s e s e xt r a c t io n , o r le ac h in g , f r om a n im al g l an ds ( e. g ., li v e r , p a nc r ea s ) a nd f ro m c r ude v e g et a bl e e xt r a c t s ( c ) F ac il it a te s d r y i ng o f we t m a s s es b y i nc r ea s ing t he s u r fa c e a re a a n d r e d uc in g th e d is t an c e tha t m o is t ur e m us t tr a v e l to r e ac h t he ou t e r su r f ac e .
Mi c r o n i z a t io n a nd s u bs eq u e nt d r y in g , i n t u rn , i nc r e a s e s t ab i li t y as occ l ude d s o l ven t i s r e m o v e d . ( d ) Im p r o v es m i xi n g , o r b l en d in g , o f s e ve ra l s ol id i ng r ed i en ts i f t he y a r e r e d uc ed t o a pp r o xi m a te ly t h e s am e s i z e ; a ls o m in i m i ze s s e g r eg a ti on a nd p r o vi de s g r ea t e r d os e u ni f o rm i t y ( e ) P e rm it s u ni f o rm d is t r ib u t io n o f c ol o r in g a ge n ts i n a r t if ic i al l y c o lo r ed s o li d p ha r m a c e u ti c a ls ( f ) I m p r o v es th e fu nc t io n o f l u b ri ca n ts u s ed to c oa t t he s u r fa c e of t he g r a nu l at i on o r p o wd e r i n c om p r ess e d t ab l et s a n d c a p s ul es ( g ) Im p r o v es th e t e xt u r e , a p pe a ra nc e , a n d p h ys ic a l s t ab i li t y of oi n tm en t s , c r e am s , an d p as t es ( 2 ) D i sa d va n t ag e s o f m il l in g ( a ) C a n c h a ng e t h e p ol y m o r ph ic fo r m o f t h e ac t i ve i ng r ed i en t , r e nd e ri n g i t l e ss a c ti v e ( b ) C a n d eg r ad e th e d r ug as a r e s u lt o f h ea t b u ild u p , o xi d a t io n , o r a d so r p ti on o f u n wa n te d m o is tu r e b ec a us e o f i nc re a s e d s u rf ac e a r e a ( c ) D ec r ea s es t h e b ul k de n s i t y o f t he ac t i v e c o m po u n d a nd e xc i pi en t s , c a us in g f l o w p r ob l em s an d s e g re ga t io n . ( d ) D ec r e as es th e p a rt ic le s i z e o f t he r a w m at e ri al s a n d m a y c r ea t e p r o bl em s wi t h s ta t ic c ha rg e , wh ic h m a y ca us e p a rt i c l e a g g re ga t io n a n d d e c re as e t h e d is s o lu t io n r a t e ( e ) I nc r ea s e s s u r f ac e a re a , wh ic h m a y p ro m o t e ai r ad s or p ti o n a nd in h ib it we t t a b i li t y ( 3 ) C o mm i nu t i o n t ec h n iq u e s. O n a la r g e sc al e , v a r i o us m i ll s a nd p u l ve ri z e r s ( e .g . , ro t ar y c u t te r , h am m e r , ro ll e r , f lu i d e ne r g y m i ll ) a re us ed d u r in g m an u fa c tu r in g . O n a s m a ll s c al e , t he ph a rm ac is t us ua ll y u se s o ne o f t h e fo ll o wi n g c om m i nu t ion t ec hn i qu es : ( a ) T r i tu r a t i on . Th e s ubs t an c e is r ed uc ed t o s m a l l p a rt ic l es b y r u bb i ng it i n a m o r t a r wi t h a p es t le . Tr i t u ra t io n a ls o d es c ri b es t h e p r oc es s b y wh i c h f ine p o wd e r s a r e i n ti m a t el y m i xe d i n a m o rt a r . ( b ) P u l ve r iz a t io n b y i n t e r ve n t i o n . S u bs ta nc es ar e r ed uc e d a nd s u bd i v i de d wi t h a n a d di t io n al m a te r ia l (i . e ., so l ven t ) th a t is ea s il y r em o ve d a f te r p u l ve ri z a t io n . Thi s t ec h ni q ue is of t en us ed wi t h gu m m y s ub s t a nc es th a t r e a gg l om e ra t e o r re s i s t g r i nd i ng . F o r e xa m p l e, c a m ph o r i s r ea d il y r e du ced a f t e r a s m a ll am ou n t o f al c oh ol o r o t he r v ol a ti l e s o l v e n t is ad d ed . Th e s o l ven t i s t h en pe r m i t te d t o e v ap o ra t e . ( c ) L e vi ga t i on . Th e p a r tic l e s i z e o f t he su bs t an c e i s r e du c e d b y a dd i ng a s u it a bl e n o ns ol v e n t ( le v ig a t in g a g en t ) t o f o rm a pa s te . Th e p as t e i s t he n r u b be d i n a m o r ta r an d pe s tl e o r us in g a n o i nt m en t s l ab an d s pa t ul a . Th is m e th o d is o ft e n us e d t o p r e v e n t a g r i tt y f e el wh en s o l id s a r e i nc or p o ra t ed i n t o d e rm at o lo gi c o r o p hth a lm ic oi n tm en ts an d s us p e n si o ns . Mi n e ra l o il is a c om m o n l e v i ga t in g a g en t. 2 . M i x in g pow d e r s. P o wd e r s a re m i xe d , o r b l en de d , b y t h e f ol l o wi ng f i v e m e th o ds :
a . S pa t u la t i o n. A s pa t ula is us ed t o b le nd sm al l a m ou n ts o f po wd e r s o n a s h ee t o f pa pe r o r a p i ll til e . ( 1 ) Th i s m e t ho d i s n o t s ui t a bl e f o r l a rg e q u an t it i es o f p o wd e rs o r f o r p o wd e r s t h at c o n ta in p ote n t s ub s ta nc es be c a us e h o m o g en eo u s bl e nd i ng m a y no t oc c u r . P.61
( 2 ) Th i s m e t ho d i s p a rt ic u l a rl y u se f ul fo r s o li d s ub s ta nc e s t ha t l i qu e f y o r f o r m e u te c t ic mi x t u re s ( i . e ., m i xt u r e s t h at m e l t a t a l o we r te m pe r at u r e th a n a n y o f t h ei r i n g re di e nt s ) wh e n i n c lo se , pr o lo n ge d c on t ac t wi t h o ne an o th er b e ca us e l i tt l e c o m p r es s io n o r c o m p ac t io n re su l ts . ( a ) Th e s e s u bs ta n c e s i nc l ud e p h en ol , c am p ho r , m e nt h ol , th y m ol , a sp i ri n , p h e n yls al ic y l a te , a n d p he n ac e ti n . ( b ) To d im in is h c on t ac t , p o wd e r s p r ep a r ed f ro m th e s e s u bs t an c e s a r e c om m o n l y m i xe d wi t h an i n er t di lu e nt ( e. g . , l ig h t m a gn es i um o xi d e o r m a gn es i um c a rb o na t e, k a o li n , s ta r ch , b e nt o ni t e ). ( c ) S il ic ic ac id ( ap p ro xi m a t e l y 2 0 % ) p re v e n ts eu t exi a wi t h a s pi r i n, p h e n yls al ic y l a te , a n d o the r t r ou bl es om e c om p ou nd s . b . T r i tu r a t i on is u s ed bot h t o c o m m in u te an d to m i x p o wd e r s . ( 1 ) I f co m m i nu ti o n is d es i r e d, a p o rc el a in o r ce r am ic m o r ta r wi t h a r ou g h i n ne r su r fa c e is p re f er r ed t o a gl as s m o r t a r wi t h a s m oo t h wo r k i ng s u r f ac e . ( 2 ) A gl as s m o r t a r is p ref e r a bl e f o r c he m i ca ls th at s ta i n a p o rc el a in o r c e r am ic s u rf ac e as we l l a s fo r s im pl e a d m i xt u r e o f su bs t an c e s wi t h o u t s p ec ia l n e ed fo r c om m i nu t i on . A g la s s m o r ta r c lea n s m o r e re a di l y af t e r us e . c . G e om e t r ic di l u t io n i s u s e d wh e n p o te n t su bs ta n c e s m us t b e m i xe d wi t h a l ar g e a m o un t of di l ue nt . ( 1 ) Th e po t en t d r u g a nd a n ap p ro xi m a t el y e q ua l v o l u m e of di l ue n t a r e p l ac e d in a m o rt a r a nd th o r ou g hl y m i xe d b y t r i tu ra t i on . ( 2 ) A s ec o nd po r ti o n o f di l ue n t , e qu al in v o lu m e to t he po wd e r m i xt u r e i n t h e m o rt a r , is a dd ed , and t r it u r at i on i s re pe a te d . Th e p r oc es s i s co n ti n ued ; e q u al v ol u m e s o f d il u en t a r e a d de d t o t h e p o wd er m i xt u r e i n t h e m o r t a r un t i l a l l o f t h e d il u en t i s i nc o rp o r a te d . d . S i f ti n g . P o wd e r s a r e m i xe d b y pa s s i ng th em th r o ug h s i ft e rs s im i la r to t h os e u s ed to s i f t f lo u r . Th i s p ro ce s s re s ul ts in a l i gh t , f lu f f y p ro d uc t. U s u al l y , i t is n o t a c c ep t ab l e f o r i nc o rp o r at i ng po te n t d r u gs i n to a d il u en t b a se . e . T um b li n g i s t he p ro c es s o f m i xi n g p o wd e r s i n a l ar g e c on t ai ne r r ot a te d b y a m o t o ri z e d p r oc es s . Th e s e b l en d er s a r e wi del y u se d i n i n du s t r y , as a re l a r ge - vo l um e p o wd e r m i xe r s t h at us e m ot o r i z ed bla d e s to bl e nd th e p o wd er i n a l ar g e m i xi n g v e s s e l. 3 . U se a nd pa c ka g i ng of p ow d e rs . D ep e nd in g on t he i r i n te n de d u se , p o wd e r s a r e p ac k a g ed an d di s p e ns ed b y p h a rm ac is t s a s bu lk po wd e r s o r d i vi de d p o wd e r s .
a . B ul k p o wd e rs a re di s pe n s e d b y t h e p ha rm a c i s t i n b u lk c on t ai n e rs . A p e r f o r a te d , o r si f t e r , c an is us e d f o r e xt e r n a l d us t in g , a nd an ae r o s ol c o n t ai n e r i s us e d f o r s pr a y i n g o n to s ki n . A w i d e- m o u t he d g l as s ja r p e r m i ts ea s y re m o v a l of a s p o on f ul of po wd e r . ( 1 ) P o wd e rs c o m m on l y di s pe ns e d i n b ul k f o rm ( a ) An t a c i d a nd l ax a t i ve p ow de r s ar e us ed b y m i xi n g th e d i r ec te d a m ou n t o f po wd e r ( us u al l y ap p roxi m a t e l y 1 t e as po o n) in a p o rt i on of li qu i d, wh i c h t h e p a ti e nt t he n d r in k s . ( b ) D o uc h e p ow d e rs a re d is s o l v ed in wa r m wa te r a nd ap pl i ed va gi n al l y . ( c ) M e d ic a te d an d no nm e d ic a t ed pow d e r s f o r e x t e r na l us e a r e us u al l y d i sp e ns ed in a s i f te r f or c o n v en i en t a p pl ic a ti on to t he s k in . ( d ) D e n ti f r i ce s , o r de n ta l c le a ns i ng p ow de r s , a r e us ed fo r o ra l h y g ie ne . ( e ) P o wd e rs f or t he ea r , n o s e, t h r oa t , to o t h s ock e t s , o r va gi n a a r e a d m i ni s te r ed wi t h an in s u f f la t o r, o r p o wd e r b l o wer . ( 2 ) N o np o t en t su b s ta n ce s a re us ua ll y d is pe n se d i n b u lk p o wd e r fo r m . Th o s e i n te n de d f o r e xt e r n a l u s e s h ou l d b e cl e ar l y l a be le d . ( 3 ) H yg r o s c o p i c, de l i que s c en t , o r vo l a ti l e p o wde r s s ho u ld be pa c k ed in g l as s j a rs ra t he r th a n p as t eb o a rd c o nt a in e rs . Am b e r or g re e n g la s s s ho u ld b e us ed if ne e de d t o pr ev e n t de c om po s i t io n o f l igh t - s e ns i ti v e c o m p on e nt s . A l l p o wd e r s s ho ul d b e s to r e d i n t ig h tl y c lo se d c on t a in e rs . b . D i vi d e d p ow de r s ar e d i s p e ns ed in in di v i d ua l do s es , u s u a ll y in f ol d e d p a p e rs ( i. e . , c h a r tu l ae ) . Th e y m a y a ls o b e d is pe ns e d i n m e t al f oi l, sm al l h e a t -s ea le d o r r es ea l ab le p l as t ic b ag s , o r o t he r c o nt a in e rs . ( 1 ) A f te r th e i n gr e di e nt s a r e we i gh e d, c o m m in u ted , an d m i xe d , th e p o wd er s m us t be ac c u r at e l y d i vi de d in t o t he p re s c r ib e d nu m be r of do se s . ( 2 ) D e pe nd i ng on th e p o te n c y o f th e d r u g s u bs t anc e , t h e p ha r m a ci s t d e ci d es wh e th e r t o w e igh e ac h p o rt i on s e pa r a te ly b e f o re pa c k ag i ng o r t o a p p ro xi m a t e p o r ti on s b y t h e bl o ck - a nd - d i vi de me t h o d. P.62
( 3 ) P ow de r p ap e r s c an b e of an y c on ve n ie n t s i ze t ha t fi ts t he re q ui r ed d o se . Fo u r b as ic t y pe s ar e us e d: ( a ) V eg e t ab l e p a r ch m ent i s a th in , s em i op aq u e, m o is tu r e - re s i s ta n t p ap e r. ( b ) W hi t e b o n d is an opa q u e p ap e r t ha t ha s n o m o is tu r e - re s i s ta n t p r o pe r t ie s . ( c ) G l as s i ne is a gl a z e d, t r a ns pa r e nt , m oi s tu r e - res is t an t pa pe r . ( d ) W ax e d p ap e r is a t ran s pa r en t wa t e r p ro o f p ape r . ( 4 ) H yg r os c o p ic a n d v o l at i l e d ru g s a re be s t p r ot ec t ed wi t h wa xe d p a p e r t ha t i s d o ub le wr a p p ed an d c o v e r e d wi t h a b o nd pa p er t o i m p r o ve t h e a p p ea r an c e . Pa r c h m e n t a n d g la s s i ne pa pe r s a r e o f li m i t ed us e f o r t h es e d r u gs . 4 . S pe c ia l p r ob l em s . V ol a t il e s ub s t a nc es , e u te ct ic m i xt u r e s , l iq ui ds , an d h yg r o sc op ic o r d el iq u es c e n t s ub s ta nc es p re se n t p r o b l em s wh e n t he y a r e m i xe d i nt o p o wd e r s t ha t r e q ui r e s pe c i a l t r ea tm e nt.
a . V o la t i le su b s ta n ce s (e . g . , c a m p h o r, m e nt h ol , e ss e nt i al oi ls ) c a n b e l ost b y vo l a ti l i z at i on af t e r t hey a r e in c o r p or a te d i n to po wd e r s . Th is pr o c e s s i s p r e ve n te d o r re t a rd e d b y t h e u s e of he a t -s ea l ed p l as t ic b a gs o r b y do ub le wr a p p i n g wi t h wa xe d o r g l as s i n e p ap e r i ns id e whi t e b o nd pa p er . b . L iq u i ds a re in c o r po r at e d i n to di v i d ed po wd e r s i n s m a ll am o u n ts . ( 1 ) Ma g n e s i um c a rb o na te , s t a rc h , o r l ac t os e c an b e ad d ed to in c re as e t h e a b so r ba b il i t y o f th e p o wd e r s b y in c re as i ng th e s u r f ac e a r e a. ( 2 ) W hen t h e li q ui d i s a s o l v en t fo r a n on vo la t il e h e a t -s ta b le c om p ou n d, it i s e va p o ra t ed g en tl y i n a wa t e r b a th . So m e f lu id e xt r a c ts an d t i nc tu r es a re t r e a te d i n t h is wa y . c . H yg r o s c o p i c an d de l iq u e sc e n t s ub s t an c es tha t be c o m e m o is t b ec a us e o f an a ff i ni t y fo r m o is tu re i n t he ai r c a n b e p r ep ar e d as d i v i de d p o wd e r s b y a d di n g i ne r t d i lu en t s . D ou b le wr a p p in g i s d es i ra ble f o r f u rt h e r p r ot ec t io n . d . E u te c t ic mi x t u re s H . C a p su l es 1 . I n t ro d uc t i o n. C ap s u le s a r e s ol i d d os ag e f o rm s in wh i ch o ne or m o r e m e di ci n al o r in e r t s u bs t an c es (a s p o wd e r , c om pac t , b e ad s, o r g r an ul a ti o n) a r e en cl os ed wi t h i n a s m a l l g el a ti n s he l l. G e la t in c a ps ul es m a y b e h a rd or s o f t. Mo s t c a ps ul es a re in t e nd e d t o b e s wa l lo we d wh o l e , b u t o c c as io n al l y , t h e c on t en t s a r e r em o v ed f r om th e g el a ti n s he l l an d us ed as a p re m e a su re d d o se . 2 . H a r d g e la t i n c ap s ul es a . P r e pa r a t io n of f i ll e d h a r d ca p su l es in cl u de s p r e pa r i ng th e f o rm u la t ion , s e le ct i ng th e a p p ro p ri a te c ap s u l e, f il li n g t he c a ps u l e s he ll s , a nd c l ea n in g a n d p ol is h in g t h e f il l ed c a p s u l es . ( 1 ) E m p t y ha r d c ap s u l e s h el ls a re m a nu f ac tu r e d f r o m a m i xt u r e of ge l at in, c o lo r an t s , an d s om e ti m es an op a ci f yin g a g en t (e .g . , ti t an iu m d io xi d e ) . The U S P a ls o p e rm i ts th e a dd i t io n o f 0 . 15 % s ul f u r d io xi d e t o p r e ve nt d e co m p os i ti o n o f g el a ti n d u ri n g m an u fa ct u r e. ( 2 ) G e la t in U S P i s o b ta ine d b y p a r ti a l h yd ro l y s i s o f c o ll a ge n o b ta i ne d f r om t h e s ki n , wh i t e c on n ec ti v e t is s u e , a nd bo n es o f an i m a ls . Ty p e s A an d B ar e o b t ai ne d b y a c i d a n d a lk a l i p r oc es si ng , re s pe ct i ve l y . ( 3 ) C a ps ul e s he ll s a r e c a s t b y d ip pi n g co l d m e t all i c m o l ds o r pi ns in t o g e la t in so lu t io ns t ha t a r e m ai n ta i ne d a t a un i fo r m t e m p e r at u re a nd an e xa ct d e g re e o f fl u id it y . ( a ) V a ri a ti on in t he v is c os i t y of th e g e la t in s o lu t ion i nc r ea s e s o r d ec r e as es t h e th ic k n es s o f t h e c a ps u l e wa ll . ( b ) A f te r th e p i ns a r e wi th d r a wn f r om t h e g el a ti n s o lu t io n , t he y a r e r o ta t ed wh i l e b ei ng d ri ed in k i ln s . A s t r o ng bl as t o f fi l te r ed a ir wi t h c o nt r o ll ed h u m i di t y is f or c e d th r ou gh t he k i ln s . E ac h c ap s u le is t he n m ec ha ni c al l y s t r ip p ed , t r im m e d , a nd joi n ed . b . S t o r ag e . H a r d c a p s u le s s ho u ld be st o re d i n tig h t l y c lo s e d g l as s c o nt a in e rs an d p r o te c t e d f r om du s t a nd e xt r e m e s o f hu m i d it y a nd t e m p e r at u re .
( 1 ) Th e s e c a ps ul es c o n ta i n 1 2% - 1 6% wa t e r , var y i n g wi t h s to r ag e c o nd i ti on s . W hen h um i dit y i s l o w, t h e c a ps u le s be c om e b r it t le . W hen h u m i di t y is hi g h, t he c a ps u le s b ec om e f l acc i d a nd s h a pe l ess . ( 2 ) S t or a ge at hi g h t em pe r a t ur es al s o a ff ec t s t he q u al i t y o f ha r d g el a ti n c a ps ul es . c . S iz es . H ar d c a ps ul es a r e a v ai la b le in a v a r i et y o f s i z es . P.63
( 1 ) E m p t y c a ps ul es a re n u m be r e d f r om 00 0 , wh ic h i s t h e l ar g es t s i ze t hat c a n b e s wa l lo we d , t o 5 , th e s m a l le st s i ze . Th e a pp r o xi m a t e ca p ac it y o f c a ps ul es r an g es f r om 600 t o 3 0 m g f o r c a ps u le s fr o m 0 0 0 t o 5 , re sp ec t i v ely . Th e c ap ac i t y v a r ie s b ec au s e o f v a r yin g d en s i t ie s o f po wd e r e d d r ug m a te r i al s a nd th e d e gr e e o f pr es s ur e u s e d to fi l l th e c a ps ul es . ( 2 ) La r g e c a ps u le s a r e av a i l ab l e f o r ve t e r i na r y m e d ic i ne . ( 3 ) S e le c ti n g c a ps u le s . C a p s u l e s i z e sh ou l d b e c h os en c a r ef u ll y. A p r o pe r l y fi l le d c ap s u l e s h o ul d h a v e it s b od y f il l ed wi t h t he dr u g m i xt u r e an d i t s c ap fu l l y e xt e n d e d d own t h e b od y. Th e c a p is m e an t to en cl os e t h e p o wd e r , no t to re t ai n a dd i t io na l p o wd e r . Ty p i c a lly , h a r d g el a ti n c ap s u l es a r e u s ed to en c ap s u la t e b e twe e n 6 5 m g a nd 1 g of po wd e r e d m a te r ia l , i nc lu di n g t h e d r u g a nd an y d il ue n ts ne e de d . ( a ) I f t he d ru g d os e i s i na d e qu a te to fi l l t he c a ps u l e , a d i lu en t (e . g ., l a ct os e ) i s a dd e d. ( b ) I f t h e am o un t o f dr u g n e ed e d f o r a u su a l d os e i s t o o la r g e t o p la c e in a s i ng le c a ps u le , t wo o r m o r e c a ps ul es m a y b e r equ i r ed . ( c ) Lu b r ic an ts s u c h as m a g n es iu m s t e a ra t e ( f r equ e n tl y , 1% ) a re ad de d to f a ci l it a te th e fl o w o f th e p o wd e r wh e n an au t om ati c c ap su l e -f i ll in g m ac hi ne i s u se d . ( d ) W ett in g a g en ts ( e. g . , s od i um l a u r yl s u l fa t e ) m a y b e a d de d t o c a ps ul e f o r m u l at io n s t o e nh a nc e d r u g d is so lu t io n . d . F il l i ng ca p s ul e s. W he t h e r o n a l a rg e - o r a s m a l l -p r od u ct io n s ca l e, th e c a p is f ir s t s e p a ra t ed f rom t he bo d y of t he c a ps ule b ef o r e f il li n g t he c a ps ul e b o d y wi t h th e f o rm u la t ion a nd th e n r e at t ac hi n g th e c a p. A u to m a t ed an d s em i au t om at e d c ap s u le - fi l li n g e qu ip m e n t f i ll th e ca p s u l e b od ie s wi t h t he f o r m u l at io n b y g r a v i t y fi ll, t am p in g , o r a s c re w- f e ed ( i .e . , a ug e r ) m ec h an is m . E xt e m p o ra ne o us l y c o m p ou n de d c aps u le s a r e us u al l y fi l le d by t h e p u nc h m et h od . ( 1 ) Th e po wd e r is pl ac ed o n p a pe r an d f l at t en e d wi t h a s p a tu la so th a t t he l a ye r of po wd e r is no m or e t ha n a p pr o xi m a t el y o ne t hi r d t h e l en g th of t he c a ps ul e . Th e pa p e r is hel d in th e l e ft ha n d. Th e bo d y o f t h e ca ps u le is h e ld i n th e ri gh t ha n d a nd re pe a t ed l y p re s s ed in t o t he p o wd e r u nt il t he c a ps ul e i s fi ll e d. Th e c ap is r ep lac e d a nd th e c a ps ul e we ig h e d. ( 2 ) G r a n ul a r m a te r ia l tha t do es no t le nd i ts el f we l l t o t h e p un ch m e t ho d c a n b e po u re d i n to ea c h c a ps u le f ro m t he po wd e r p ap e r o n wh i c h it wa s we i g h e d .
( 3 ) C r ys t a l l i n e m at e ri a ls , e s p ec ia l l y th os e t h at c o n si st o f a m as s o f f i l am en t -l ik e c r y s ta ls ( e.g . , qu in i ne s a lt s ) wi l l no t f i t i n to a c a ps u le ea s i l y u n le ss th e y a re po wd e r ed . ( 4 ) A f te r th e y a re fi l le d , c a ps ul es m u st be cl ea n ed a nd po li s he d . ( a ) O n a sm a l l s ca l e, c ap s ul es a re c l ea n ed i n di v id u al l y o r i n sm a ll n u m b er s b y r u b bi ng t he m o n a c lea n ga u ze o r c l ot h . ( b ) O n a l a r ge sc a le , m a n y c a p su le - f il li n g m a c h in e s h a ve a c l ea ni n g va c u um th a t r em o v es any e xt r a n e o us m a t e ri al as t h e c ap s u le s l ea ve t he m ac h in e . 3 . S o f t g el a t i n c ap s ul es a . P r e pa r a t io n ( 1 ) S o ft ge la t in c a ps u le s a r e p r ep a r ed f ro m g el a tin s h e ll s. G l y c e r i n o r a p o l yh y d ri c a lc oh o l ( e .g . , s o r bi t ol ) i s a dd e d t o t h ese s h e ll s t o m ak e t he m e l as t ic o r pl as t ic - li k e . ( 2 ) Th e s e s h el ls c o nt a in p r e s e r va ti v e s (e . g. , m e thy l a n d p r op yl pa r ab e ns , s o r bi c ac i d) t o p r e v en t th e g ro wt h o f f u ng i . b . U s es . So f t g el a ti n s hel l s a re o bl on g , e ll i pt ic al , o r sp h er ic a l. Th e y a r e u s ed to c o n ta in li q ui ds , s us p en si o ns , p as t es , d r y p o wd e r s , o r p el l et s. ( 1 ) D r ug s t h at a re c om m e r c ia ll y p r ep a re d i n s o ft c a ps ul es in c l u de d e m e cl oc y c li n e h y d r oc hlo r i de ( D ec lo m yc i n , L ed er l e ) , c hl o ra l h y d r a te , d i go xi n ( L a no xi c a ps , G laxo S m i t h K li n e ), v i t am in A, a nd v i t am in E . ( 2 ) S o ft ge la t in c a ps u le s a r e u s u a ll y p re p a re d b y t h e p l at e p r oc es s o r b y t h e ro t a r y o r r ec ip r oc a ti ng d ie p ro ce s s . 4 . U n i fo r m i t y a n d d i s i nte g r a t io n a . Th e un i f o rm i t y o f d o s a g e f o rm s c an be de m o ns t r at e d b y ei t h er we i g ht va r i a ti o n o r c on t en t un i fo r m it y m e t ho d s. Th e o f f ic i al c om p en d ia s h ou ld be c o ns ul t ed fo r de t ai ls o f th e s e p ro ce d ur es . b . D i si n t eg r a t i on te s ts a r e no t u s u a ll y r eq u i re d f o r c a ps ul es un l es s t he y h a ve be e n t r ea t ed to r es i s t s ol u ti on in ga s tr ic f lu id ( e nt e ri c c oa t ed ) . I n th is c as e , t h e y m us t m ee t the r e qu i re m e n ts fo r di s i n te g r a ti on o f e nt e ri c -c oa t ed t a b le ts . P.64
I . T AB L E T S 1 . I n t ro d uc t i o n a . Th e o ra l r ou t e i s t h e m os t im po r ta n t m et h od fo r a dm in is t er i ng d ru gs for s ys t em ic e f f ec t . O r a l d r ug s c an b e gi v e n as s ol i ds o r l iq ui d s . ( 1 ) Ad va n t a g e s o f s o l id d o sa g e fo r m s ( a ) A cc ur a t e d os ag e ( b ) E as y s hi pp i ng an d ha n dl i ng ( c ) Le ss s h el f s pa c e n eed e d p e r d os e t h an fo r li qu i d ( d ) N o p r es e r v a ti o n r eq ui r e m e n ts ( e ) N o t as t e -m as k i ng p rob l em ( f ) G e n er a ll y m o r e s t ab le t ha n l i qu id s , wi t h lo n ge r e xp i r a ti o n d at es
( 2 ) Ad va n t a g e s o f l i q uid d o sa g e f o r ms ( a ) F or s o m e d ru gs ( e. g ., a ds o rb e nt s , a nt ac i ds ) , g r e a te r e f f ec ti v e n es s t han s o li d f o rm ( b ) U se f ul f or pa t ie n ts wh o ha v e t ro u bl e s wa l l o win g s o li d d os a ge fo r m s b . T ab l e ts a re th e m o s t c o m mo n l y u s e d s o l id do s a ge f o rm . ( 1 ) Ad va n t a g e s ( a ) P r ec is io n a n d l o w c on t e nt v a r ia b il it y o f th e un i t d os e ( b ) L o w m a n uf ac t u ri n g c o s t ( c ) E as y t o p ac k a ge a nd s hi p ( d ) S im pl e to id en t i f y ( e ) E as y t o s wa l lo w ( f ) A p p ro p ri a te fo r s p ec ia l - r el ea s e f o rm s ( g ) B es t s ui t ed t o l ar g e -s c a l e p r od uc t io n ( h ) Mo s t s t a bl e o f a l l o ral d os ag e f o rm s ( i ) E s s en t ia ll y t am p e rp r oo f ( 2 ) D i sa d va n t ag e s ( a ) S om e d r ug s r es is t c om p r es s i on in t o t ab l et s . ( b ) S om e d r ug s ( i .e . , t h os e wi t h p o or we t t i ng , s low d i s s ol ut i on p ro p er t ie s , i n t er m ed ia t e t o l a rg e d os e s , o p ti m u m a bs o rp t io n h i g h in t he ga s t r o in t es ti na l t r a ct , or a n y c om bi n at i on o f th es e f e a tu r es ) m a y b e di f fi cu l t t o f o rm u la t e to p r o vi de ad e qu a te bi o a v ai l ab i li t y . ( c ) S om e d r ug s ( e .g . , t ho s e wi t h a n o bj ec ti o na b le t as t e o r o d or , th os e s e ns it i v e to o xy g e n o r a tm os p he r ic m o is tu r e ) r e qu i r e e nc ap s u l at i on o r e n t r ap m e n t b ef o r e c o m pr e s s i on . Th es e d r ug s a r e m o re ap p ro p r ia t e i n c a ps ul e f o rm . 2 . T ab l e t d es i gn a nd f or m u l a ti o n a . C h a ra c te r i s t ic s o f i de a l ta b le t s ( 1 ) F re e o f de f ec ts (e . g ., c hi ps , c r ac k s , d is co l or a ti o n , co n ta m i n at i on ) ( 2 ) S t ro n g e no u gh to wi t h s ta n d t he m e c h a ni c a l s tr e s s es o f p ro d uc ti o n ( 3 ) C h em ic al l y an d p h y s ic a ll y s ta bl e o v e r ti m e ( 4 ) C a pa bl e o f re l ea s i n g m e di c i n al a g en t s i n a p re d ic t ab le a nd re p r od uc ibl e m a nn e r b . T ab l e t e xc i p ie n ts . Tab l e ts a r e m an u fa c tu r ed by w e t g r a n ul a t io n , d r y g r a n u la t i on , or d i re c t co m p r es s i on . R eg a rd l ess o f th e m et h od of m a nu f ac tu r e , t a bl e ts f o r o r a l i ng es t io n u su a ll y c on t a in e xc i pi e nt s, wh i c h ar e c om p on e nt s a dd e d t o t he ac t i v e i ng r e di en t s t ha t h a v e s p ec ia l f u nc ti o ns ( Ta b l e 3 - 9 ) . ( 1 ) D i l ue n ts a re fi l le r s de s ig n ed to m a k e up th e re q ui r e d b ul k o f t h e t ab l et wh e n t h e d r ug do s a g e am o un t i s i na d eq u at e . D i lu e n ts m a y al so im p ro v e c o he si o n, pe r m i t d i re c t c o m p re ss io n , o r p r om o te f l o w. ( a ) C o mm o n d i lu e n ts inc l ud e k ao li n , l ac t os e, m an n i to l , s t a rc h , m ic r oc r y s ta l li ne c e ll u lo s e , po wd e r e d s ug a r , a nd c a l c iu m p ho s p h at e . ( b ) S e le c t io n o f t he d ilu e n t i s b as ed on t he e xp e r i en ce o f t he m a nu f ac tu r e r a s we l l as o n th e c os t o f th e d il u en t a n d i ts c om p at i bi li t y wi t h t h e o t he r ta b le t i n g re di en t s . F o r e xa m p le , c al c i um sa l ts c an n ot be us e d a s
f i ll e rs f or t et r ac y c li n e p ro d uc ts b ec au s e c a lc iu m i n t er f e re s wi t h t he a b so r p ti on o f t et r ac y c li ne f r om th e g as t r oi n te st i na l t ra ct . ( 2 ) B i nd e r s a n d a d he s ive s a r e a dd e d i n e it h e r d r y o r li qu i d f o rm to p r o m o t e g ra n ul a ti o n o r to p r om ot e c oh es i v e c om p a ct s d u ri n g d ir e c t c om p r es s i on . ( a ) C o mm o n b i nd i n g a ge n t s i nc lu d e a 10 % -2 0 % a q ue o us p r e pa r at i on of c o r ns ta r c h , a 25 % - 50 % s o l u ti on o f g lu c o se , m ol ass es , v a r io us na t ur a l g um s ( e . g ., ac ac ia ) , c e ll ul os e d e r i v a ti v e s ( e .g . , m et h y lc e ll ul os e , c a r bo xy m e t h y l c el lu l os e, m ic r oc r y s ta l li ne P.65
c e ll ul os e ) , g el a ti ns , an d p o v i d on e . Th e na t u ra l g um s a r e va r i ab le in c om p os it i on an d a r e u s ua l l y c o nt am i na t ed wi t h ba c te r i a.
Table 3-9. Some Common Tablet Excipients Diluents Calcium phosphate dihydrate NF (dibasic) Calcium sulfate dihydrate NF Cellulose NF (microcrystalline) Cellulose derivatives Dextrose Lactose USP Lactose USP (anhydrous) Lactose USP (spray dried) Mannitol USP Starches (directly compressible)
Starches (hydrolyzed) Sorbitol Sucrose USP (powder) Sucrose-based materials Binders and adhesives Acacia Cellulose derivatives Gelatin Glucose Povidone (PVP) Sodium alginate and alginate derivatives Sorbitol Starch (paste) Starch (pregelatinized) Tragacanth Disintegrants Alginates
Cellulose Cellulose derivatives Clays Crospovidone (cross-linked PVP) Starch Starch derivatives Lubricants PEGs Stearic acid Stearic acid salts Stearic acid derivatives Surfactants Talc Waxes Glidants Cornstarch Silica derivatives
Talc Colors, flavors, and sweeteners FD&C and D&C dyes and lakes Flavors available in two forms (spray dried, oil) Artificial sweeteners Natural sweetener D&C, drugs and cosmetics; FD&C, food, drugs, and cosmetics; NF, National Formulary; PEG, polyethylene glycol; PVP, polyvinylpyrrolidone (more commonly, povidone); USP, United States Pharmacopeia. ( b ) I f t h e d ru g s u bs ta nc e i s a d v e rs el y a f fe c t e d b y a n a q ue o us b i nd e r, a n o n a qu e ou s bi n de r c a n b e u s e d o r t he bi nd e r c a n be ad d ed dr y . Th e b i nd i ng ac ti o n is us u al l y m o r e e ff e c t i ve wh e n t he b i nd e r i s m i xe d i n l i qu i d form. ( c ) Th e am o un t of bi n der o r ad he si ve us e d d ep en d s o n t he e xp e r i en ce of t h e m an u fa c tu r e r as we l l a s o n t h e o th e r t a bl e t i ng r e di e nt s . O ve r we t t i n g u s ua ll y p r od uc e s g ra n ule s th a t a re t oo ha r d t o a ll o w p r o pe r t ab le t in g . U n d e r we t t in g u s u a ll y p r od u c e s t a bl et s t h at a re too s o f t a n d t en d to c r um ble . ( 3 ) D i si n t eg r a n ts a re add e d t o ta bl e t f o rm ul a ti o ns t o f ac il i ta t e d i si n te g ra t io n wh e n t he ta b le t c o nt ac t s wa t e r in th e ga s t r o in t es ti n al t ra ct . D i s in t eg r an t s f un c ti on b y d r a wi n g wa t e r i nt o t h e ta b le t , s we l l in g , a nd c a us in g t h e t ab l et t o b u rs t . ( a ) Ta b le t di s i nt e g ra t io n m a y be c ri ti c al to th e s ub s eq u en t d is s o l ut i on of th e d r u g a nd t o s a t is f ac to r y d r u g b io a va il ab i li t y . ( b ) C o mm o n d i si n t eg r an t s in c l ud e c o rn s ta r c h an d po t at o s t a rc h; s t a rc h d e r i va ti v e s ( e .g . , s od iu m s t ar c h gl yc o la t e) ; c e ll ulo s e d e ri v a t i v es (e . g. , s o di um c a r bo xy m e t h y l c el l ul os e , c r os c a rm el l os e s o d iu m ) ; c l a y s ( e .g . , V E E G U M, b e n to n it e ) ; a nd c a t io n e xc h a n ge r es in s . ( c ) Th e to t al am o un t o f d i s i n te g r an t is n o t a l ways a dd e d t o t h e d r ug d i lu e nt m i xt u r e . A p o r ti on c a n b e a d de d , wi t h t he l u br ic a n t, to t he pr e pa r ed g r a nu l at i on of t he dr u g. Th i s ap p r oa ch c a us es dou b l e di si n te g r at i on of t he t a b le t . Th e p or t io n o f di s i n t eg r an t th a t is ad d ed la s t c au se s t he t ab le t to b r e ak in t o s m al l p i ec es , o r c h u nk s . Th e p o r ti on th a t i s a dd e d f i rs t b r ea ks t h e p i ec es o f ta b le t i n to f i n e p a rt ic le s .
( 4 ) L ub r i c an t s , a n ti a dhe r e n t s, an d gl i da n t s h av e o ve r l ap pi n g f un c ti on . ( a ) L ub r i c an t s r e du c e t he f r ic ti o n t ha t occ u rs be twe e n t h e wa ll s o f t h e t a b le t a n d t he wa l ls o f t he d ie c a vi t y wh e n t h e t abl e t i s e je c te d . Ta l c , m a gn es i um s t ea r at e , a nd c a lc i um s t ea r a te ar e c o m m o nl y us e d . P.66
( b ) An t i a d he r e n ts r ed uc e s ti c k in g , o r a d he s i on , o f t he ta b le t g r an u la t io n o r p o wd e r t o t he f ac es o f the p un c h es o r t he di e wa ll s . ( c ) G l i da n t s p ro m ot e t he f lo w o f t he t ab le t g r a nu l a ti on o r p o wd e r b y r e d uc in g fr ic t io n a m o n g p a r ti c l e s. ( 5 ) C o lo r s an d d ye s d i s g u is e o f f -c ol o r d r ug s , p ro vi d e p r od uc t i d en t i fi ca t io n , a nd pr o duc e a m o r e a es t he t ic al l y a p p ea li n g p ro d uc t . F o od, d r u g , a n d c os m e ti c d ye s a r e a pp li e d as s o lu t io ns . La k es ar e d y e s t h at h a ve be e n a bs o rb ed on a h y d r ou s o xi d e . L ak e s a r e t y pi ca l l y u s e d a s d r y p o wd e r s . ( 6 ) F la vo r i n g a g en t s a re us u al l y li m i t ed to c h e wa b le t ab le t s o r t a bl e ts tha t a r e i n t en de d to di s s ol v e i n th e m ou t h . ( a ) W ate r -s ol u bl e f l a v or s u s u a ll y h a v e p oo r s t ab i li t y. F o r t hi s r e as on , fl a vo r o i ls or d r y po wd e r s a r e ty p i c al l y us ed . ( b ) F la v o r oi ls m a y be ad d e d t o t ab l et g ra n ul a ti on s i n s ol ve n ts , d is p e rs ed o n c l a ys a nd ot h er ad s orb e n ts , o r e m ul s i fi e d i n aq u e ou s g ra n ul a ti n g a ge nt s . U s u al l y , th e m a xi m um am o un t o f oi l t h at c a n b e a d d ed to a g r an ul a ti o n wi t h o u t a f f ec ti n g i ts ta ble t c h a ra c te r is ti cs is 0 . 5% - 0 . 75 % . ( 7 ) Ar t i f i c i al sw ee t e ne rs , li k e fl a vo rs , ar e t y pi c al l y us e d o nl y wi t h c h e wa b le ta b le ts o r t ab le t s t h at a re in t en d ed to d i s s ol v e in th e m ou t h . ( a ) S om e sw e e tn e ss m ay c o m e f ro m t he di l ue n t (e . g . , m a n ni t ol , l ac t os e ). O t h e r ag en t s ( e .g . , s ac c h a r in , as pa r ta m e) m a y a ls o b e a d de d . ( b ) S ac c ha r i n h a s a n u np l ea s an t a f te r t as t e. ( c ) As p a r t am e i s n o t s tab l e i n t h e p r es en ce of m o i s t u r e a nd he a t. ( 8 ) Ad s o r b e nt s (e . g ., m a g n es iu m o xi d e , m ag n es i u m c a r b on a te , b e nt o ni t e, s i li co n d io xi d e ) h ol d q uan t i ti es of f lu id in an ap p ar e n tl y d r y s ta t e. 3 . T ab l e t t yp e s a n d c las s e s. Ta b le ts a re c l as s i fi e d a c c o rd in g to th e ir r ou t e o f ad m i n is t ra t io n , d r ug de l i v e r y s ys t em , a nd f or m a n d m e t ho d o f m a nu f ac tu r e ( Ta bl e 3 - 10) . a . T ab l e ts f o r o r a l i n ges t i o n a r e d es ig n ed to be s wa l l o we d i n ta c t, wi t h th e e xc e p t i on of c h e wa b le t ab l e ts . Ta bl et s m a y be c oa t e d f o r a n um b e r o f r e a so ns : to m as k t h e t as t e , c o lo r , o r o d o r o f t h e d r u g ; t o c o n t ro l d r u g r e l ea se ; to p ro t ec t t h e d ru g f ro m t he ac id e n vir o nm e nt o f t he s t om ac h ; t o i n co r po r a te an o th e r d r ug a n d p r o vid e s eq u en ti a l re l ea s e o r a v o id i n co m p a ti bi l it y ; o r t o i m pr o v e a pp ea r a nc e. ( 1 ) C o mp r e ss e d t a bl e t s a r e f o rm e d b y c o m p r es s i o n a nd h a v e n o sp ec i al c o at i ng . Th e y ar e m a de fr o m p o wd e r ed , c r ys ta l li ne , o r g r an ul a r m at e r ia ls , a l on e o r in c o m b in a ti o n wi t h e xc i p i en t s s u ch as b i n d e rs , di s i n te g ra n ts , d i lu e nt s , a nd c o lo r an t s .
( 2 ) M u l t ip l e c o mp r e ss ed t a b le t s a r e l a y er e d o r c om p r ess i on - c o a te d . ( a ) L a ye r e d t a b l e ts ar e p r e pa r e d b y co m p r es si ng a ta bl e t g r an u la ti o n a r o un d a p re v i o us l y c om p r e s s ed g ra nu l at i on . Th e o p e ra t io n i s r ep e at e d t o p r o du c e m u l ti pl e l a y e rs . ( b ) C o mp r e ss i o n -c o at ed , o r d r y- c o a t e d , t ab l e ts a r e p re p a re d b y f ee d ing p r e vi ou s l y c om p re s s ed ta b le t s i nt o a s p ec ia l ta ble t i ng m ac h in e . Th i s m ac h in e c om p re s s es an o u t e r s h e ll ar o un d t h e t ab l e ts . Thi s p r oc es s a pp l ie s a t hi n ne r , m o re un i fo rm c o at i ng th a n s u g a r co a tin g , a n d i t c an be us ed s a fe l y wi t h d ru gs th a t a re s e ns i ti v e t o m o is t u re . Th i s p ro ce s s c a n b e us ed t o se pa r a te in c o m p a ti b le m a te r ia ls , to P.67
p r o du c e r ep e at - ac t io n o r p r ol o ng e d -a c t i on pr o du c t s or t o p r od uc e t a bl e ts wi t h a m u l ti la y e r e d a pp ea r a nc e .
Table 3-10. Tablet Types and Classes Tablets for oral ingestion Compressed Multiple compressed Layered Compression coated Repeat-action Delayed action and enteric coated Sugar coated and chocolate coated Film coated Air suspension coated Chewable
Tablets used in the oral cavity Buccal Sublingual Troches, lozenges, and dental cones Tablets used to prepare solutions Effervescent Dispensing Hypodermic Triturates ( 3 ) R e pe a t -a c t io n ta b le ts a r e l a y er e d o r c om p res s i o n -c oa t ed ta b le ts in wh i c h th e ou t er la y e r o r s h el l r a pi d l y d is i nt e gr a t e s in t he s t om ac h ( e .g . , R e p e ta bs , Sc h er i ng ; E xt e n t ab s , W ye th ) . Th e c om p o n en ts of t he in ne r la y er o r in n e r t ab l et a re in s o l ub l e i n g as t ri c m ed i a b ut s o lu bl e i n i n te s ti na l m ed ia . ( 4 ) D e la ye d - a c t i o n a nd e n t e r ic - c oa t e d t a bl e ts d e la y t h e r e le as e o f a d ru g f r o m a d o s a ge f or m . Th is de l a y i s i n te nd e d t o p re v e n t d e s t r uc t io n o f t h e d r u g b y g as t ri c j ui c e s , t o p r e v e nt i rr i ta t io n o f th e s t om ac h l in i ng b y th e d r u g , o r t o p r om o te ab s or p t io n , wh ic h i s b e tt e r i n t h e i n te s ti ne t ha n i n t h e s t om ac h . ( a ) E n te r i c -c o a te d ta bl et s ar e c o at e d a nd re m ai n i n ta c t in t he s t om ac h , bu t yi e l d t h ei r i n g re di e nt s i n t h e i n te s ti ne s ( e .g . , Ec o tr i n , Gl a xo S m i th K l in e ). E n t e ri c -c oa t ed t ab le t s a re a fo rm o f d el a y e d- ac t ion t ab l et . H o we ve r , n o t a ll d e la ye d - ac ti o n t ab l et s a re e nt e r ic o r ar e i n te n de d t o pr o du ce an en t e ri c e f f ec t . ( b ) A ge n ts us ed t o c o a t th e s e ta b le ts in c l u de fa t s, f a tt y a ci ds , wa xe s , s h el la c , a nd c e ll ul o s e ac e t a te ph t ha l at e . ( 5 ) S u ga r - c oa t ed an d ch o c o la t e -c o a te d ta b le t s a r e c om p re s s ed t ab le t s t h a t a r e c o a t ed fo r v a ri ou s re as o ns . Th e co a ti n g m a y be ad d ed t o p ro t ec t t h e d r u g f r om a i r a n d h um i di t y , to p ro vi de a b a r rie r t o a d r u g 's ob je c ti o nab l e t a s te or s m el l , o r t o i m p ro v e t he ap p ea r a nc e o f t he t ab l et .
( a ) Ta b le t s m a y b e c oa t ed wi t h a c ol o re d o r an unc o lo r ed s u ga r . Th e p r o ce s s i nc l ud es se a l co a t i ng ( wa t e r p ro o fi n g) , s u b co a t in g , s yr u p c o a ti n g ( f o r s m o o th i ng an d c ol o rin g ) , a n d p o li s hi n g . Th es e s t ep s t ak e p la c e in a s e r ie s o f m ec ha ni c a l l y op e r a te d c oa t in g p an s . ( b ) D i sa d va n t ag e s o f s ug a r -c o at e d t a bl et s i nc l ude t he ti m e a nd e xp e r ti s e r e q ui r e d f o r t he p ro c e s s a n d t h e i nc r ea s e in ta b let s i z e a nd we i g ht . Su g a rc o at e d t ab l et s m a y b e 50 % la r ge r an d h e a v ie r tha n th e o r i gi na l t a bl e ts . ( c ) C h oc ol a te -c o a te d t a bl e ts a re r ar e to d a y . ( 6 ) F il m - co a te d ta b l et s a r e c om p r es s e d t ab l et s th a t a r e c oa t ed wi t h a t hin l a ye r of a wa t e r - i ns ol ub le o r wa t e r -s ol ub l e p ol ym e r ( e .g . , h yd r o xyp r o p y l m e th y l c e l lu lo s e, et h y lc e ll u lo s e , po v i d on e , P E G ) . ( a ) Th e fi lm is u s u a ll y c ol o r ed . It is m o re du r a bl e , l es s b ul k y , a n d l es s t im e c o ns um in g t o ap pl y t h an s ug a r c oa t in g . A l th o ug h t h e f il m t y p ic a ll y i nc r eas es t a b le t we i gh t b y o nl y 2 %- 3 % , i t i nc r e as es fo rm u lat i o n e ff ic i en c y , re s i s t a nc e t o ch ip p in g , a nd ou t pu t . ( b ) F il m - c oa ti n g s ol u ti ons us ua l l y c o nt ai n a f il m fo r m er , an al lo y i n g s u bs ta n c e , a pl as t ic i z e r, a s u r fa c ta n t, op ac i fi e rs , s we e t e ne rs , fl a vo rs , c o lo r s , gl os s a n ts , a n d a v o l a t il e s ol v e n t. ( c ) Th e v o la t il e s ol v e n ts u s ed in th es e s ol u ti o ns a r e e xp e ns i v e a n d p o t en t ia ll y t o xi c wh e n re le a s e d i n to th e a t m o s p h er e . S pe c i f ic al l y fo r m u la t ed a q u eo u s d i sp e r s io n s o f p o l ym e rs ( e. g . , e th yl ce l lu l os e ) a r e n o w a va il a bl e a s a l te r n at i v es t o o rg a nic s o l v en t - ba s e d c o at in g s o lu t io ns . ( 7 ) Ai r s u s pe n si o n -c o a te d t ab l e ts a re fe d i n to a v e r t ic a l c yli n de r an d s u pp o r te d b y a c ol um n of a i r t ha t en t er s f r om th e b o t to m o f t he c y li nd e r . A s t h e c oa t in g s ol u ti o n e nt er s th e s ys te m , i t is r ap i dly a p p li ed t o t he s us p en d ed , ro t at i ng s o lid s (W u r s te r p r oc e ss ) . Ro u n di ng co a ts c an be a p pl i ed in < 1 hr wh e n bla s ts of wa r m ai r a r e re lea s ed in th e c ha m be r . ( 8 ) C h e wa bl e ta bl e ts di s in t e g ra t e sm oo t hl y a nd r ap i dl y wh e n c h e we d o r a l lo we d t o d is s o l v e i n t he m o u th . Th es e ta bl e ts c o n t ai n s pe c i a ll y c o l or e d a n d f l a v o re d m an ni t ol and y i e ld a c re am y b as e . ( a ) C h e wa bl e ta bl e ts a re e s p ec i al l y us ef u l i n f o rm u la t io ns fo r c h il d re n . ( b ) Th e y a r e c o m m on l y us e d f o r m ul ti vi t am in t ab le t s a nd a re us ed f or so m e a n t ac id s a nd an t ib i ot ic s . b . Ta b le t s us e d i n t he o ra l c a v i t y ar e a l lo we d t o d i s s ol v e in th e m ou t h . ( 1 ) B uc c a l a nd s u bl i ng u al t ab l et s a ll o w a bs o r pt i on t h ro u gh th e o r al m u c o s a a f t e r t he y d is s o l v e i n t h e b uc c a l p o uc h ( b uc c a l t ab l e ts ) o r be lo w t h e to n gue ( s u bl in g ua l t a bl e ts ) . Th es e fo rm s a r e u se f ul fo r dr u g s t ha t a r e d es t r o y ed b y g a st r ic ju ic e o r po o rl y a bs o r be d f r om th e i n te s ti nal t r ac t . E xa m p l es i nc l ud e s u bl in g ua l n i t ro gl y c e ri n ta b le t s , wh i c h di s s o l v e p ro m pt l y t o g i v e r ap i d d r ug e f f ec ts , an d b uc c a l p r oge s te r o ne ta b le ts , wh i c h d i s s ol v e s l o wl y . P.68
( 2 ) Tr o c h e s , lo z e n ge s , an d de n ta l c on es di s s ol v e s lo wl y i n t he m o ut h a n d p r o vi de p ri m a r il y l oc al e ff e c ts .
c . Ta b le ts us ed t o p re p ar e s o l ut i on s a re di s s ol ve d i n wa t e r be f o re a d m i ni s t ra ti o n . ( 1 ) E f fe r v e s c en t ta bl e ts a r e pr e pa r ed b y c o m p r es s i ng g ra nu l a r e ff e r ves cen t s a lt s o r o t he r m a t er i al s (e . g . , c i t r ic a c i d , t a r ta r ic a c id , s od i um b ic a r bo n ate ) t h a t r e le as e c a rb o n d io xi d e ga s wh e n t he y c o m e in t o c on t ac t wi t h wa t e r. C o m m e rc i al al k a li n i z in g a n al g es ic ta b le ts a re of te n m a de to e ff e r v es c e t o e n co u ra g e r a pi d d is s o l uti o n a nd a bs or p ti o n ( e .g . , A l ka - S el t z e r , Ba y e r ) . ( 2 ) O t he r ta b le t s us e d t o p r e pa r e s ol ut i on s i nc lu de d i s pe ns i ng ta b le ts , h yp o d er m i c t a bl e ts , a nd t a b le t t r i tu r a te s . 4 . P r oc es s i ng p ro bl e m s a . C ap p in g i s t he p ar t ia l o r c o m p l et e s ep a r at i on of t h e t op o r b ot t om c r o wn f r o m t he m a in bo d y o f t he t ab l et . La m i na t io n i s s e p a ra t io n o f a t ab l et in t o t wo o r m or e d is t in c t l a y er s . Th es e p r ob l em s a re u s ua ll y c au s e d b y e n t r ap m e n t o f a i r d u ri ng p r o c e s s in g . b . P ic ki ng is re m o v al of th e s u r fa c e m a t er i al of a t a b le t b y a pu nc h . S t ic kin g i s a d he s i o n o f t ab l et m a te r i al to a d ie wa l l . Th es e p r o bl em s a re c a us e d b y e xc e s s i v e m o is t u re o r t he i nc lu si on o f s u bs t a nc es wi t h lo w m e lt i ng t e m p e r at u re s i n t h e f o rm u l a ti on . c . Mo t t l in g i s u ne q ua l c ol o r d is t r ib u ti o n, wi t h l i gh t o r da r k a r ea s s ta nd i ng o u t o n a n o t he r wi s e u n ifo r m s u rf ac e . Th is p r ob l em oc c u r s wh e n a d r ug ha s a d if f e re n t c o l o r t ha n t h e t a bl e t e xc i p ie n ts or wh e n a d r u g h as c ol o r ed d e g ra d at i on p ro du c ts . Co l o ra n ts s o l v e t he p ro b lem b u t c a n c re a te ot h e r p r o bl em s . 5 . Ta b le t e v a l ua t io n a n d c o nt r o l a . Th e ge ne r a l a pp ea r a nc e o f ta b le ts is an i m p o r ta n t fa c t o r i n c on s u m e r a cc e pt a nc e . I t a ls o a ll o ws m o ni t o ri n g o f l ot - t o -l o t u n i fo r m i t y , ta bl e t -t o - ta b le t u n i fo r m i t y , a n d e le m e n ts o f th e m an u fa c tu r in g p ro c es s . Th e a p pe a ra n c e o f t h e ta bl e t i nc lu d es v is ua l i d en t it y a nd o v e ra l l a pp e a r an c e . Th e a p pe a ra nc e o f t he ta b le t i s c o n t ro l led b y m e as u re m e n t o f a t tr i b ut e s s u c h as s i z e , s hap e , c o lo r , o d or , ta s te , s u rf ac e , t e xt u r e , p h ys ic a l f la ws , c on s i s t e nc y, an d l e gi b il i t y o f m a rk in gs . b . H a rd n es s a nd r es is tan c e t o f r ia b il i t y a r e n ec es sa r y f o r t a bl e ts t o wi t h s t an d th e m ec ha n ic al s h oc k s of m a nu f ac t u re , p ac ka g in g , a nd sh ip p in g, a n d t o e ns u r e c o ns u m e r a c c e pt a nc e . H a r dn es s i nv o l v e s b o t h t ab le t d i si n te g ra t io n a n d d r ug d i s s ol u ti on . C e rt a in ta b le t s t h at a re in t en d ed to d i ss ol ve s l o wl y a r e m a de h a rd . O th e r t a bl e ts th at a r e i nt e nd e d t o d is s o l ve r a p id l y a re m a de s o f t. F ri a bi l it y i s t he te n de nc y of t h e t ab l et to cr u m b le . ( 1 ) Ta b le t ha r dn es s t es te r s m ea s u r e t h e d eg r e e o f f or c e r eq u ir e d t o b r eak a t a b le t . ( 2 ) F ri a bi la t o rs de t er m i ne f r ia bi l it y b y a ll o wi n g t he t ab l et t o r ol l a n d f al l wi t h i n a r o ta t in g t um b li ng a pp a ra t us . Th e t a bl et s a r e we i gh ed b ef o re an d a f t e r a s pe c i f ie d n u m b e r o f r ot a ti o ns , a nd t he we ig h t l os s i s d et e rm in e d . ( a ) R es is t an c e t o we i g h t l o ss i n di ca t es th e a bi l it y o f t he ta b le t t o wi t hs t an d a b r as io n d u r in g h an d li n g, p ac k a gi n g, an d s h ip pi ng . C om p re s s e d t ab l et s th a t l o se < 0 . 5% - 1% of t he i r we i g h t a re us ua ll y c on s id e r ed ac c e p ta b le .
( b ) S om e c he wa b l e t a bl et s an d m os t e f fe r ve s c en t t a bl e ts ar e h i gh l y f ri a ble a n d re qu i r e s p ec i al un i t p a c k ag i ng . c . Ta b le ts a re r ou ti n el y we i g h e d t o e ns u r e t ha t th e y c o n t ai n t he p ro p e r a m ou n t o f d r ug . ( 1 ) Th e U S P d e fi n es a we i gh t v a r ia ti o n s ta n da r d t o wh i ch t ab le t s m u s t c o nf o rm . ( 2 ) Th e s e s t an d a rd s a ppl y t o ta bl e ts th a t c on t ai n 5 0 m g o r m o r e o f d r ug s u bs ta n c e wh e n t h e d r ug s ub s ta nc e i s 5 0% o r m or e ( b y we i g ht ) of th e d o sa g e f o rm u n it . d . C o nt e nt un i fo r m i t y is e v a l u at e d t o e ns u re th a t e ac h ta bl e t c on t ai ns th e d e si r ed am ou n t o f d r u g s u b s t a nc e , wi t h li t tl e v a ria t i on am on g c on t en t s wi t h i n a b at c h . Th e U S P d e f in es c o nt e nt u ni fo r m i ty t e s ts fo r ta b le ts t ha t c o nt a in 50 m g o r le s s of d r u g s ub st a nc e. e . D is in t eg r a ti o n is e v al ua t e d t o e ns u re t ha t t h e dr u g s u bs ta nc e i s f u ll y a va i la b le fo r di s s ol u ti o n a n d a bs o rp t io n fr o m t he g a st r o in t es ti n al t ra ct . ( 1 ) A ll U S P ta bl e ts m us t p a s s a n of f ic ia l d is in t eg ra t i on te s t t ha t i s c o nd uc t ed in v i t ro wi t h s p e c i al eq u ip m e n t . ( a ) D is in t eg r a ti o n t im es fo r u nc oa t ed U S P t a bl e ts a r e a s l o w a s 2 m in ( n i t ro g l yc e r in ) to 5 m i n (a s pi r in ) . Mo s t h a ve a m axi m u m di si n te g r at i on ti m e o f le s s th a n 3 0 m i n . ( b ) B uc c a l t a bl e ts m us t d i s i n te g ra t e wi t hi n 4 hr . ( c ) E n te r ic -c o at e d t ab l ets m u s t sh o w n o e v i d en ce o f d is in t eg r a ti o n a ft e r 1 h r in si m u la t e d g as t ri c f lu i d . I n si m ul at e d i nt e st i na l fl u id , t h e y s h ou ld d i si n te g ra t e i n 2 hr pl us t h e ti m e s p ec if i ed . P.69
( 2 ) D is s o l ut io n re q ui r em e n ts in t he U S P h a ve rep l ac e d e ar l ie r di si nt e g ra ti o n r e q ui r em e nt s f o r m an y dr u g s . f . D is s ol u ti on c h a ra c t e r is t ic s a r e t es te d to de t e rm i ne d ru g a bs o rp t io n a nd p h ys io l og ic a v ai la b il i t y . ( 1 ) Th e U S P g i v es s t a nda r d s f o r t ab l et di s s ol u ti on . ( 2 ) A n i nc r ea s e d e m p h as i s o n te st i ng ta b le t d is sol u t io n a nd de t e rm in i ng d r u g b io a v a il ab i li t y ha s in c r ea s e d t h e us e o f s o ph i s t ic a te d te s t i ng s y s t em s . J . A e ro s o l p r od uc t s 1 . I nt r od uc t io n . Ae r os ol p r o du c ts , o r a e r os ol s , a re p r es s u ri z e d do s a g e f o r m s . Th e y a r e d es i gn ed t o d el i v e r d r ug s ys t em ic a ll y o r t o pi c a ll y wi t h t he a i d o f a li q ue f ie d o r p r o pe l le d g as ( p ro p el la n t ). Ae r o s o l p r od uc t s co ns is t o f a p r ess u ri z a b le c o n ta in er ( t i n- p la t ed s t ee l , a lu m in u m , gl as s , o r p la s ti c ); a va l v e t ha t al lo ws t h e p r es s u r i z e d p r od uc t t o be exp e l l e d f ro m t he c o n ta ine r ( e i th e r c on t in u ou s l y o r i nt e r m i t te n tl y ) wh e n t he ac t u a to r is p r es se d ; a nd a d i p t u be th a t c on v e y s the f o rm ul a ti o n f r om t h e bo t t om of th e c o nt ai n e r t o t h e val v e as s e m b l y . Ae ro s ol s a r e p r ep a re d b y s pe c ia l m et h od s ( c o l d f il li ng , p r e ss u re fi ll i ng ) be c a us e o f th e g as e ou s c o m po ne n ts .
2 . S y s te m i c o r p u lm on a ry d r u g d e li v e r y is p ro v i de d b y a e r os ol d ru g d el i ve r y s ys t em s , o r m e t e re d d os e i nh al e rs ( MD I s ) . Th e s e d e v ic es al l o w a dr u g t o b e i n ha l ed as a f in e m is t o f d r u g o r d r u g -c on t ai ni n g p a r ti c l e s . MD I s u se s p ec i a l m e te r i ng v a l v es to re g ula t e th e a m o un t of f or m u la t i on an d d r ug t ha t i s d i sp e ns ed wi t h e ac h d o s e ( i .e . , e ac h a c t u at i on of t h e c on t ai ne r ) . Ae r os ol p r o du c ts a r e u s e d fo r top i c a l d r ug de l i v e r y. Th e fo r m ul a ti on s r a ng e f r om s o lu t io ns to di s p e rs i on s . Me t e r i n g val v e s m a y a lso b e us e d wi t h t op ic a l a e r os ol p ro d uc ts to r eg ula t e th e a m o un t of d ru g ap p li e d p e r a pp li c a t io n . 3 . P r op el l an ts us e d i n ae r o s o l p r od uc t s a . C om p re s s e d g as es i nc l ud e c a rb on di o xi d e , n i tr o g en , an d n i tr o us o xi d e. A e r o so l p r od uc t s t ha t c on t a in c om p r es s e d g as ten d to lo se p re s s u re o v e r t i m e as th e p r od u c t is d is p en s e d . Th e d ro p i n p re s s u r e r e fl ec ts t he e xp a n s i on of th e he ad s p a c e in th e c on t ai n e r ( i .e . , i n cr e as e i n t he v o l um e t h a t t h e g as c an oc c u p y ) a s f o rm ul a ti o n is wi t h d ra wn f o r us e . F o r t hi s r e a so n , h ig he r in i ti al p res s u r es a re t ypi c al l y u s ed wi t h c om p re s s ed ga s b a se d s y s te m s th a n wi t h l i qu e fi ab l e g as - ba s e d f or m u la ti o ns . b . Li q ue f ia b le ga s e s i nc lu d e s at u r at e d h yd r oc a rbo n s ( n -b u t an e , is o bu t an e, p r o pa n e ); c h lo r o fl uo r oc ar b o ns ( C F Cs ) , i nc lu d in g t e t r af l uo r od ic h lo r oe t ha ne ( p r o pe ll a nt 1 14 ) , d ic hl o ro d i fl uo r om e th a ne ( pr o pel l a n t 12 ) , a n d t r i c h lo r o fl u o ro m e t ha ne (p r o pe l la n t 1 1 ); di m e t h yl e t h e r; an d h yd r o f lu o ro c a r b on s , s u c h as 1 ,1 , 1, 2 - fl uo r o et h ane ( p ro p el la n t 1 3 4a ) a n d 1 , 1 d i f lu o ro e th a ne ( pr o pe ll an t 15 2 a ). Th e n e ga t i v e ef f e c t of ol d e r C F C s o n a t m o s p h e ri c o z o ne an d th e po t en t ia l f o r g lo b al wa r m in g l ed t o t he wo r l d wi d e r e du c t i on in CF C p r od uc t io n u n de r th e Mo n t r e a l P ro t oc ol . Th is p l an ca ll e d f o r a ge ne r a l b a n o n C F C p ro d uc ti o n i n in du s t ri al i z e d co u nt r i es b y J an u a r y 1 9 96 . As a re s ul t , t h e us e o f C F Cs in p h a rm ac eu t ic al p ro du c ts i s b e in g p h as ed ou t . Te m p o ra r y e xe m p ti o ns f o r C F C s in MD I s wi l l e ve n t ua ll y l a ps e ( in 20 08 ) as s t a bl e, s a f e, an d ef f e c t i v e a l te r na t i ve f o r m u l at io n s a re de v e l ope d wi t h m o re ac c e p ta bl e p r o pe ll a nt s ( e .g . , h yd r o f lu o ro c a r b on s ) . 4 . A d van t ag es o f a e ro s o l p r o du ct s i nc lu d e t he c on v e n i en c e of pu s h - b ut t on d i sp e ns in g o f m ed ic a ti o n a n d t he st a bi li t y a ff o r ded b y a c lo se d , p r ess u r i ze d c o nt a in e r t h at m i ni m i z e s t h e l ik el i ho od o f t am pe r in g an d p r o te ct s t h e c o nt e nt s f r om li gh t , m oi s t u r e , a i r ( o xy g e n ) , an d m i c r ob ia l c on t am in a ti o n. A e r o so l f o rm ul a ti o ns a n d p ac k a g in g c om po n en t s (v a l v e s , a ct u at o rs ) pe r m i t a wi d e r an ge o f p r od uc ts t o be di s p en se d as s p rays , f oa m s , o r s em is o li ds . 5 . Th e pr i nc ip al di s a d v an t a ge of ae r os o l p r od uc ts is en v i r on m e n ta l (e . g. , d i sp os a l o f p r es s u r i z ed p a c k ag es , ve nt i ng of p rop e l l a nt s t o th e a t m o s p h e re ) . K . C o n t ro ll e d -r e le as e d os a ge fo r m s 1 . I nt r od uc t io n . Co n t ro ll ed - r e le as e d os a ge fo r m s a r e al s o k n o wn as d e la ye d - r el ea s e , s us t ai ne d - ac t io n , p ro l on g ed - ac tio n , s us t ai ne d - r el ea se , p r o lo n ge d - re l ea s e , t im e d- r e l ea s e , s lo w- r e l e as e , ext e n d e d - ac t io n , a nd e xt e n d e d - re l ea s e fo r m s . Th e y a r e de si g ne d t o re le a s e d ru g s ub s t a nc e s l o wl y t o p r o v id e p r o lo nge d ac ti o n i n t he bo d y .
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2 . A d van t ag es o f c o n t ro lle d - r el e as e f o rm s a . F e we r pr o bl em s wi t h p a t ie n t c o m p l ia nc e b . U se o f le s s to t al d ru g c . Fe we r l oc a l o r s y s te m ic s i de e ff ec t s d . Mi n i m a l d r u g ac c u m u la t i on wi t h l o ng - t er m d os a g e e . F e we r pr o bl em s wi t h p o t en t ia t io n o r l o ss o f d ru g ac ti vi t y wi t h lo n g -t e rm use f . I m p r o v ed t re a tm en t ef fi c ie nc y g . Mo r e r a pi d c on t r ol of th e pa t ie n t 's c o nd i ti o n h . Le ss fl uc t ua t io n i n d r ug l e v el i . Im p r o v ed bi oa v a i la b il ity f o r s o m e d ru gs j . Im p r o v ed ab il i t y to p rov i d e s p ec ia l e f fe c ts (e . g., m or n in g re li e f o f a r t hr i ti s b y b e dt im e d o s i ng ) k . R ed u c e d c os t 3 . S us t ai ne d - re l ea s e fo rm s c an be g ro up e d a c c or d i ng t o t he i r p h a rm ac e ut ic al m e c h a nis m . a . C oa t e d b ea ds or g ra nu l es ( e. g ., S pa ns u le s, G la xo S m i t h K li ne ; Se q ue ls , W ye th ) p r o du c e a b lo o d l e v e l p r o fi le s im i la r to tha t ob t ai n ed wi t h m ul t ip l e d o si n g. ( 1 ) A s o lu ti o n o f t h e d r ug s u bs t a nc e i n a n o na que o us s o l ven t (e . g ., al c o ho l ) i s c oa t ed on t o s m a ll , i n er t b ea ds , o r g ra n ul es , m a d e o f a co m b in a ti o n o f s u ga r an d s ta r c h . W hen t h e d r u g d os e is la r g e, th e s t a rt i ng g ra nu l es m a y b e c om p os ed o f t he d ru g i t s e lf . ( 2 ) S om e o f t h e g r an ul e s a r e l e ft un co a te d to p rov i d e im m e di a te r el ea se o f t h e d r u g. ( 3 ) C o at s o f a li pi d m a ter i a l ( e .g . , b e es wa x) o r a c e ll ul os ic m a t e ri al ( e. g . , e t h ylc e ll ul os e ) a r e a p pl ie d to t he re m a i ni n g g ra nu l es . So m e g ra n ul es r e c ei ve fe w c o a ts , a nd s o m e r ec e i ve m a n y. Th e va r i o us c o at i ng th ic k n es s es p r o du c e a s us ta i ne d - re l ea s e e f fe ct . b . Mi c r o en c a p s u la t io n i s a p ro c e ss b y wh ic h s ol id s , l iq u id s , o r g as es ar e e n ca se d i n m ic r os c o pi c c a ps ul es . Th in c o a ti ng s o f a “ wa l l ” m a te r ia l a r e f o r m e d a r ou n d t h e s u bs ta n c e to be en c ap s u la t ed. ( 1 ) C o ac er v a t io n i s t h e m os t c om m o n m e th o d o f m ic r o en c a ps u la ti o n. I t o cc u rs wh e n a h y d r op hi l ic s u bs t an ce is a d de d to a c o l lo id a l d r ug di sp e rs io n a n d c au s e s l a y e ri n g a nd t h e f o rm a ti on o f m i c ro c ap s ul es . ( 2 ) Fi lm - f o rm in g s ub s ta nc es t ha t a r e u s e d a s t h e c o at i ng m a te r i al i n cl ud e a va r i e t y of na t u ra l a n d s yn t h et ic po l ym e r s . Th e se m a te r i al s in c l u de s h el l ac s , wa xe s , g e la t in , s ta r c h es , c el l ul os e a c e t at e p h th a la t e , a nd e th y l c e ll u lo s e . A f t e r t h e c oa t in g m at e ri al d is s o l v es , a ll o f t he d rug i ns id e t h e m i c ro c a ps u le i s i m m ed i at e l y a v a i la bl e f o r di s s ol u ti o n a nd ab s o rp t i on . Th e t hi ck n es s o f th e wa l l c an v a r y f ro m 1 to 20 0 m m , d ep en d in g o n t he am o un t o f c o at i ng m a te r i al u s ed (3 % - 30 % o f t ot al we i g h t) .
c . Ma t r i x t a b l et s u s e in s o l ub l e p la s t ic s (e . g. , p o ly e t h yl e ne , p o l yv i n y l a c et a te , po l y m e t ha c r y la te ) , h y d ro p hi li c p ol y m e rs ( e . g ., m e t h y lc el lu l os e, h yd r o xyp r o p y l m et h y lc e llu l os e ) , o r f a tt y c om po u nd s (e . g. , va r io us wa xe s , g l yc e r y l t r is te a r at e ) . E xa m p le s i nc lu d e G r a du m e t ( A b b ot t ) an d Do s p a n ( A ve n t is ) . ( 1 ) Th e m os t c om m o n m e t h od of p re p ar a ti o n is m i xi n g of t he dr u g wi t h th e m a t ri x m a t e ri a l f ol lo we d b y c om p re s s io n o f th e m a t e ri a l i nt o ta bl e ts . ( 2 ) Th e pr im a r y do s e , or t h e p o r ti o n o f t he d ru g to b e re l ea s e d i m m ed ia t ely , i s p l ac ed on th e ta bl e t as a l a y e r, o r c oa t . Th e r es t of th e d o s e is re le as ed s l o wl y f r om th e m at r i x. d . O sm o ti c s y s t e m s i nc lu d e t h e O r o s s y s t em ( A lz a ) , wh i c h i s a n o ra l o sm o ti c p um p c om po s e d o f a c o r e t a bl e t a nd a s e m ip e rm ea b le c o at i ng tha t h a s a s m a ll ho l e ( 0 .4 m m in di am e te r ) fo r dr u g exi t . Th e h o le is p ro du ce d b y a l as e r b ea m . E xa m p le s i n c l ud e G lu co t r ol XL ( gl ip i z i de e xt e n d ed - r el ea s e t a b le ts , P fi z e r ) a n d P r oc a r d ia XL ( n if e di pi n e e xt e n d e d- r e le as e t a bl e ts , P f i ze r ) . ( 1 ) Th i s s y s t em r eq ui r es o n l y osm o ti c p r es su r e t o b e e f f ec ti v e . It is e ss e nt i al l y in d ep en d en t o f p H c ha n ge s i n t he en v i r o nm en t . ( 2 ) Th e dr u g - re le as e ra te c a n b e c h an ge d b y c han g in g th e t a bl e t su r f ac e a r e a , t he na t u re of t he m e m b ra ne , or t he di am e ter o f th e d r ug - r el e as e a p e r tu r e. e . I on - e xc h an g e r es i ns c a n be c om p le xe d wi t h d ru g s b y p as s a ge of a c a ti o ni c d r ug s o lu t io n t h ro u g h a c ol um n t h at c o n ta i ns th e re si n . Th e d ru g i s c om p le xe d t o th e re s i n by r e p l ac em en t o f h y dr o ge n at om s . E xa m p l es i n cl ud e Io n am i n c a ps ul es ( C el l te c h ; re s i n c om pl exe s o f p he n te r m i ne ) an d t h e Pe n nk in e ti c s y s t em (C e l l te c h ) , wh ic h i nc o r po ra t es a p ol ym e r b a r ri e r c o at i ng an d b e ad te c h n ol o g y in ad di t io n to th e i on - e xc h a n ge m ec h an is m . P.71
( 1 ) A f te r th e c om po n en ts a r e c om pl e xe d , t he re s in - d r ug c o m p le x i s wa s h ed a n d t a bl e te d , e nc ap s u l ate d , o r s u sp en d ed in an aq u e ou s ve h ic le . ( 2 ) R el e as e o f d r ug f r om t h e c om pl e x d e p en ds on t h e i on ic en v i r o nm en t wi t h i n th e g as t r oi n te s ti na l t ra c t an d o n th e p r op er t i es of t he re s i n . Us ua l ly , r e l ea se is gr e at e r i n t h e h i gh l y ac id ic s t om a ch tha n in th e l es s a c i di c sm al l i n t es ti n e. f . C o m p le x f o r m a ti on is u s ed fo r c e r ta i n d r ug s ub s ta nc e s t ha t c om bi n e c h em ic al l y wi t h o t h er age n ts . Fo r e xa m pl e , h y d r ox y p r o p y l - β - c y c l o de xt r i n f o r m s a c h em ic a l c o m p l ex t h a t c an be on l y sl o wl y s ol u bl e f r om bo d y fl u id s , d e p en di n g o n t he p H o f th e en v i r on m e n t . Ta n n ic a c id (i . e ., t an na t es ) c om p le xe s wi t h t he am ino g r ou ps of we a k b as es d i s s ol ve at a s lo w r a t e i n t h e g as t r oi n te s ti na l t r ac t, t h er e b y p r o v i di ng f o r a p r o lo n ge d re le as e o f dr ug . E xa m p l e s o f t h e l at t e r i nc l ud e b r om ph e ni r am in e ta n n at e ( Br o v e x, A t h l on ) a n d c hl o rp h en i ra m i n e/ p he n y l e ph r in e t a nn a te s ( Ry n a t a n, W alla c e ) . P.72
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 28 : E a c h o f t he qu es t i o ns , s ta t em en t s , o r i n co m p l et e s ta t em e nt s i n t h is s ec t io n c an be c o r re c tl y a ns we r e d or c om p le t ed b y on e o f t h e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r . 1 . W hi c h s u bs t an c e i s c l a ss i f ie d a s a w e ak e le c t r o l yt e ? ( A ) g lu c o s e ( B ) u r ea ( C ) e p he d ri n e ( D ) s od i um c hl o ri d e ( E ) s uc ro s e V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . T h e p H va l u e is ca l cu l a te d m a t h em a ti c al l y a s t h e ( A ) l og of t he h y d ro xy l i o n ( O H - ) co nc e nt r a ti on . -
( B ) n eg a ti v e lo g o f th e OH c o n c e n tr a ti o n. +
( C ) l og o f t he h y d ro g en io n ( H ) c on c en t ra t io n . +
( D ) n e ga ti v e l og of th e H c o nc en t r at io n . +
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( E ) r a ti o o f H / O H c on c en t r a ti o n. V i e w A n s we r 2 . T h e a n sw e r i s D [ se e] . 3 . W h ic h p r o p e r t y i s c l a ss i f ie d a s c o l li g a ti ve ? ( A ) s ol ub i li t y of a s ol u te ( B ) o s m ot ic p re s s u re +
( C ) h y d r og e n i on ( H ) c on c en t r at i on ( D ) d is s o c i a ti o n o f a s olu t e ( E ) m i s c i bi li t y o f t he li q ui d s V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . 4 . T h e c o ll i g a t i ve p r o pe r t i e s o f a s o l u ti o n a r e re l a ted t o t he ( A ) p H of th e s o lu ti o n. ( B ) n um be r of io ns in t he s ol u ti o n. ( C ) t o ta l n um b e r o f s ol ute p a rt ic l es i n t h e so l ut i on . ( D ) n um b er o f u ni on i z e d m o le cu l es i n t h e s o l ut i on. ( E ) p K a o f t h e s o l ut i on . V i e w A n s we r 4 . T h e a n sw e r i s C [ se e] . 5 . T h e p H o f a b u f fe r s ys t e m c a n b e ca l cu l a te d w i th t h e ( A ) N o y e s -W hit n e y e q ua ti o n . ( B ) H e nd e rs o n - Ha s s el b al c h e qu a ti o n. ( C ) Mi c h a e li s- Me n t e n e qu a t io n . ( D ) Yo u n g e q ua t io n . ( E ) S t ok es eq u at i on . V i e w A n s we r 5 . T h e a n sw e r i s B [ se e] . 6 . W h ic h m e c ha n is m i s m o s t o f t e n re s po n s ib l e f o r ch e m ic a l d e g ra d a ti o n ? ( A ) r ac em i z a ti o n
( B ) p ho t ol y s is ( C ) h y d r ol y s is ( D ) d ec a rb o xy l a t i o n ( E ) o xi d a t io n V i e w A n s we r 6 . T h e a n sw e r i s C [ se e] . 7 . W h ic h e q u a ti o n i s u s ed t o p r e d i ct t h e s ta b i li t y o f a d r u g p r o du c t a t r o om t e m pe r a t u re f r om e x p e ri m en t s a t ac c el e ra t e d te m pe r a t u re s ? ( A ) S t ok es eq u at i on ( B ) Yo u n g e q ua t io n ( C ) A r r h en iu s e q ua t io n ( D ) Mi c h a e li s- Me n t e n e qu a t io n ( E ) H i xs o n - C r o we l l e qu at i o n V i e w A n s we r 7 . T h e a n sw e r i s C [ se e] . k kk 8 . B a se d o n t h e r e la t i o n b e tw e e n t h e d eg r e e o f io n i z a t i on a nd t he so l u bi l i t y o f a w e ak ac i d , t h e d r u g as p i r in ( p K a 3 .4 9 ) w i l l b e m os t so l u bl e a t ( A ) p H 1. 0 ( B ) p H 2. 0 ( C ) p H 3. 0 ( D ) p H 4. 0 ( E ) p H 6. 0 V i e w A n s we r 8 . T h e a n sw e r i s E [s e e] . 9 . W h ic h s o l u t io n i s us e d a s a n as t r i n ge n t ? ( A ) s t ro ng io d in e s ol u ti on U S P ( B ) a lu m i n um a c e t a te top i c a l s ol u ti on U S P ( C ) a c e t ic a c i d N F ( D ) a r om a ti c am m o n ia s p i r it U S P ( E ) b en z a lk o ni um c h lo r ide s o l ut i on N F V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . 1 0. T he pa r t i c le s iz e o f th e d i s pe r s e d s ol i d i n a s us p e ns i o n i s u s ua l l y g r e a t e r t ha n (A) 0.5 µm (B) 0.4 µm (C) 0.3 µm (D) 0.2 µm (E) 0.1 µm V i e w A n s we r 1 0 . T he a nsw e r i s A [ se e] . 1 1. I n t h e e x t em p o ra n eo u s p r e p a r at i o n o f a s us p en s i o n, le vi g a t i on i s u sed t o ( A ) r e du c e th e z e ta po t en t i al . ( B ) a v o id ba c te r ia l g r o wt h . ( C ) r e du c e pa r t ic le s i z e . ( D ) e n ha nc e v is c os i t y . ( E ) r e du c e v i s c os it y . V i e w A n s we r 1 1 . T he a nsw e r i s C [ se e] . 1 2. W hi c h c o mp o u nd i s a n a t u r al em u l si f yi n g a g en t ? (A) acacia ( B ) l ac t os e
( C ) p ol y s o rb a te 2 0 ( D ) p ol y s o rb a te 8 0 ( E ) s or b it a n m o n op a lm ita t e V i e w A n s we r 1 2 . T he a nsw e r i s A [ se e] . A c ac i a ,P .7 3
1 3 . Va n is h i ng c r ea m i s a n o in t me n t th a t m a y b e c la s si f i ed as ( A ) a wa t e r -s ol u bl e b as e. ( B ) a n o le a gi no u s b as e. ( C ) a n a bs o rp t io n b a s e . ( D ) a n e m u ls i on ba s e . ( E ) a n o le ic ba s e . V i e w A n s we r 1 3 . T he a nsw e r i s D [ se e] . 1 4. R e ct al s u pp o si t o r i es i n t e nd e d f o r ad u l t u s e u s u al l y w ei g h a p p ro x im a t e l y ( A ) 1 g. ( B ) 2 g. ( C ) 3 g. ( D ) 4 g. ( E ) 5 g. V i e w A n s we r 1 4 . T he a nsw e r i s B [ se e] . 1 5. I n t h e f u s i on me t h od o f m a k in g c o c oa bu t t e r s up p o s it o r i es , w h ic h s u bs t a n ce is mo s t l i ke l y t o b e us e d to lu b r i ca t e the m ol d ? ( A ) m i n e ra l o il ( B ) p r op y l e ne gl y c ol ( C ) c et y l al c o h ol ( D ) s te a r ic a c i d ( E ) m ag ne s i um s i li c a t e V i e w A n s we r 1 5 . T he a nsw e r i s A [ se e] . 1 6. A ve r y f i n e p ow de r e d c h e mi c al i s d e fi n ed as o n e th a t ( A ) c om pl e te l y pa s s es thr o u gh a # 80 s i e v e . ( B ) c om pl e te l y pa s s es thr o u gh a # 12 0 s ie v e . ( C ) c om pl e te l y pa s s es thr o u gh a # 20 si e ve . ( D ) p as s e s t h ro u gh a # 60 si e ve a n d n ot m o r e t h an 4 0% th r o ug h a #100 sieve. ( E ) p as s e s t h ro u gh a # 40 s i e v e a n d n ot m o r e t h an 6 0% th r o ug h a # 6 0 s ie v e . V i e w A n s we r 1 6 . T he a nsw e r i s B [ se e] . 1 7. W hi c h t e c hn i q ue is t yp i c a l l y u s e d t o mi l l ca m p ho r ? ( A ) t r it u r at i on ( B ) l e v ig a ti o n ( C ) p ul v e r i z a ti o n b y in t e rv e n t i on ( D ) g e om et r ic di lu t io n ( E ) a t t ri ti o n
V i e w A n s we r 1 7 . T he a nsw e r i s C [ se e] . 1 8. T he d is p e ns i n g p h a r ma c is t us u a ll y b l e n d s po t e nt p ow de r s w i th a la r g e a mo u n t o f d i l u en t b y ( A ) s pa t ul a ti on . ( B ) s i f t in g . ( C ) t r i tu r a ti on . ( D ) g e om et r ic di lu t io n . ( E ) l e v ig a ti o n. V i e w A n s we r 1 8 . T he a nsw e r i s D [ se e] . 1 9. W hi c h t yp e o f p a p e r b e s t p r o t ec t s a d i vi de d h yg r o s c o p i c p ow d e r? ( A ) wa xe d p a pe r ( B ) g la s s in e ( C ) wh i t e bo n d ( D ) b lu e b o nd ( E ) v e g e ta bl e p a rc hm e nt V i e w A n s we r 1 9 . T he a nsw e r i s A [ se e] . 2 0. W hi c h c a ps u l e s iz e h as t h e sm a ll e s t c ap a ci t y? (A) 5 (B) 4 (C) 1 (D) 0 ( E ) 0 00 V i e w A n s we r 2 0 . T he a nsw e r i s A [ se e] . 2 1. T he sh e l l s o f s o f t g e l a ti n ca p su l es ma y b e m ad e e l as t i c o r p la s tic - l i ke b y t h e a d d i t io n of ( A ) s or b it o l. ( B ) p o v id o ne . ( C ) p ol y e t h y l en e g l y c o l (P E G ) . ( D ) l ac t os e. ( E ) h y d r o xy p r o p y l m e t h y lc e ll ul os e . V i e w A n s we r 2 1 . T he a nsw e r i s A [ se ea n d] .2 2 . T he U n i te d S ta t e s P h a r m ac o pe i a ( U S P ) con t e n t u n i fo r m i t y t e s t f o r t a b l et s is us e d t o e n s u re w h i ch q ua l i t y? ( A ) b io e qu i v al e nc y ( B ) d is s o lu t io n ( C ) p o te nc y ( D ) p u ri t y ( E ) t o xi c i t y V i e w A n s we r 2 2 . T he a nsw e r i s C [ se e] . 2 3. Al l o f t h e f ol l ow i ng s t a t em e n ts ab o u t c he mi c a l d e g ra d a ti o n a r e t rue e xc e p t ( A ) a s t em pe r a tu r e i nc r ea s es , d e gr a da t io n d ec r ea s es . ( B ) m os t d r ug s d eg r ad e b y a f ir s t- o r de r pr o ce s s . ( C ) c he m i c a l d e gr a da t ion m a y p r od uc e a t o xi c p ro d uc t . ( D ) c he m i c a l d e gr a da t ion m a y r e s u l t in a l os s o f a c ti v e in g r ed ie n ts . ( E ) c he m i c a l d eg r a da t ion m a y a f fe c t t he th e r ap eu t ic ac t i v it y o f a drug.
V i e w A n s we r 2 3 . T he a nsw e r i s A [ se ea n d] .k A e
-Ea/RT
k A E a RT 2 4. Al l
o f t h e f o l low i n g s t a te me n t s c o nc e r n in g z e r o -or d e r d eg r a d at i o n a r e t r u e e x c ep t ( A ) i ts r at e i s i nd e pe nd en t o f t he c o nc en t r at i on . ( B ) a pl ot o f c o nc e nt r a ti on ve r s u s t im e yie l ds a str a i gh t l i ne on r e c ti li n ea r pa p er . ( C ) i ts ha l f -l i fe is a c h ang i ng pa r am e te r . ( D ) i ts c o nc e nt r a ti on r em a i ns un c h a ng ed wi t h r esp e c t t o t im e. ( E ) t h e s l o pe of a p lo t o f c on c e n t ra t io n ve rs us tim e y ie l ds a r at e c o ns ta n t . V i e w A n s we r 2 4 . T he a nsw e r i s D [ se e] . C t P . 74
2 5 . Al l o f t h e f o l low i n g s t a t em e n ts ab o u t f i r s t -o r d e r de g r a da t i on a r e t r u e ex c ep t ( A ) i ts r at e i s d ep e nd en t o n th e c on c en t ra t io n . ( B ) i ts ha l f- l if e i s a c h ang i ng pa r am e te r . ( C ) a pl o t o f t h e l og a ri t hm o f c o nc e nt r a ti o n v e r sus t im e y i e ld s a s t r ai g ht li ne . ( D ) i ts t 9 0 % is in d ep e nd en t o f t he c o nc en t r at i on . ( E ) a pl ot o f t he lo g a ri thm o f co nc e nt r a ti o n v e r s us t im e a ll o ws th e r a t e c on s ta n t t o b e d et e rm i ne d . V i e w A n s we r 2 5 . T he a nsw e r i s B [ se e] . t k t2 6 . A sa t i s fa c t o r y s u p p os i t o r y b a s e m us t m e e t a l l o f th e fo l l ow ing c r i t e ri a e x ce p t ( A ) i t s ho ul d h a v e a n ar ro w m e l ti n g r a ng e . ( B ) i t s ho ul d b e no ni r r it at i n g a nd no ns e ns it i z i ng . ( C ) i t s ho u ld di s s ol v e o r d i s i n te g ra t e r a pi dl y i n t he b od y c a v it y. ( D ) i t s ho u ld m e lt < 3 0 ° C. ( E ) i t s ho ul d b e i n e rt . V i e w A n s we r 2 6 . T he a nsw e r i s D [ se e] . 2 7. C o co a b u t t e r ( t h e o b ro m a o i l ) e xh i b its a l l o f th e fo l l ow in g p ro p e r t ie s ex ce p t ( A ) i t m el ts a t t em pe r a tur e s b e t we e n 3 3 ° C a nd 35 ° C . ( B ) i t i s a m i xt u r e o f gl y c e r i de s . ( C ) i t i s a p o l y m o r ph . ( D ) i t i s u s e f ul i n fo r m u lat i n g r ec t al s u pp os i to r ie s . ( E ) i t i s s o l ub le in wa t e r . V i e w A n s we r 2 7 . T he a nsw e r i s E [s e e] . T he o b r oma c ac a o. 2 8. U n i t e d St a t es P ha r m aco p e ia ( U S P ) te s ts t o e ns u r e th e qu a li t y o f d r u g p r o d u c ts in t ab l e t f o r m i n c lu d e a l l o f th e fo l l ow i ng e xc ep t ( A ) d is in t eg r a ti on . ( B ) d is s o lu t io n . ( C ) h a rd n es s a nd f ri ab i li ty. ( D ) c on t en t u n if o rm i t y . ( E ) we i g h t v a ri at i on .
V i e w A n s we r 2 8 . T he a nsw e r i s C [ se e] . D i r e c ti o ns f o r qu e s ti o ns 2 9 - 42 : Th e q u es ti o ns and i nc om pl e te s t a te m e n ts i n t h is s ec t io n c an be c o r re c tl y a ns we r e d o r c om p le t ed b y on e o r m o re o f th e s ug g es te d a ns we r s . C h o os e th e a ns we r , A- E . 2 9 . Fo r m s o f w a te r t ha t a r e su i t ab l e f o r us e i n p a r e n te r a l p r e pa r a t i on s i n c l ud e I . p u r if i e d w a t e r U S P. I I . w a te r f o r in j ec t i on US P . I I I . s t e r i le w a te r f o r i n je c t i on U S P . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 9 . T he a nsw e r i s D [ se e] . 3 0. T he pa r t i c le s in an i de a l s u s pe n si o n s h o ul d s a t is f y w h ic h of t he f o ll ow in g c r i te r i a? I . T he i r si z e s ho u l d b e u n i f o r m. I I . Th e y s h o u l d b e s t a t io n a r y o r m o ve r a n do m ly. I I I . Th e y s h o u l d r e ma i n d i s c re t e . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 0 . T he a nsw e r i s E [s e e] . 3 1. T he se d i me n t a ti o n o f p a r t i c le s i n a s us p en s io n ca n be mi n i mi z e d b y I . a dd i n g s od i u m b en z oa t e . I I . i nc r e as i ng t he vi s c os i t y o f t h e su s pe n s io n . I I I . r ed u ci n g t h e p a r t ic le s iz e o f t he ac t i ve in g re d i en t . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 1 . T he a nsw e r i s D [ se e] . 3 2. I ng r ed i e n ts t ha t ma y b e u s e d a s s u sp e nd i n g a ge n t s i n c lu d e I . m et h yl c e l l u l os e . I I . ac a ci a . I I I . ta l c. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t
V i e w A n s we r 3 2 . T he a nsw e r i s C [ se e] . 3 3. M e c ha n i sm s th a t a r e t h o u g ht t o p r o vi d e s t a bl e em u l si f i ca t i on s i n c lud e t he I . f o r ma t i on o f i n t e r fa c ia l f i lm . I I . l ow e ri n g o f in t e r f ac ia l t en s i on . I I I . p re s en c e o f c h a rg e o n t he i on s . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 3 . T he a nsw e r i s E [s e e] . 3 4. N o ni on i c su r f a ce - ac t i ve a g e n ts us e d a s s yn t h e t i c em u l si f i e rs i nc l ud e I . t r a ga c an t h . I I . so d i um la u r yl s u l f a te . I I I . s o r b i ta n e s t e rs ( S pan s ) . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 4 . T he a nsw e r i s B [ se e] . 3 5. Ad va n t a g e s o f s ys t e m i c d r u g ad m i ni s t r at i o n b y r e c t a l s u pp o si t o r ie s inc l u de I . a vo i da n ce o f f i r s t -p as s e ff e c ts . I I . su i t ab i l i t y w h en t he o r a l r o ut e is no t f ea s ib le . I I I . p re d ic t a bl e d ru g r ele a s e a nd a bs o r p ti o n . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 5 . T he a nsw e r i s C [ se ea n d] .3 6 . T ru e s ta t em e n ts a b o u t t h e m i ll i n g o f p ow d e rs i nc l ud e I . a fi n e p a r t ic l e s iz e i s e s se n t ia l if t he l ub r i c an t i s t o f un c t io n p r o p e r l y. I I . an i nc r e as e d s u r fa c e a r e a m a y e n h a n c e th e d i s so l u t io n r at e . I I I . m i l li n g m a y c a u s e de g r a da t i o n o f th e r mo l ab i l e d r u g s. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 6 . T he a nsw e r i s E [s e e] . P . 75
3 7 . Su b s ta n ce s u s ed t o i n s ul a t e p ow de r c om po n e n ts t ha t l iq u e f y w h en m i x ed i nc l ud e I . t a lc . I I . ka o l in . I I I . li g h t m ag n es i um o xid e . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 7 . T he a nsw e r i s D [ se e] . 3 8. A c e ra m i c m o r ta r ma y b e p r ef e r a bl e to a g l ass m o r ta r w h e n I . a vo la t i le o il i s a dd e d t o a p ow d e r m ix t u r e . I I . co l o r ed su b s ta n ce s ( d ye s ) a r e m ix e d i n t o a p ow d e r . I I I . c o mm i n ut i o n i s d e sir e d i n a d di t i on t o m i xi ng . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 8 . T he a nsw e r i s B [ se e] . 3 9. D i vi de d p ow de r s m a y b e d is p en s ed i n I . i nd i vi d u al - d os e pa cke t s . I I . a b u lk co n t ai n e r . I I I . a p e r fo r a t ed , s i f t e r -t yp e c o n t a i ne r . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 9 . T he a nsw e r i s A [ se ea n d] .4 0 . T ru e s ta t em e n ts a b o u t t h e f u nc t i o n o f ex c i p ie n ts u se d i n ta b l et f o r m u la t i on s i n c lu d e I . b in d e r s p r o mo t e g r a nu l a t i on du r i n g t h e w et g r a n u la t i on p r oc e ss . I I . g li d an t s h e l p p r om o te t h e f l ow of t he t ab l e t g r a n u la t i on d u r in g m a n u fa c tu r e . I I I . lu b r ic a n ts h el p th e p a t i en t sw al l ow th e ta bl e t s . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 0 . T he a nsw e r i s C [ se e] . 4 1. W hi c h m a nu f a c tu r i n g va r i a b l e s w o u ld b e l i kel y t o a f f e c t th e di s so l u ti o n o f a p r e d ni s o ne t a b l e t i n t h e b o d y? I . t h e a mo u n t a nd t yp e o f b i nd e r a d d ed
I I . t he am o un t an d t yp e o f d is i n te g r an t ad d e d I I I . th e fo r c e o f co m p res s i on u se d d u r i n g t a ble t i n g A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 1 . T he a nsw e r i s E [s e e V I .2 . b . (3 )] .4 2 . Ag e n ts t ha t m a y b e u s ed t o c o a t e nt e r i c - co a te d ta b l et s in cl u d e I . h yd r o x yp r o p yl m e t h yl c e l lu l os e . I I . ca r b ox ym e t h yl c e l l u l o s e . I I I . c e l lu l os e a c e ta t e p ht h a l a te . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 2 . T he a nsw e r i s B [ se e] . D i r e c ti o ns f o r qu e s ti o ns 4 3 - 46 : E a c h o f t h e f ol l owi n g t a bl e t -p r oc es si ng pr o b le m s c a n b e t he r es ult o f o n e t h e f ol l o wi n g r ea s o ns . Th e p r oc es si n g p ro b lem s m a y b e u se d m o re t ha n o n ce o r n ot a t al l . Ch o os e t he b es t a ns we r , A- E . 4 3 . Pi c ki n g A e xc e s s i v e m o is t ur e i n t h e g r a nu la t io n B e n t ra pm e nt o f a ir C t a bl e t f r ia b il i t y D d e g ra d ed dr u g E t a bl e t h a rd ne s s V i e w A n s we r 4 3 . T he a nsw e r i s A [ se e] . 4 4. M o t t l in g A e xc e s s i v e m o is t ur e i n t h e g r a nu la t io n B e n t ra pm e nt o f a ir C t a bl e t f r ia b il i t y D d e g ra d ed dr u g E t a bl e t h a rd ne s s V i e w A n s we r 4 4 . T he a nsw e r i s D [ se e] . 4 5. C a pp in g A e xc e s s i v e m o is t ur e i n t h e g r a nu la t io n B e n t ra pm e nt o f a ir C t a bl e t f r ia b il i t y D d e g ra d ed dr u g E t a bl e t h a rd ne s s V i e w A n s we r 4 5 . T he a nsw e r i s B [ se e] . 4 6. S t ic k in g A e xc e s s i v e m o is t ur e i n t h e g r a nu la t io n B e n t ra pm e nt o f a ir C t a bl e t f r ia b il i t y D d e g ra d ed dr u g E t a bl e t h a rd ne s s
V i e w A n s we r 4 6 . T he a nsw e r i s A [ se e] . D i r e c ti o ns f o r qu e s ti o ns 4 7 - 49 : E a c h o f t h e f ol l owi n g p r oc es s e s c an be de sc r i be d b y o ne of t he f o l lo wi n g c om m i n ut i on pro c ed u re s . Th e p ro c e s s es m a y b e us e d m o r e th an o n ce o r n ot a t al l . Ch o os e t he b es t a ns we r , A- E . 4 7 . R ub b i ng o r g r i n di ng a su b s ta nc e in a m o r ta r t h a t h as a ro u g h i n ne r s u r f a ce A t r i t u r a ti o n B s p at ul a ti o n C l e v i ga t io n D p u l v e ri z a t io n b y i nt e r ve n t io n E t um b li n g V i e w A n s we r 4 7 . T he a nsw e r i s A [ se e] . 4 8. R e du ci n g an d s u b d i vi di n g a su b s ta n ce b y a d d i n g a n e a si l y r e m o ve d s o l ve n t A t r i t u r a ti o n B s p at ul a ti o n C l e vi ga t io n D p u l ve ri z a t io n b y i nt e r ve n t io n E t um b li n g V i e w A n s we r 4 8 . T he a nsw e r i s D [ se e] . 4 9. Ad d i ng a su i t ab l e a ge n t to f or m a p as t e a n d t h e n r u b bin g o r g ri n d in g th e pa s te i n a mo r t a r A t r i t u r a ti o n B s p at ul a ti o n C l e vi ga t io n D p u l ve ri z a t io n b y i nt e r ve n t io n E t um b li n g V i e w A n s we r 4 9 . T he a nsw e r i s C [ se e] . P . 76
D i r e c t i on s fo r q ue s t io ns 5 0 -5 3 : E ac h o f th e fo llo wi n g c o n t ro ll e d -r e le as e d os a ge f o r m s i s re p re s e n te d b y o n e o f th e f o ll o wi n g d r ug p r o du c t s . Th e do s a g e f or m s m a y b e us ed m o r e t ha n o nc e o r n ot at al l . Ch oo s e t he b e s t a ns we r , A- E . 5 0 . Io n am i n c ap s u le s A m a t r i x f o r m ul a ti on s B i o n -e xc h a n ge re s i n c om p le x C d r u g c o m p l e xe s D o sm o ti c s y s t em E c oa t ed be a ds o r g ra n ul e s V i e w A n s we r 5 0 . T he a nsw e r i s B [ se e] . 5 1. T ho r az i n e S p an s ul e c a ps u l es A m a t r i x f o r m ul a ti on s B i o n -e xc h a n ge re s i n c om p le x C d r u g c o m p l e xe s D o s m o ti c s y s t em E c oa t ed be a ds o r g ra n ul e s V i e w A n s we r 5 1 . T he a nsw e r i s E [s e e] . 5 2. R yn a t a n pe d i a t ri c s u sp e ns i on A m a t r i x f o r m ul a ti on s
B i o n -e xc h a n ge re s i n c om p le x C d r u g c o m p l e xe s D o sm o ti c s y s t em E c oa t ed be a ds o r g ra n ul e s V i e w A n s we r 5 2 . T he a nsw e r i s C [ se e] . 5 3. P r o car d i a X L A m a t r i x f o r m ul a ti on s B i o n -e xc h a n ge re s i n c om p le x C d r u g c o m p l e xe s D o sm o ti c s y s t em E c oa t ed be a ds o r g ra n ul e s V i e w A n s we r 5 3 . T he a nsw e r i s D [ se e] . P . 77
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C [ s ee I V . A . 1. a ; I V . A .3 . d] . G l u c os e, u re a , a nd s u c ro s e a r e n on el e c t r ol y t e s . S o d iu m c hl o ri d e is a s t ron g e l ec t r ol y t e . E l ec t ro l y t es a r e s u bs ta nc e s t ha t fo rm i o ns wh e n d is s o l v ed in wa t e r . Th u s t he y c a n c on d uc t an e le c t r ic c u r r en t t h r ou gh t he s o lu t io n . I o ns a r e p a r ti c l e s t h a t b ea r el ec t r ic al c h a rg e s : C a ti o ns a r e p os i ti v el y c ha r g ed , a n d a ni on s ar e n e g at i vel y c ha r g ed . St r on g el ec t r ol yt es a re c om pl e t el y i on i z ed in wa t e r at a l l c o nc en t r at i on s . W eak e le c t ro l y t es (e . g ., ep h ed r in e ) ar e o n l y p a r ti a ll y i oni z e d at m os t c o nc en t r at i on s . B ec a us e n on e le ct r o l y te s d o n o t f o rm io ns wh e n i n s o l u ti on , t h e y a re no nc o nd uc t o rs . 2 . T he an sw e r is D [ s ee I V . A . 3. b ]. Th e p H is a m e as u r e o f th e ac id i t y , o r h yd r o ge n io n c o nc en t r at i on , o f an a q u eo us +
s o lu t io n . Th e p H i s t he lo g a ri t hm of th e re c i p r oc a l of th e h y dr o ge n i o n ( H ) c o nc en t r at i on e xp r e s s ed i n m ol es pe r li t er . B ec au s e t he lo g a ri t hm o f a r ec i p ro c a l e q u al s t he ne g at i v e l o gar i t hm of t he nu m b e r , t he p H is t he ne g at i v e l o ga r it h m o f t h e +
H c o nc en t r at i on . A p H of 7 . 0 in d ic a te s n eu t r al it y. A s th e p H de c re as es , the ac i di t y i n c re as es . Th e p H of a rte r i al bl o od is 7 . 35 - 7 .4 5 ; o f u ri n e, 4. 8 - 7. 5 ; o f g as tr i c j ui c e , a p p ro xi m a t el y 1 . 4; an d of c er e b ro s p i na l f lu i d, 7 .35 - 7 . 40 . Th e co n c e p t o f pH wa s i n t ro d uc ed b y S ör e ns en in t he ea r l y 19 0 0s . A lk a lin i t y is th e n e ga t i ve l og a ri t hm o f -
[ O H ] an d i s i n v e rs el y r e la t e d t o a ci di t y. 3 . T he an sw e r is B [ s ee I V . A . 2. d ]. O s m ot ic p re s s u re is an exa m p l e of a c ol li g at i v e pr o p e rt y . Th e os m o t ic p r es s u r e i s t h e m ag n it u de of p re s s u re n ee d ed to s t o p os m o s is ac r os s a s em ip e rm e ab le m em b r an e b e t we e n a s olu t i on an d a pu r e s ol ve n t. Th e c ol li g at i v e p r op e r ti es o f a s o lu t io n d e pe nd on t he to t a l n um be r of di s s oc ia te d an d u n di s s oc ia t ed s o lu t e p a r ti c l e s . Th es e p r o pe r t ie s a r e i n de pe n de n t o f t he s i z e o f t he so lu t e . O t he r c o ll ig a ti v e p ro p e rt ie s o f s o lu t es a r e re d uc ti o n i n th e va po r p re s s u re of th e s ol u ti o n, e l e va ti on o f i ts bo il i ng po i n t, an d d e p re s s io n o f i ts f re e z i ng po i nt . 4 . T he an sw e r is C [ s ee I V . A . 1. b ]. Th e c ol l ig a ti v e pr o pe r t ies o f a s ol u ti o n a re r el a te d t o t h e t ot a l n um be r of s o lu t e p a r ti c l e s t ha t i t c o nt a in s . E xa m p l es o f c o l li ga t i v e p r o pe r t ie s a r e t he os m o ti c
p r e ss u re , l o we r i ng of t he v a p o r p r es su r e , e le v a t ion o f t h e b oi li n g p oi n t, and d e p re ss io n o f th e fr e e z ing , o r m e l ti n g, po i nt . 5 . T he an sw e r is B [ s ee I V . A . 3. e ]. Th e H e n de r s o n - H as s e lba l c h eq u at i on fo r a we a k a c i d a n d i ts s a lt is a s f ol l o ws :
wh e r e p K a i s t he ne g a ti v e l og of t he di s s oc ia t io n c o ns ta n t o f a we a k a ci d a n d [ s al t ] /[ ac i d] is th e ra t io of t h e m o l ar c o nc e nt r a ti on o f s a lt an d a ci d u s e d to p r e pa r e a b u f fe r . 6 . T he an sw e r is C [ s ee V . D . 1 ]. A l t h ou gh al l o f th e m ec ha n is m s l is t ed ca n b e re sp o ns i bl e, t he c h em ic al de g r ad a ti o n o f m e di c i n al c om p ou n ds , p a r ti c u l ar l y es t er s i n l iqu i d f o rm ul a ti o ns , i s us u al l y ca us e d b y h yd r o l ys is . Fo r th is r ea s on , d r u gs th a t h a ve es t e r fu nc t io n al g ro up s a r e f o r m u l at e d i n d r y fo r m wh e n e v er po s s i bl e . O xi d a t i o n i s a no t he r c om m o n m o de of d e g ra d at i on an d i s m i n im i z e d b y in c l u di n g a nt i oxi d a n t s (e . g. , as c o r bi c ac i d ) in d ru g f o r m u l at io n s . P ho t ol y s is i s re d uc ed b y p ac k ag in g s us c ep ti b le p ro d uc ts i n am b e r o r o p a qu e c on t ai ne r s . D ec ar b o xy l a t i o n , wh i c h is t he r e m o v al of C O O H g r ou ps, a f fe c t s c om p ou n ds th a t i nc lu de c a r bo xyl i c ac i d. R ac em i za t i o n ne u t ra li ze s t h e e ff ec t s o f a n o p t ic al l y ac ti v e c o m p o und b y c o n v e r ti ng ha l f o f i ts m o le c u l es i n to t he i r m ir r o r - im ag e c o nf i gu r a ti on . As a r es u lt , t he de xt r o r o t a to r y a nd l e v o r o ta t or y f o rm s c an cel e ac h o t h e r o ut . Th is t y pe o f de g r ad a ti o n a f fe c t s o nl y dr u g s t ha t a r e c ha r ac t e ri z e d b y o p t ic al is om e ri s m . 7 . T he an sw e r is C [ s ee V . E . 3 .d ] . Te s t i ng o f a d r ug f or m ula t i on to de t e rm in e i ts s he l f l i fe c a n b e a c c el e ra t ed b y a p pl yi n g t h e A r r he ni u s eq u a ti on t o d at a o b ta i ne d a t hi gh e r t em p e ra t u re s . Th e m e th o d i n v ol v e s d e te rm in i ng t he r at e c on s ta n t ( k) va l u es f o r th e d eg r a da ti o n o f a d r u g a t v a ri ou s e le v a t e d t e m p e r at u re s . Th e lo g o f k is p l ot t ed ag a in s t th e r e c ip r oc al o f t he ab s o lu t e t em p e ra tu r e , a n d t he k v a l ue fo r d e g ra d at i on at r oo m t em p e r a tu r e is o b t ai ne d b y e xt r a p o la t ion . P.78
8 . T he an sw e r is E [ s e e I V . A . 3. g ]. Th e s ol u bi li t y o f a we a k a c id v a r ie s as a f u nc ti o n o f p H. B ec au s e p H a n d p K a ( th e d i ss oc ia t io n c on s ta n t) a re r el a t ed , s ol u bi li t y is als o re l at e d t o t he d eg r ee o f i o ni za t io n . As pi r in is a we a k ac i d t ha t is c om pl e tel y i o ni z e d a t a p H t h at is 2 un i ts g r e a te r th an i ts p K a . Th er e f o re , it is m os t s ol u bl e a t p H 6 .0 . 9 . T he an sw e r is B [ s ee V I . B . 7] . A l u m i nu m a c e t at e a n d a lu m in um s u ba c e t a te s o lu ti o ns a re as t ri ng e nt s t h at a r e u s e d a s a n ti p e rs pi r an t s a nd as we t d r es s i ng s f o r c on ta c t d e rm a ti ti s . S t r on g i od i ne s o lu t io n a n d b en z a lk on i um c h lo r i de ar e to pi ca l a nt i b ac te r i al s ol u ti o ns . Ac et i c a ci d i s a d d ed to p ro du c ts a s a n a c id i fi e r. A r om at ic am m on i a s pi r it is a r es p ir a to r y s t im ul a nt . 1 0 . Th e a n sw e r i s A [ s ee I V . B .1 . a] .
A s us pe ns i on is a t wo - ph a s e s y s t em th a t c o n si s ts o f a f i ne l y po wd e r e d s o l id d i sp e rs ed in a l iq u id v e hi c le . Th e p a rt ic l e s i z e o f t h e s us p en de d s ol i d s h ou l d b e a s s m a l l as po s s ib l e t o m in im i z e s ed im e nt a ti o n, bu t i t is u s ua ll y > 0. 5 µm . 1 1 . Th e a n sw e r i s C [ s ee V I . E .3 . a] . L e vi g at io n i s t h e p r oc es s o f bl en d in g a n d g ri n di ng a su bs t an c e to s e p ar a te t h e p a r ti c l e s , r ed uc e t h ei r s iz e , a nd f or m a pa st e . L ev i g a t io n i s p e rf o rm ed b y a d di n g a s m a l l am o un t o f s u it a bl e l e v i ga t in g a ge n t (e . g. , gl y c e r in ) to th e s ol i d a nd b l en d in g t h e m i xt u r e wi t h a m o r ta r a n d p es tl e . 1 2 . Th e a n sw e r i s A [ s ee V I . D .3 ] . A c ac i a, o r g um a r a bi c , is t h e e xu d a t e o b ta in e d f ro m th e s te m s an d b r an c h e s o f va r i o us s p ec ie s o f Ac ac ia , a wo o d y p l an t n a ti ve to A f r ic a. Ac a c i a i s a n a tu r a l e m ul si f y i ng ag e nt th a t p ro v i d es a s ta bl e e m ul s i on o f l o w v i s co s i t y . Em u ls io n s a r e d r o pl e ts of on e o r m o r e im m i s c ib l e l iq ui ds di sp e rs e d i n a no t he r li qu i d. Em u l s i on s a r e i n he r e nt l y un s t a bl e : t h e d r o pl e ts t e nd t o co a le sc e i n to la r g er an d l a r ge r d ro ps . Th e p u r po s e of an em ul s i f y i n g a ge n t is t o k e e p t he d r op le t s d is pe r s e d a nd p r e v e nt t h em f ro m c oa l es c i ng . Po l y s o rb a te 20 , p o l ys o r bat e 80 , an d s o rb it a n m on op a lm i ta t e a r e al so em ul s i f ie rs , bu t a r e s y n t he t ic , n o t n at u r al , s u bs t an c e s . 1 3 . Th e a n sw e r i s D [ s ee V I . E .2 ] . O i n t m e n ts a r e t y p i c a ll y us e d as em ol l ie n ts to s o f te n th e s k i n , as p ro t ec ti v e b a rr i e rs , o r as ve hi c l es f or m e di c a t i on . A v a r i et y o f o i nt m e n t b as e s a re a v ai l ab le . V a n is hi n g c r e am , a n e m u ls io n t y pe o f oi nt m en t b as e , is a n o i l -i n - wa t e r e m u ls io n th at c on t ai ns a h ig h p e rc en t ag e o f wa te r . S te a ri c a c i d i s us e d to c re a te a t hi n fi lm on the sk in wh e n t h e wa t e r e v a po r ate s . 1 4 . Th e a n sw e r i s B [ s ee V I . F. 2 .a ] . B y c o n v en t io n , a r ec ta l s u p p os it o r y fo r an ad u lt we i gh s a p pr o xi m a te l y 2 g . S u p po si t o ri es f or in f an t s a n d c h i ld r en a re s m al le r. V a gi n al s u pp os i to r ie s typ i c al l y we i g h a pp r o xi m a te l y 5 g . R e c ta l s up p os it o ri es a re u s u a ll y sh a pe d l ik e a n el o ng a te d b u ll e t ( c y li n d ri c a l a nd t ap e r ed a t o ne en d ) . V ag i na l s u pp os i to r ie s a r e u sua l l y o v oi d . 1 5 . Th e a n sw e r i s A [ s ee V I . F. 4 .c ] . I n t he fu s i o n m e t ho d o f m ak i ng s u pp os i to r ie s , m o l ds m a de of al um i nu m , b r a s s , o r n i ck el - co pp e r a l lo y s a r e u s ed . Fi ne l y po wd e r e d dr u g m i xe d wi t h m e l te d c oc o a b ut t e r i s p o u re d i n to a m o l d t hat i s lu b r ic at e d v e r y l ig h tly wi t h m i ne r al oi l . 1 6 . Th e a n sw e r i s B [ s ee V I . G ; Ta bl e 3 - 8] . Th e U S P d e fi ne s a v e r y f i n e c h em ic a l p o wd e r a s o n e t h at c o m p le t el y p as s e s t h r o ug h a s t an d a rd #1 20 s ie v e , wh i c h ha s 1 25 - µm op e ni n gs . Th e U S P c la s s i fi c a t io n f o r po wd e r e d v eg e ta bl e a n d a ni m al d r u gs d i f fe rs f r o m t ha t fo r po wd e r e d ch e m i ca ls . To b e cl as s i f ie d a s v e r y f i n e, po wd e r e d veg e ta b le a nd an im al d ru gs m u st p as s c om p le t el y t h ro u gh a # 80 s i e v e , wh ic h h as 18 0 - µm op e ni n gs . 1 7 . Th e a n sw e r i s C [ s ee V I . G .1 . c . ( 3 . (b ) ] . P u l ve r i z at i on b y i n te r v e nt i o n is th e m il l in g t ec h ni q u e t h at is us ed fo r d ru g s u bs ta n c e s t ha t ar e g um m y a nd t en d t o re a gg lo m e r a t e o r r e si st g ri nd i ng (e . g . , c am p ho r , i o di ne ) . In th is s en s e , in t er v e n t io n i s t he a dd i ti on o f a s m a ll am o u n t o f m a te r i al th a t a id s m i l li ng a n d c a n b e re m o v e d e as i l y a f t er pu l v e r i z at i on is c om pl e te . F o r e xa m pl e , c am ph o r c a n be r ed uc e d r ea d il y i f a s m al l a m o u nt o f v o l at i le so l ve nt ( e . g ., al c o h ol ) is a d de d . Th e s ol v e n t i s t he n a l lo we d to e vap o r at e .
P.79
1 8 . Th e a n sw e r i s D [ s ee V I . G .2 . c] . Th e p h a rm ac is t u s e s g eo m et r ic di lu t io n to m i x p o t e nt s u bs t an ce s wi t h a la r g e a m ou n t o f d il u en t . Th e po t e nt d ru g a n d a n e qu al a m ou n t o f d il u en t a r e f i rs t m i xe d i n a m o r t a r b y t ri t u ra t io n . A v o l um e o f di lu e nt eq u al t o t he m i xt u r e in th e m o rt a r is a d d ed , a n d t he m i x i s aga i n t r i tu r a te d . Th e p ro ced u r e i s r ep e at e d, a nd eac h ti m e , d i lu e nt eq u al in v o lu m e to t he m i xt u r e t he n i n t h e m o rt a r i s a dd e d, un t il all o f t he d i lu e nt is in c o r po r a te d . 1 9 . Th e a n sw e r i s A [ s ee V I . G .3 . b . (4 ) ] . H yg r o s c o pi c a nd v o la t il e d r u gs a r e b es t p r o te c ted b y wa xe d p a p e r , wh i c h i s wa t e r p r o o f. Th e p ac k et m a y be do u bl e - wr a p pe d wi t h a bo n d p ap e r t o i m pr o ve t he a p p ea r an c e o f t he c om p le t e d p o wd e r . 2 0 . Th e a n sw e r i s A [ s ee V I . H .2 .c . ( 1 )] . H a r d c a ps ul es a re nu m be r e d f r om 00 0 (l a rg es t ) to 5 (s m a ll es t ) . Th e i r a p pr o xi m a t e c a pa ci t y r an g es fr o m 6 00 t o 3 0 m g; ho we v e r , t h e c ap ac i t y of t he c a ps ul e d e p en ds o n th e d e ns it y o f th e c ont e n ts . 2 1 . Th e a n sw e r i s A [ s ee V I . H .3 . a a nd b] . Th e s he l ls o f s o ft ge l at i n c ap s u l es ar e p l as ti ci ze d b y t h e a dd i ti on o f a p o l yh yd r i c a l co h ol (p o l y ol ) , s uc h a s g l y c e r i n o r s o rb it o l. A n a n t if u ng al p re s e r v a t i ve ca n al so be a d d ed . Bo t h h a rd an d s of t g el at i n c ap su le s c an be f il l ed wi t h a po wd e r o r a n o th e r d r y s ub s ta nc e . S o ft ge l ati n c a ps ul es a re al s o us efu l do sa g e f o rm s f or f lu ids o r s em is o li ds . 2 2 . Th e a n sw e r i s C [ s ee V I . H .4 . a] . A c on t en t un i fo rm i t y te s t i s a te st o f p ot e nc y. To e n s u r e t h at ea ch t ab le t o r ca ps u le c o nt a in s t he in t en d ed am o un t o f dr u g s ub s t a nc e, t h e U S P p ro v i de s t wo t e s ts : we i gh t va r i a ti o n a nd c o n te n t u nif o r m i t y . Th e c on t en t un i fo r m it y t es t c an be us e d fo r a n y d o sa g e u ni t , b ut is r eq uir e d fo r c o at e d t ab l et s , f or t a bl e ts i n wh ic h th e a c ti ve i n g re d ie n t m a k e s u p < 50 % of t he ta b le t , f o r s us p e ns i on s i n s i n gl e -u n it c o n t ai ne r s o r i n s o f t c a ps u le s , an d fo r m a n y s ol i ds th a t co n ta i n a d d ed s u bs ta nc e s. Th e we i g h t va r i a ti o n t es t c a n b e us ed f o r l iq ui d - fi ll e d s of t c ap s ul es , fo r a n y d os ag e fo r m u n it t h a t c on t ai ns at le as t 50 m g o f a s i n gl e d r ug if t he d r ug m ak es up a t l ea s t 5 0 % o f t h e b u lk , f o r s ol id s t h at d o no t c on t ai n a d de d s ub s ta nc e s, an d f o r f r e e ze- d r i ed s o lu t io ns . 2 3 . Th e a n sw e r i s A [ s ee V . A a n d V . B ] . Th e r e ac t io n v el oc i t y , o r d e g ra d at i on r at e , o f a pha r m ac eu t ic al pr o du c t is a f f ec t ed b y s e ve ra l fa c t o rs , i nc l ud i ng t em pe r a tu r e, so l ve nt s , a n d li g h t. Th e d e g ra da t i on r at e i n c re as es t wo t o t h re e t im es wi t h ea c h 10 ° in c rea s e i n t em pe r a tu r e . Th e e f f ec t o f t e m p e r at u re o n r ea c ti on r a t e i s g i ven b y th e Ar r he n iu s e q ua t io n : k = Ae
-Ea/RT
wh e r e k i s t h e r ea c ti o n ra t e c on s ta n t, A i s t h e f r eq u e nc y f ac to r , Ea is th e e n e rg y o f a c ti va t io n , R is t he ga s c o n s t a nt , an d T is th e a bs o l u te te m p e r at u re . 2 4 . Th e a n sw e r i s D [ s ee V . B .2 . a ].
I n ze r o -o r de r de g ra d at i on , t he c o nc en t r at i on of a d r u g d ec r ea se s o ve r t im e . H o we ve r , t h e c ha n ge of c o nc en t r at i on wi t h re sp ec t to ti m e is un c h a ng ed . I n t he e q u at io n :
t h e fa ct th a t d C / dt is ne ga t i v e s ig n if i es th a t t he co n c e n t ra t io n i s d ec r ea s in g . H o we ve r , t h e v el oc i t y o f t h e c on c en t ra t io n c ha n ge is c o ns t an t . 2 5 . Th e a n sw e r i s B [ s ee V . B .2 . b .( 2 ) ]. Th e h a lf - li f e ( t 1 / 2 ) is th e t i m e r eq ui r e d f o r t he co nc e nt r a ti o n o f a d r u g t o de c r ea s e b y o n e h al f . F o r a f ir s t- o r der d e gr a da t io n :
B e c au se bo t h k a n d 0 .6 93 a r e c o ns t an t s , t 1 / 2 i s a c o ns ta n t . P.80
2 6 . Th e a n sw e r i s D [ s ee V I . F. 3 ]. A s a ti sf ac t o r y s up p os it o ry b a s e sh o ul d r em a in fi rm a t r oo m t em p e ra t ur e . P r e f e ra b l y , i t sh ou l d n ot m e l t < 3 0 ° C t o a v oi d p r em at u r e s o f te n in g d u r in g s to r a ge an d i ns e r ti o n. I t sh o ul d a ls o b e i ne r t , no n s e ns i ti z i n g, no n ir r i ta t in g , a n d c o m pa ti b le wi t h a v a r i et y o f d r u gs . Mo r e o v e r , i t s ho uld m e l t j us t b el o w b o d y tem p e ra t ur e a n d s ho ul d d is s o l v e o r d i si n te g ra t e r a pi dl y i n t he f lu i d o f t he b od y c a v i t y i n to wh i c h i t is in se r t ed . 2 7 . Th e a n sw e r i s E [s ee V I . F. 3 .c . (1 ) ] . C o c oa bu t t er is a f at t ha t i s o b ta in e d f r om th e s eed o f T h eo b ro m a ca c a o . C h e m i ca l l y , i t i s a m i xt u re o f s te a ri n , p al m i t in , and o th e r g l y ce r id e s t ha t ar e i n so lu b le in wa t e r a n d f re e l y s o lu bl e i n e t h er an d c hl o r of o rm . De p en d in g o n th e f u si o n t em pe r a tu r e , c o c oa b ut t e r c a n c r y s ta l li z e in t o a n y on e o f fo u r c r ys ta l fo r m s . C o c oa bu t t er is a g oo d ba s e f o r r ec t al s u pp o si to r ie s , a l th ou g h i t i s l ess tha n id ea l f o r va gi n al or u re t h ra l s up p os i to r ie s . 2 8 . Th e a n sw e r i s C [ s ee V I . I. 5 ]. To s a t is f y th e U S P s ta nda r d s , ta b le ts a re r eq u ir ed t o p as s o ne of t wo t es ts . A we i g h t v a r ia t io n t es t i s us e d i f t h e ac t i v e i ng r e di en t m a k e s u p t he bu lk o f th e ta b le t . A c on t en t un i fo rm i t y te s t i s u s e d i f t h e t ab l et is co a t ed o r i f t he ac t i v e i ngr e d ie n t m ak e s u p < 5 0 % o f t h e bu l k o f t h e t ab l et . Ma n y t ab l e ts fo r o r a l a dm in is t ra ti o n a r e r e q ui r e d t o m e e t a di s i n te g r a ti on t es t. D is i nt e gr a ti o n t im es a re s p ec if i ed in t he i n di vi d ua l m on o gr a ph s . A d is s o l ut i on te s t m a y be r e qu i re d i ns t ea d i f th e a c ti ve c om p on e nt o f t he ta b le t h a s l im it e d wa t e r so lu b il it y . H a r d ne ss a n d f r ia b il ity wo u l d a f f ec t t h e d is in t eg r a ti on a n d d is s o l ut i on ra t es , b ut h a rd n es s an d fr i ab il i t y t e s ts a r e i n - ho us e q u al i t y c on t r ol te s ts , n o t o f fi ci al U S P te s t s . 2 9 . Th e a n sw e r i s D ( I I , I I I ) [s ee V I . A. 1 ]. W ate r f o r i nj ec t io n U S P is wa t e r th a t h as be en pur i f ie d b y d is t il la t io n o r b y r e v e r s e o sm o si s . Th is wa t e r i s us e d t o p r ep a r e p ar e nt e r al s o l ut i on s t ha t ar e s u bj ec t to fi n al
s t e ri li za t io n . F o r p a re n ter a l s ol u ti o ns th a t a r e p r ep a r ed as ep t ic al l y an d n ot s u bs eq u en t l y s t er i li z e d , s t e ri le wa t e r fo r in je c ti on U S P is us e d. S te r il e wa te r f o r i n je c ti on U S P is wa t e r f or i nj ec t io n U S P t h at ha s b e e n st e r il i zed an d s ui t ab l y p a ck ag e d. Th i s wa t e r m ee t s t h e U S P r eq ui r em e nts f or st e ri l it y . B ac t e ri os ta t ic wa t e r f o r in je c ti on U S P is s t er il e wa t e r f o r i n je ct i on U SP t h at c o n ta i ns o n e o r m o r e a n t im ic r ob ia l a g en ts . It c a n be us ed in pa r en t e ra l s ol u ti o ns i f th e a n ti m i c ro b ia l a d di t i ves a re c om p at i bl e wi t h t h e o th e r i ng r e di ent s in th e s ol u ti o n, bu t i t c a nn o t b e u s ed in ne wb o r n s . P u ri fie d wa t e r U S P i s n ot us ed i n p a re n te r al p re pa r a tio n s. 3 0 . Th e a n sw e r i s E ( I , II , I I I) [s e e I V . B .2 ] . A n i de al s u s p e ns io n wo ul d ha v e pa r t ic le s o f u ni f or m s i z e , m in im al s e di m en t a ti o n, a n d n o i n te r ac t io n b e t wee n pa r t ic le s. A lt h ou g h t he s e i de al c ri t er i a a r e r a re l y m e t , t h e y ca n b e a p pr o xi m a ted b y k e e pi ng th e pa r ti cl e s i z e a s sm al l a s p os si ble , t he d e ns i ti es of t he s o li d a nd t he di sp e rs i on m e di um a s s im il a r as po s s i bl e, an d th e d i sp e rs io n m ed i um a s v is c o u s as po s s ib l e. 3 1 . Th e a n sw e r i s D ( I I , I I I ) [s ee I V . B. 2 ]. A s S to k es ' s l a w i nd ic a tes , th e s ed im e nt a ti o n r a te o f a su s p e ns io n i s sl o we d b y r e d uc in g i t s d en s i t y , re du c in g t h e si ze o f t he s u sp e n de d p a rt ic l es , o r i n c re a s i n g i ts vi s co si t y b y in c o r p o ra ti ng a th ic k e ni n g a ge n t. S od i um be n z o at e i s a n a n tif u n ga l a g e nt an d wo u ld no t re du c e t he se di m en t at io n rat e o f a s us pe ns i on . 3 2 . Th e a n sw e r i s C ( I , II ) [ s e e VI . C . 3] . A c ac i a a nd m e th y l c el lu l os e a r e c om m o n s us pe n din g ag e nt s. A ca c i a i s a na t u r al p r o du c t, an d m e th y l c e ll ul o s e is a s y nt h et ic po l y m e r . B y in c re as i ng th e vis c os i t y of t h e l i qu id , th es e a g en ts e n a bl e p a rt ic l es to re m a in s u sp e nd e d f o r a l o ng e r p e ri o d . 3 3 . Th e a n sw e r i s E ( I , II , I I I) [s e e V I . D .3 ] . E m u ls if y i n g a ge n ts p r o v id e a m e ch a ni c a l b a r ri e r to c o a le s c en c e . Th e y al s o r e du ce t h e n a tu r a l t en d en c y o f th e d ro pl e ts in th e i n te r na l ph as e (o il o r wa t e r ) of t h e e m ul si o n t o c o a le s c e . Th r e e m ec h an is m s a p pe a r t o be in v o l v e d. S om e e m u l s i f ie rs p r o m o t e s ta bi l it y b y f o rm i n g s t ro n g, pl i ab le in t e rfa c ia l f i lm s a ro u nd th e d ro p le t s . E m u ls if y i n g a ge n ts a ls o r e d uc e i n te r fa c i a l t en s i on . Fi n al l y , i o ns (f r om t he e m u ls i fi e r ) i n th e i n te r f ac ia l f i lm c an l e ad to ch a rg e re p ul s i o n t h a t ca us es d ro p le ts t o r e p el on e a n o th e r , t he r eb y p r e v e nti n g c oa le s c e nc e. 3 4 . Th e a n sw e r i s B ( I I I) [ s e e V I. D . 3 ]. A l l o f th e s ub s ta nc es li s te d a re em ul si f y i ng ag en ts , bu t o n l y s o rb i ta n e s t e rs a re n o ni o ni c s y n th e ti c a ge n ts . Tr a ga c an t h, li ke ac ac ia , is a n at u ra l e m u ls i f y ing a ge n t. S o d iu m l au r y l s u lf a te is a n an io n ic s u r fa c t a nt . Sor b i ta n es te r s ( k n o wn co l lo q ui a ll y a s Sp a ns b e c a us e o f t h ei r t r ad e n am es ) ar e h y d ro p h ob ic an d f o rm wa t e r -in - o il e m ul si o ns . Th e po l y s or ba t es ( k n o wn c o ll o qu i al l y a s Twe e n s ) a r e a ls o n oni o ni c , s yn t he t ic s o r bi t an de r i v at i v e s . H o we ve r , t he y a r e h yd r o ph i li c a nd th e r ef o re f o rm oi l i n - wa t e r e m ul s i on s . S o diu m l a u r y l su l fa t e, as an a l k a li s o ap , is a ls o h yd r op h il ic an d t h us f or m s oi l -i n - wa t e r em u ls io ns . P.81
3 5 . Th e a n sw e r i s C ( I , II ) [ s e e VI . F .1 an d 2 ] .
R e c t al s u pp os i to r ie s a r e u s ef u l f o r d el i v e ri n g s y ste m ic m ed ic a ti o n u nd e r c e r t ai n c i rc um s ta nc es . Ab s o r p tio n of a d r ug f ro m a re c tal s u p po s i t o r y i n v o l v es re le a s e of t h e d r u g f r om th e s up pos i to r y v e h ic le , d i f fu s i on th r o ug h th e r e c t al m u co s a , an d t r a ns p or t to t he c i rc ul a tio n th r o ug h t h e r ec t al ve in s . Th e r ec t al ve in s b ypa ss t he l i ve r , s o t hi s r o ut e a v oi ds r ap i d h ep a ti c d eg r ad a ti o n of ce r ta i n d r ug s ( f i rs t- p a ss e f f ec t ) . Th e r ec ta l ro u te i s a ls o u s e f ul wh e n a d rug c a n no t b e g i v e n o r al l y ( e . g ., b e c a us e o f v om i ti n g) . H owe v e r , t h e e xt e n t o f d r ug r e le a s e an d a bs o rp t io n is va r i a bl e . I t d e pe n ds o n th e p ro pe r t ie s o f t h e d r ug, t h e su p po s i t o r y b as e , an d th e e n vi r on m e n t i n t h e r ec t um . 3 6 . Th e a n sw e r i s E ( I , II , I I I) [s e e V I . G .1 . c] . Mi l l i n g i s t h e p ro c e s s of m ec h an ic a ll y r ed u c i ng t he p a rt ic l e s i z e of s o li ds b e f o re t h e y a re fo r m u l at e d i nt o a f in a l p ro d uc t . To wo r k e f f ec t i v el y, a l ub r ic an t m u s t c oa t t h e s u rf a c e of th e g r a nu la t i on o r p o wd e r . H e nc e fi n e p a r ti c l e si ze is es s e nt i a l. D e c r ea s i n g t he pa r t ic le s i z e i nc r ea s e s t he su r f ac e a r ea an d c an en h an c e t h e d i ss ol u ti on r a te . Th e rm ola b il e d r u gs m a y un d er g o d e g ra da t io n b ec a us e o f t h e b u il d up of he a t d u ri n g m il l in g . 3 7 . Th e a n sw e r i s D ( I I , I I I ) [s ee V I . G .2 . a. ( 2 ) ]. S o m e so l id s u bs ta n c e s (e . g . , as p ir i n, ph e n y ls al icy l a t e , p he n ac et i n, t h ym ol , c am p ho r ) l i qu e f y or f or m e u te c ti c m i xt u r e s wh e n in c l os e , p r ol o ng ed c o n tac t wi t h o n e a n ot h er . Th es e s ub s t a nc es a re be s t i ns ul a ted b y t he ad di t io n o f li gh t m a gn es i um o xi d e o r m agn e s i um c a r bo n at e . O t h e r i n er t di lu e nt s t h at c a n be us e d a r e k a ol in , s t a rc h, a nd be n ton i t e. 3 8 . Th e a n sw e r i s B ( I I I) [ s e e V I. G . 2 .b ] . W hen p o wd e rs a re m i xe d , if c o m m in u ti o n is es pec i al l y im po r ta n t , a p o rc e la i n o r c e r am ic m o rt a r t h at ha s a r o ug h i nn e r s u rf ac e i s p r e f er r e d o ve r t h e s m o oth wo r k i ng s u r fa ce o f a g l as s m o r ta r. B e c a us e a gl as s m o r t a r c le a ns m o re ea si l y a ft e r u s e , it is p r e f er r e d f o r c h em ic a ls th a t m a y s t ai n a po r ce l ain o r c e ra m i c m o r t a r as we l l a s f o r s im p le m i xi n g of s u bs t anc es t ha t d o n o t r e qu i re c o m m i nu t io n . 3 9 . Th e a n sw e r i s A ( I ) [ s ee V I . G .3 . a a nd b] . P o wd e r s fo r o ra l u s e c a n b e d is p en s e d b y t h e p ha r m ac is t i n b ul k f o rm or d i vi de d i n t o p r em ea s u r ed do s e s ( d i v i de d p o wd e r s ). D i v ide d p o wd e r s a r e t r a di ti o na l l y d i sp e ns ed in fo l de d p ape r p ac k e ts (c h ar t ul a e ) m a d e o f p a rc hm e nt , bo nd p a p er , g l as si n e, o r wa xe d p a p er . H o we ve r , i nd i v id u al dos es c a n b e p ac ka g ed in m e ta l fo il o r sm al l p la s ti c b ag s i f th e po wd e r n ee ds g re a te r p r o te ct i on f ro m h um id i t y o r e va p o ra t io n . 4 0 . Th e a n sw e r i s C ( I , II ) [ s e e VI . I .2 . b] . Ta b l e ts f or o ra l i n ge s t i on us u al l y c o nt a in e xc i pi en t s t h at a re ad d ed to th e f o r m u l at io n fo r th e ir s p ec i al fu nc t io ns . Bi n de r s an d ad h es i v es a r e a d de d t o p ro m o t e g r a nu l at i on o r c o m p ac t ion . D il u en ts a re fi l le r s t ha t a r e a dd e d t o m ak e u p th e r e q ui r e d t ab l et bu lk . Th ey c a n a ls o a id in t he m an u f ac tu r i ng pr o c e ss . Di sin t e g ra n ts a i d i n t a bl e t d is in t eg r at i on i n g as t ro i nt es t in a l f l u ids . Lu b ri c a n ts , a n ti a dh e ren t s , a nd g l id a nt s a id in r ed uc i ng fr i c ti on o r a dh es i on be t we e n p a r ti cl es or be t we e n t a bl e t a nd d i e . F o r e xa m p le , l u b ri c an t s a r e u se d i n t h e m a n uf a c tu r e o f t a bl e ts to re d uc e fr ic t io n wh e n t h e t a bl et is ej ec t ed f r om th e d ie ca v i t y. Lub r i c a n ts a r e u su a ll y h y d ro p h ob ic s u bs ta n c e s t ha t c a n a ff ec t th e d is so l ut i on ra t e o f t h e a c t i v e i n gr e di e nt .
4 1 . Th e a n sw e r i s E ( I , II , I I I) [s e e V I .2 . b . (3 ) ] . D i s in t eg r an t s a r e a dd ed t o t ab le t fo r m u la t io ns t o f a ci l it a te di s i n te g ra t io n in g a st r o in t es ti n al fl ui d s . Di s in t eg r a ti on o f t he ta b l et i n t he b od y is c r i ti ca l t o i t s d i ss ol u ti on a nd s u bs eq ue n t a bs o r pt i on an d b io a va i la b il i t y . Th e bi n de r an d t h e c om p r es s i on fo r c e us ed d u r in g ta bl e t m an u fa ct u rin g af f ec t t h e h a rd n es s of t h e t a b le t a s we ll as ta b le t di s in t eg r a ti on an d d r u g d i s s o l ut i on . 4 2 . Th e a n sw e r i s B ( I I I) [ s e e V I. I .3 . a .( 4 ) ] . A n e nt e ri c -c oa t ed t ab le t h a s a c o at in g th a t r em a in s i n ta c t i n t he s t om ac h , b u t d i ss ol ve s i n t he in t es t in es t o y i e ld th e t a bl e t i ng re d ie n ts th e r e. E nt e r ic c oa t i ng s i n cl ud e v a ri o us fa ts , fa t ty a c id s , wa xe s , an d s he ll a c s . Ce ll u lo s e ac e ta t e ph t h al a te r e m ai ns in t ac t i n t he s t om ac h b e c a us e i t d is so l ve s o n l y wh e n t h e p H > 6 . O t h e r e n t e ri c- c o a ti n g m at e ri a ls i nc l ud e p o vi do ne ( po l y v in y l p y r r o li d on e ), po l y vi n yl ac e ta t e p h t ha la t e , a nd h y d ro xy p r o p y l m e th y l c e l lu lo s e p hth a l a t e . 4 3 . Th e a n sw e r i s A [ s ee V I . I. 4 ]. 4 4 . Th e a n sw e r i s D [ s ee V I . I. 4 ]. 4 5 . Th e a n sw e r i s B [ s ee V I . I. 4 ]. P.82
4 6 . Th e a n sw e r i s A [ s ee V I . I. 4 ]. S t i ck in g i s a dh es i on of ta b le t m a te r i al to a d ie wa l l . I t m a y b e c au s ed b y e xc e s s i ve m o is tu r e o r b y th e u s e of i n gr e di e nt s t h at ha v e low m e l t in g te m p e ra t u re s. Mo t t l i n g i s u n e ve n c o l or di s t ri bu t io n. I t i s m os t o f te n c au se d b y p o o r m i xi n g o f t h e t abl e t g r a nu l at i on bu t m a y al s o o c c u r wh en a d e gr a de d d r u g p r od uc es a c ol o re d m e ta b ol i te . Ca p pi n g is s e p a ra t io n o f th e t o p o r bo t t om c r o wn o f a ta bl e t fr o m t h e m a in bo d y . C ap pi n g im p li e s t ha t c om p r ess e d p o wd e r i s n o t co h es i v e . R e as o ns fo r c a pp i ng i n c l ud e e xc e s s i v e f o rc e o f c om p re s s io n , u s e o f i ns u ff ic i en t b i nd e r, wo r n t a b le t t o ol i ng eq ui pm e nt , a n d e nt r a pm en t o f ai r du r i ng p ro ce s s in g . P ic ki ng is a d h er e nc e o f t a bl e t s u r fa c e m a t e ri a l t o a p u nc h . I t c a n b e c au s e d b y a g ra n ul a ti o n t h a t i s t oo da m p , b y a s c r a t c h e d p un c h , b y s ta t ic c h a rg es on th e p o wd e r , a n d p a r ti c ul a rl y b y t he us e o f a pu nc h ti p t h at is e n g ra ve d o r em b oss e d . 4 7 . Th e a n sw e r i s A [ s ee V I . G .1 . c; V I . G .2 ] . 4 8 . Th e a n sw e r i s D [ s ee V I . G .1 . c; V I . G .2 ] . 4 9 . Th e a n sw e r i s C [ s ee V I . G .1 . c; V I . G .2 ] . C o m m i nu t io n i s t he p ro c e s s o f r e du ci ng t he pa r tic l e s i z e o f a p o wd e r to in c r ea s e it s f i n en es s . S e v e ra l c om m in u t io n t ec h ni q ue s a re s ui t a b l e f o r sm a ll - s c al e u s e i n a p h a rm ac y . Tr i t u ra t io n i s u s ed bo t h t o c om m i nu t e a n d t o m i x d r y p o wd e r s . I f c om m i n ut i on is d es i r ed , t h e s ub s ta nc e i s r u bb e d i n a m o r t a r t ha t h a s a rou g h i nn e r s u r fa ce . Pu l v e r i z at i on b y i n te r v e n ti o n is of t en us ed f o r s u b s t a nc es th a t t end t o a g gl o m e r at e o r r es is t g r in d in g . A s m al l a m o u nt o f e as i l y re m o v e d (e . g. , v ol a t il e ) s o l ven t i s a dd e d. A f te r th e s u bs t an c e is p u l v er i ze d , th e s ol v e n t is al l o wed t o e va p o ra t e o r i s o t he r wi s e r em o v e d. Le v i g at i on is o f t en us ed to p re p ar e pa s te s o r o i n tm en ts . Th e p o wd e r is r ed uc e d b y ad d in g a s u i t ab le no n s o l v en t (l e v i ga t i ng ag e nt ) t o f or m a pa s t e a n d t he n e i th e r ru bb i ng th e p as t e i n a m o r ta r wi t h a p es tl e o r r u b bi n g i t o n a n o in t m e nt s la b wi t h a s pa t ul a . S pa t u la t io n a nd t um bl in g a re
t e ch n iq u es t h at a re us ed t o m i x o r b le nd po wd e r s , n o t t o r e du ce th em . S pa t u la t io n i s b l en di n g s m al l a m o u n ts o f p o wd e rs b y s t ir r i ng th e m wi t h a s pa t ul a o n a s h ee t o f p a p er o r a p i ll ti l e. Tu m bl i ng is bl en d in g l a rg e a m o u n ts o f po wd e r in a l a rge r o ta t in g c o nt a in e r . 5 0 . Th e a n sw e r i s B [ s ee V I . K .3 . e] . 5 1 . Th e a n sw e r i s E [s ee V I . K .3 . a] . 5 2 . Th e a n sw e r i s C [ s ee V I . K .3 . f] . 5 3 . Th e a n sw e r i s D [ s ee V I . K .3 . d] . C o n t r ol le d - re l ea s e do s ag e fo r m s ar e d es i gn e d t o r e l e a se a d ru g s lo wl y f o r p r o lo n ge d a c t i on in th e bo d y . A v a ri e t y of ph a rm ac e ut ic a l m e c h a ni s m s a re u s e d to p r o vi de t he c o nt r ol l ed r el e as e . I on - e xc h a ng e re s in s m a y be c om p le xe d t o d r u gs b y p a ss in g a c a ti o ni c d r ug s o l u ti on t hr o ug h a co lu m n t h a t c o n ta i ns th e r es i n. Th e d r u g i s c om pl e xe d t o t h e r es in b y r ep l ac em en t o f h y d ro g e n a to m s . Re l ea se of d r u g f r om t h e c om pl e x d e p en ds on t h e i o ni c e n vi ro nm en t wi th i n t h e g as t ro i nt es t in a l tr a c t a nd o n th e p r o pe r ti es o f t he re s in . Co a t ed be ad s ( e . g., Th o r a z i ne S pa ns u le c ap s ul es ) or g r a nu l es p r o du c e bl o od le v e l s s i m i l a r t o t ho s e o bt a i ne d wi t h m u l ti p le do s in g . Th e va r i o us c o at i ng th ic k n es s es p ro d uc e a s us t ai n ed- r e l ea s e ef f ec t . Ma t r i x d e v i c es m a y us e in s ol u bl e p la s ti c s , h yd r oph i li c p ol ym e rs , o r fa t t y c om p ou n ds . Th es e c o m po n e nt s a r e m i xe d wi t h t he d r ug an d c om p re s s ed in t o a t a b le t . Th e p ri m a r y d os e, o r th e p o rt i on of t he d ru g to be r el e as ed im m e di a t el y , is p l ac e d o n t he ta b le t a s a l a y e r o r c o at . Th e re m a in d e r o f t h e d os e i s r el e as e d s l o wl y f r o m t he m a t ri x. R e l a t i v el y i ns o lu bl e ta nn a t e- am in e c om p le xe s p r o v id e f or a p r o lo n ge d g as t r oi n te s t i na l ab s o r p ti on ph as e a n d s us t ai n ed s ys t em ic c o nc e n t r at i on s o f t he we a k b as es . Os m o t ic s ys t em s em p lo y os m o t ic p re s s u re to co n t ro l th e r el ea s e o f t he ac ti v e in g re d ie n t fr o m t h e f o rm ul a ti o n. O sm o ti c t a bl e t f o rm ul a ti on s p r o vi de a s em i pe r m e ab l e m e m br a ne as a c oa t in g t h at su r r ou n ds th e o s m o ti c a ll y a ct iv e c o re . Th e c oa t in g a l lo ws wa t e r t o di f fu se in t o t he c o r e b u t d o es n o t a ll o w d r u g to d if f us e o u t . A s wa t e r f lo ws i n to th e ta b le t , t h e d ru g d is s olv e s . Th e l as e r -d r il l ed ho le i n t he c o at i ng al lo ws t h e d r ug s o l u ti on wi t h in t he ta b le t to f lo w t o t he ou t si de a t a r a t e t ha t i s e q ui va le n t t o th e r a te o f wa t e r fl o w i n to th e ta bl e t . Th e os m o t ic p r es s u re g r ad ie n t a n d a ze r o -o r de r dr u g - rel e as e ra t e wi l l be m a in t ai n ed as lo n g as e xc e s s os m o t ic al l y a c ti ve so lu t e ( e . g. , e l ec tr o l y t e ) r em a in s i n t he t ab l e t c o r e .
4 Biopharmaceutics and Drug Delivery Systems L aw re n ce H . B lo c k
I. INTRODUCTION A. B i o p h a r m ac e u ti c s is t h e s tu d y o f t he r el a ti on o f th e p h ys i c a l a n d c h em ic a l p r o pe r t ie s o f a d ru g t o i ts bi o a v ai la b il i t y , p ha r m ac ok i ne t ics , an d p h ar m a c o d yn am ic a n d t o xi c o lo g ic e f fe c ts . 1 . A d ru g p ro d u ct is th e f i ni s h e d d os ag e f o rm ( e.g . , ta bl e t , c a p su le , s ol u tio n ) th a t c o nt a in s t he ac t i v e d r ug i n g re d ie n t i n as s o c i a ti o n wi t h n on d r ug ( us ua ll y i na c ti v e ) i n g re d ie n ts (e x ci p ie n t s ) t h a t m ak e u p t he ve h i cle , o r f o r m ul a t io n m a t r ix. 2 . Th e ph r as e d r ug de li v e r y s y s te m i s o ft e n us e d i n te r c h a ng ea b l y wi t h t he t e rm s d r u g p r od uc t or do s a g e fo r m . H o we ve r , a d r u g de l i ve r y s ys t e m i s a m o re c om p r eh e ns i v e c o nc e pt , wh i c h in cl u de s t he d ru g fo r m ul a ti on an d th e d yn am ic i n t er a ct i on s am o ng th e dr u g , i ts f or m u l at i on m a t rix, i t s co n t ai ne r , a n d t he p a t ie n t. 3 . B i oa va i l ab i l i t y i s a m e a s u r em e nt of t he ra t e an d e xt e n t ( a m o un t ) o f s y s t em ic a b so r p ti on o f t he t he r ape u t ic al l y ac ti v e d ru g . B . P h a r ma c ok i ne t i cs is t h e s t ud y o f t h e t im e c o ur s e o f d r u g m o ve m e n t i n t h e b o d y d u r in g a bs o r pt i on , d is t r ib u t io n , a nd el im in a ti o n (e xc r e t i o n a nd bi o tr a ns f orm a ti o n ). C . P h a r ma c od yn a m i c s is t he s t ud y o f t h e r e la t ion o f t h e d ru g c o nc en t ra t io n o r a m ou n t a t t h e s i t e o f a c t io n ( re ce p t or ) an d i ts ph ar m ac o lo gi c r e sp on s e as a f un c ti on o f ti m e.
II. DRUG TRANSPORT AND ABSORPTION A. T r a n s p o r t o f d r ug mo l e cu l e s a c ro s s c el l mem b r a ne s . D ru g a bs o rp t io n r eq ui r es t h e d r u g t o b e t r an s p o r ted ac r os s va ri ou s c el l m em b r an es . D ru g m ol ec u les m a y e n t e r t he bl o od s t r e am an d be t ra ns p o rt e d t o t he t i s s ue s a n d o rg a ns o f the b od y . D r u g m o le c u l es m a y c r os s a dd i ti o na l m em b ra ne s t o en t er ce ll s . D r u g m o le c ul es m a y a l so c r os s a n i n tr ac e ll ula r m e m b r an e , s uc h a s t he n uc le a r m em b ra ne o r e n d op la s m ic re t ic ul um , to r e ac h t he si t e o f ac t io n. F ig u r e 4 - 1 d em on s t r a tes so m e of t h e k e y t ra ns p or t p ro c e s s es in v o l ve d i n d r ug ab so r p ti o n .
Figure 4-1. The key drug transport processes in intestinal epithelial cells. 1, Transcellular passive (diffusion and partitioning); 2, paracellular transport (diffusion and convection); 3, carriermediated transport; 4, P-glycoproteinmediated efflux. [Modified from Brayden DJ, Pharm News 4(1);1997:11-15.]
P.84
1 . G e ne r a l p r i n ci p le s a . A c e l l m em b r an e i s a s em ip e rm e ab le s t r uc t u re c o m p o s e d p r im a ri l y of l i pi ds an d p r o t ei ns . b . D r ug s m a y b e t ra ns por t e d b y p as s i ve di f f u si on , p a r ti t i on i n g, ca r r i e r -m e d ia t e d t r a n s po r t , pa r a ce l l ul a r t r a n s po r t , o r ve s i cu l a r t r a n s po r t . c . Us u al l y , p ro t e in s , d r ug s b ou n d t o p r ot e i ns , an d ma c r om o le c u le s d o n o t e as i l y c r os s c el l m em br a ne s . d . N o n po l a r l i p id - s ol u bl e d r ug s tr a v e rs e c e ll m e m b ra ne s m o re ea si l y tha n do i o n i c o r p o l a r w a t e r -s o lu b l e d r u g s. e . L ow m o le c ul a r w e ig ht d r u g s d if f us e a cr o s s a c e ll m em b r an e m or e ea si l y t ha n d o h ig h m o le c u la r w e igh t d r u gs . 2 . P as s i ve d i f f us i o n a nd p a r t i ti o ni n g a . W i th i n t h e c yt o p l a s m o r in in t e r s ti t i al f l ui d , m os t dr u gs un de r g o t r ans p o rt b y s im p le di f fu s i o n. b . F ic k 's l aw o f di f f u si on . S i mp l e p as s i ve di f f us i o n i n v ol ve s t h e t r an s fer o f d r u gs f r o m a n a r ea of hi g h c o nc e nt r a ti o n ( C 1 ) t o a n a r ea o f l o we r c o nc en t r a ti on ( C 2 ) a cc o r di ng t o F ic k 's la w o f d if f us io n :
wh e r e d Q / d t is t he ra t e of d r ug di f fu si o n, D is th e d i f fu si o n c o e f fi ci en t fo r th e d ru g , A i s t he s u r f ac e a r ea of th e pl an e ac ro s s wh i ch t ra n s f e r o c c u rs , h is th e t hi ck n es s o f t h e re g io n t h ro u gh wh i c h d i ff u s i on oc cu r s, an d ( C 1 - C 2 ) i s t he di f fe r e nc e b e t we e n t h e d r u g c o nc e nt r a ti o n in a r ea 1 a nd ar e a 2 , re s p e c t i v e l y . c . P ass i v e d r u g t r an s p o rt a c r o s s c el l m em b ra n es i n v o l v es th e s uc c e s s i ve p a r t i t i on i ng o f a s ol u te b e t we e n a q ue o us a n d l ipi d ph as es as we l l a s d i f fu s i o n wi t h i n th e re s p ec t i v e p has es . Mo d i f y i ng Fi c k ' s l a w o f di f fu s i o n t o ac c om m od a t e t he p a r ti t io n in g o f d r u g g i v es t h e f ol l o wi n g:
Th e r a t e o f d r ug di f fu s i on , d Q /d t , n o w r e f le ct s i ts d i re c t d ep e nd en c e o n K, t h e oi l to wa t e r p a r ti t io n c oe f fi c i e nt o f t h e d r ug , a s we ll as o n A a n d ( C 1 - C 2 ) . d . I on i z a t i on o f a w ea k e l e c t ro l yt e i s a f f ec te d by t h e p H o f t h e m e d iu m in wh i c h t h e d r u g is di s s ol v e d a s we l l a s b y t he p K a of t he d r u g. Th e n o ni o ni ze d s pe c ie s is m o r e li p id s o lu b le th a n th e io ni ze d s p ec ie s, an d it p a rt i ti o ns m o re r ea di l y a c r os s c e ll m em b r an es . 3 . C a r r ie r - m ed i a te d t ran s p o r t a . Ac t i ve t r a n sp o r t o f the d r ug ac r os s a m em br an e is a c a r r ie r -m e di a te d p r o ce s s t h a t h as th e fo ll o wi n g c ha r a c t e ri s ti c s . ( 1 ) Th e dr u g m o v es a g ain s t a c o nc en t r at i on gr a die n t . ( 2 ) Th e pr o c e s s re q ui r es e n e rg y.
( 3 ) Th e c a r ri e r m a y b e s e l ec t i v e f o r c e r t ai n t y pe s o f dr u gs th a t r es em b le n a t u ra l s u bs t ra t es or m e t ab ol i tes t ha t a r e n o rm al l y ac t i ve l y t r an sp o r te d . ( 4 ) Th e c a r ri e r s y s te m m a y b e s a tu r a te d a t a hi gh d r ug c o nc en t r at i on . ( 5 ) Th e pr o c e s s m a y be c om p et i ti ve ( i. e . , d ru g s wi t h s im il a r s t ru c tu r es m a y c om p et e f o r th e s am e c a rr i e r) . b . F ac i l it a t ed d if f u si o n i s a ls o a ca r r ie r -m e di a ted t r an s p o r t s y st em . H o we v e r , f a ci l it a te d d i ff us i on oc c ur s wi t h (i . e. , in th e d i re c ti o n o f ) a c o nc en t r at i on gr a d ie n t a n d d o es n o t r e qu i re ene r g y . 4 . P a ra c el l u la r t r a ns p or t . D r u g t r an sp o r t a c r o s s t i gh t (n a r ro w) j u nc t io ns b e t we e n c e ll s o r t r a ns en d ot h el ia l c h an n el s o f c el ls i s k no wn as p a ra c el l u la r t r an sp o r t . It i n vo l ves bo t h d if f us io n an d th e c o n ve c ti ve ( b ul k ) f l o w o f wa t e r a nd ac co m p a n y i ng wa t e r - s o lu bl e d r u g m o l ec u le s t h ro u gh th e p a r ac el l ul a r c ha n ne ls . 5 . V es i cu l a r t ra n sp o r t is t he pr o c e s s o f en gu l fi ng p a rt ic l es o r di ss ol v e d m a te r i al s b y a ce ll . Ve s i c ul a r t r an s p o r t i s t he on l y t r an s p o rt m ec ha n is m t ha t d o es n ot r e qu i re a d r ug to be in an aq u eou s s ol u ti o n t o b e a bs o rbe d . Pi n o c yt o s i s a n d p ha g o c yt o s i s a r e fo r m s o f v es ic u la r t ra n s p o r t. a . P i no c yt o s i s i s t h e e ng u l fm en t o f s m a l l s o l ut e o r f lu id v o lu m es . P.85
b . P h ag o c yt o s i s i s t he e n g ul fm e nt of la r g er pa r ti c le s, o r m a c ro m o l ec ul es , g en e r al l y b y m ac r op h ag es . c . E nd o c yt o s i s a n d e xoc yt o s i s a r e t h e m o v e m en t o f m a c ro m o l ec ul es in to a nd ou t o f t he c e ll , re s p ec t i v el y . 6 . O t h e r t r a n sp o r t m e ch a n is m s : t r a ns p o r te r pr o t e i ns . V ar i ou s t r a ns po r t e r p r o t e i ns ( e. g ., P - gl yc o p r o t e i n ) a r e em b ed d ed in t h e l ip i d b il a y e r o f c el l m em b r an es i n ta n de m i n α - h el ic a l t ra n s m em b ra n e r eg i on s o r d om a in s . Th e se p ro t ei ns a re a d e no s i ne t ri p ho s p h at e - ( A TP ; e n e rg y ) d ep e nd e nt “ p u m ps , ” wh ic h c an fa ci l it a t e t he e f f lu x o f d r ug m o le c ul es f r o m t he c e ll . B ec au s e the s e t r an sm em b ra n e e f fl ux p u m p s a r e of t en fo u nd in c o nj un c ti o n wi t h m e t ab ol i z i ng e n z y m e s s u ch as c yt o c h r o m e P4 5 0 3 A4 , t h ei r ne t ef f ec t i s to s u bs t a nt ia l l y re d uc e i nt r a c e ll u la r d ru g c on c e n t ra t i on s. Th u s t he y d et e rm i ne , t o a l ar g e e xt e n t , th e p h arm ac o ki ne t ic d is p os i ti on a n d c i rc u la ti n g p la s m a c on c en t r a ti o ns o f d r u gs (e . g. , c y c lo s po r in , n i fe d ip in e , d i go xi n ) t h a t a r e s u b s t r a te s f o r t he s e p r ot e in s . B . R o u t es o f d r u g a dm in i s t r a ti o n 1 . P a re n t e ra l ad m in i s t ra t i o n a . I n t ra ve n o us b ol u s i nj e c t io n . Th e d r ug is i nj ec t ed di r ec t l y i n to t he bl oo d s t r e am , d i st r ib u t es t h r ou gh o u t t he b od y , an d a c ts ra p id l y . A n y s id e e f fe ct s , i nc lu din g an i n t en se ph a rm ac ol o gi c re s po ns e , a na p h y la xi s , o r o ve r t to xi c i t y, al s o oc c ur r a pi d l y . b . I n t ra - a r t e ri a l i n je c t ion . Th e d ru g i s i nj ec t ed in t o a s p ec i fi c a r te r y t o ac h ie v e a h i gh d ru g c on c en t ra t io n in a s pe ci f ic ti s s ue be f o re d r ug di s t r ib u ti o n oc c urs t h r o ug ho u t t h e b od y . I nt ra - a r te r i al i n je c t i on is u s ed f o r d ia g no s t ic ag e nt s an d o cc a si on a ll y f o r c h em o the r a p y . c . In t r a ve n o us in f u si o n. Th e d ru g i s g i v en in t r av e n o us l y a t a c on s ta n t inp u t ra t e. C o n s ta n tr a te in t r a v en o us in f us io n m ai n ta i ns a r el a t i v el y c o ns t an t pl as m a d r u g
c o nc en t r at i on on c e th e in f us i on r at e i s a pp r o xi m a t e l y e q ua l t o th e d r ug ' s e l im in a ti o n r a t e f r om th e bo d y (i . e ., o n c e s t e ad y st a t e is r eac h ed ) . d . I n t ra m us c ul a r in j ec t io n . Th e d r u g is in je c te d d e e p in t o a s ke l et a l m u s c l e. Th e r a t e o f a bs o r pt i on de p end s o n th e v as c u la r i t y o f th e m us c l e s i te , th e l ip i d s o lu bi l it y o f t he dr u g, an d th e f o rm u l a ti on m a t ri x. e . S u bc u ta n e ou s i n j ec t io n . Th e d r u g is in je c te d b e n ea t h t he s k i n . Be c a us e th e s u bc ut a ne o us re g io n i s le s s v a sc ul a r t h an m us c le t i s su es , d r u g a bs o rp ti on is le ss r a p id . Th e f ac t o rs th a t a ff e c t a bs o rp ti o n f r om in t ra m us c u la r de p ot s a ls o af f e c t s u bc ut a ne o us a b s o r pt i on. f . M is ce l l an e ou s pa r e n te r a l r ou t e s ( 1 ) I n t ra - a r t ic u la r i nj e c ti o n . Th e d r ug is i n je ct e d i n to a j oi n t. ( 2 ) I n t ra d e rm a l ( i n t r ac ut a n e ou s ) i n j ec t i on . Th e d r u g is in je c te d i n to th e d e rm is ( i . e ., t he v as c u l a r r eg i on o f th e s ki n b el o w t h e e pi d e rm is ) . ( 3 ) I n t ra t h ec a l i n je c ti o n. Th e d ru g i s i nj ec t ed in to t he sp in a l f lu i d. 2 . E n te r a l a d mi n is t r a t ion a . B u cc a l a nd s ub l i ng ua l a dm i ni s t r a ti o n. A ta bl e t o r lo z e n ge is p l ac ed u n d er t he t o n gu e (s u bl i n gu a l ) o r in c o n ta c t wi t h t he m uc osa l ( bu c ca l ) s u rf ac e o f the c h e ek . Th i s t yp e o f a dm in is t r at io n al lo ws a no n po la r , l i pi d - s o lu b le dr u g t o b e a bs o r b ed a c r oss t he ep i th el i al li nin g of t he m o ut h . A f t er buc ca l o r s u bl i ng ua l a dm i nis t r at i on , t h e d r u g is ab s o r b ed di re c tl y i n to th e s ys te m i c c ir c u la ti o n , b y p as s i ng th e l i ve r a n d a n y f i rs t -p as s e f fe c ts . b . P e r o ra l ( o ra l ) d r u g ad m i n is t r a t io n . Th e d ru g i s a dm in is t e re d o r al l y , is s wa l l o we d , a n d u nd e rg oe s a bs o r pt i on f ro m t he ga s t ro i nt es t in a l t r ac t t h rou g h t h e m es e nt e r ic c i rc ul a ti o n t o t h e h ep a ti c p o rt a l v e i n i n t o th e l i ve r a nd th e n t o t h e s ys t em ic c i rc ul a ti o n. Th e p e r or a l r o ut e i s t he m o s t c om m o n r o ut e o f a dm i ni s t ra t io n . ( 1 ) Th e pe r o ra l r o ut e i s th e m os t c o n ven i en t a n d t h e s a fe s t r ou t e. ( 2 ) D is a d v an t ag es of t his r ou t e i nc lu d e t he f ol lowi n g . ( a ) Th e dr u g m a y n o t b e a b s o r be d f ro m t he ga s tro i n te s t i na l t r ac t c on s i s ten t l y o r c om p le t el y . ( b ) Th e d ru g m a y b e d i ge s te d b y g as t r oi n te st i na l e n zy m es o r d ec om po s ed b y t he a c id p H o f t h e s to m a c h . ( c ) Th e dr u g m a y i r r it a te m uc os al ep i th e li al c e ll s o r c o m p l e x wi t h t h e c o n te n ts o f t he g a st r o in t es ti n al t ra c t . ( d ) S om e d r ug s m a y b e in c om pl e te l y ab s o r b ed bec a us e o f f i rs t - pa s s e f f ec ts o r p r e s ys t em ic el im in a ti o n (e . g . , t he d ru g i s m e t ab o li z e d b y th e l i v e r b ef o r e s y s t e m i c a b so r p ti on oc c u r s ). ( e ) Th e ab s o r p ti on r at e m a y be e r ra t ic b ec a us e o f de l a yed ga s t r ic em p t yi n g o r c h an g es i n i n te s t i na l m oti l it y . P.86
( 3 ) Mo s t d ru gs a re xe n ob i o t i cs or ex o g en o us m o l ec ul e s a nd , c on se q ue nt l y , a re a b so r be d f ro m t he ga s tro i n te s t i na l t r ac t b y p a ss ive d i f f u si o n a n d p a r ti t io n i n g. C a r r i e r - m ed i a te d t ra n sp o r t , pa r a ce l l ul a r t ra n sp o r t , an d ve si c ul a r t r ans p o r t p l a y s m a l le r , b u t c ri t ic al , ro l es , pa r ti cu l a rl y f o r e nd o ge n o us m ol ec u le s .
( 4 ) D r ug m o le c u l es a r e ab s o rb ed t h ro ug h ou t th e g a s t r o i n t es ti n al t ra ct ; but t h e d u o d en a l r e g io n , wh ic h h a s a l a r ge s u r fa ce a re a b ec a us e o f t h e vi l l i an d m ic r o vi ll i, i s th e p r im a r y a bs o r pt i on s i te . Th e l a rg e b lo o d s up p l y p ro vi de d b y t h e m es e nt e r ic ve s s el s al l o ws th e d r u g to b e a bs o rb e d m o r e e f fi c i e n tl y ( se e I I . A .2 ) . ( 5 ) Al t e r e d ga s t r ic em pt yi n g a f f e c t s a r r i v al of th e d ru g i n t h e d uo de n um f o r s ys t em ic a bs o r pt i on . G as t r i c e m p t yi n g t i m e i s af f e ct e d b y f oo d c on t en t , e m ot i on al s t a te , a n d d r ug s t ha t a l te r g as t ro in t es t in al t ra c t m o ti l it y ( e .g . , a n ti c h o li ner g i cs , n a r co t ic a n al ge s i c s , p r ok i n e ti c a ge n ts ) . ( 6 ) N o rm al in t es t in al m o ti l it y f r om pe r i s ta l s is b rin g s t he d ru g i n c on t ac t wi t h t h e i n t es ti n al ep i th el i al c e ll s . A s u f fi c i e nt pe r i od of co n t ac t ( r es i de nc e t im e ) is ne e de d t o p e r m i t d r ug ab s or p ti o n ac r os s t h e c e l l m e m b r a nes f ro m t h e m u c o s al to the s e r os a l s u r fa ce . ( 7 ) S om e d r ug s , s u c h as c i me t i d in e a n d a ce t am in o p h en , wh e n g i ven in an i m m e di a te - r el e as e p er o ra l do sa g e f o rm t o fa s t e d s u bj ec ts p ro d uc e a s y s t em ic d ru g c o nc en t r at i on ti m e wi t h two p e a k s . Th is do u b le - pe a k p h en o me n o n is a tt r ib u t ed to va r i a bi l it y i n s to m a c h em p t y i n g, v a r ia b le in t es ti n a l m o t il i t y , a nd en t e ro h epa t ic c yc li n g. c . R ec t a l a dm i n is t r a ti on . Th e d ru g i n s ol u ti on (e n em a ) o r s u pp os i to r y f or m is p l ac e d in t he r ec tu m . D ru g di f fu si o n f r om th e s olu t i on o r r el e as e f r om th e s u pp os i to r y l ea ds to ab s o r p ti o n a c r o ss t h e m u c os a l s u r f ac e o f t h e r ec t um . D r u g a b so r be d i n th e l o we r t wo t hi r ds of t he r ec tu m e nt e r s t he s ys t em ic c i rc u lat i o n d i r ec tl y, b y p as s i ng t he liv e r a n d a n y fi rs t - pa s s eff e c ts . 3 . R es p i r a to r y t r a c t a dm i n is t r a t i on a . I n t ra n as a l a dm i n is t ra t i o n . Th e d ru g c on t ai ned i n a s ol u ti o n o r s us pe ns i on is a d m i ni s te r ed t o t he na s al m u c o sa , ei t he r a s a s p ra y o r as dr o ps . Th e m e d ic a ti o n m a y be us e d f o r l oc al (e .g . , na s a l d ec on g es t an ts , i n t ra n as al s t e ro id s ) o r s ys t e m i c e f f ec ts . b . P u lm o na r y i n h a l a t i on . Th e d ru g , as li q ui d o r s o li d p a r ti cl es , i s i nh al ed p e ro r al l y ( wi t h a ne b ul i z e r o r a m et e r e d- d os e a e ro so l ) i n to t h e p u lm on a r y t re e . I n ge n e ra l , p a r t i c le s > 60 µ m a r e p ri m a ri l y d e po s i t ed in th e tr a c h ea . Pa r t i c le s > 20 µm d o n ot r e a ch th e b r o nc hi ol es , an d pa r t i c le s < 0. 6 µ m a re n ot de p os it e d a nd a re e x h al e d . P a r t ic le s b e t we e n 2 a n d 6 µ m c a n r ea c h t he al ve o l a r du c t s, al t ho u gh on ly p a r t ic le s o f 1 -2 µ m a r e re t a in e d in t h e a l ve o li . 4 . T r an s de r m al a nd t opi c a l a d mi n is t r a t io n a . T r an s de r m al ( pe r c u ta n e ou s ) d r u g a bs or p ti o n i s t h e pl a ce m e n t o f t h e d r u g ( i n a l o t io n , o in tm e nt , c r ea m , p a s t e , o r p a tc h ) o n t h e sk i n s u r f ac e f o r s y s te m i c a b so r p ti on . A n oc c l us i v e d r es s i n g o r f i lm i m p r o ves s ys t em ic d ru g a bs o rp t io n f ro m t h e s ki n . S m a ll li p id - s o lub l e m ol ec ul e s , s u c h as ni t r og l y c er i n, ni co t in e , sc o p ol a m i ne , c l on id i ne , fe n ta n y l , a nd s t e ro i ds (e . g. , 17 - β - es t ra d io l , t es t os t er o ne ) , a r e r e a di l y a b so r be d f ro m t he s k i n . b . D r ug s (e . g. , a n ti b ac t er i a ls , l oc al an e st h et ic age n ts ) a re ap pl i ed t op i ca ll y t o t h e s ki n fo r a lo c a l e f f ec t . 5 . Mi s c el la n eo us r ou t es o f d ru g a dm i ni s t r a ti on inc l ud e o p h th a lm i c , o t ic , u r e t h r a l, a n d va gi n a l a dm in is t ra t io n . Th es e r o ut e s o f a dm in i st r a ti o n a re ge n e ra ll y u s ed fo r l o ca l t h e ra pe u ti c a c t i v i t y. H o we ve r , so m e s ys t em ic d ru g a bs o r pt i on m a y oc c u r .
C . L o ca l d ru g ac t i vi t y v e r s us s ys t e m i c d ru g abs o r p t i on . Th e r o ut e of a d m i ni s t ra ti o n , a bs or p ti on s i t e , a nd bi oa v a i la bi l ity o f t he d ru g f r om th e d os a ge fo r m a r e m a jo r fa c t o rs in th e d e s i g n o f a d r u g p r od uc t. 1 . D r ug s i n te nd e d f o r l oc a l a c t i vi t y, s u c h as to pi c al an t ib io t ic s , an t i -i n fec t i v es , a n t if u ng al ag e n ts , a nd loc a l a ne st h et ic s a r e f o rm u l a te d i n d os a ge fo r m s th a t m i ni m i ze s y s t em ic a bs o rp t i on . Th e c on c e n t ra ti o n o f t he se dr u gs at th e a pp l ic a ti on s i te a ff ec t s t he i r a c t i v i t y . 2 . W he n s ys t e m i c a b so r p t i o n i s d es i re d , t he bi oa va i la b il i t y o f th e d r ug f ro m th e d o sa g e f o rm a t th e a bs or p t io n s i te m us t be c o ns id e r ed ( e. g . , a d r u g g i ven i n t ra ve n ou s l y i s 1 00 % b io a v a il a bl e b ec a us e a ll of t h e d r ug is p l ac ed di r ec tl y i n to th e s ys t em ic c i rc ul a ti o n) . The am o un t , o r d o s e , o f d ru g in th e d os a ge fo r m i s b a se d o n t h e e xt e n t o f d r ug ab s o rp t i on an d t h e d es i re d s ys t em ic dr u g c on c e n t ra ti on . Th e t y pe o f do sa g e f o rm (e . g ., im m e di a te r el ea s e , c o nt r ol le d r el ea s e ) af f ec ts t he ra t e o f dr u g a b so r p ti on . P.87
III. BIOPHARMACEUTIC PRINCIPLES A. P h ys i c o c h em i ca l p rop e r t i es 1 . D r u g d i ss o l ut i o n. F or m os t d r u gs wi t h l im it e d wa t e r s ol u bi li t y, th e ra t e a t wh i c h t h e s ol i d d r ug en t er s i n to s o l ut i on (i . e ., t he ra t e o f di s s ol u ti o n ) is of t en t he r a te l i m i ti n g s te p i n b i oa v a il ab i li t y . Th e N o ye s - W h i t ne y e q u a t i on de sc ri b es the d if f us io n c o nt r o ll ed r at e o f dr u g d is s o l ut i on ( d m /d t ; i . e. , the ch a ng e i n t h e am o un t o f d ru g i n s o lu t io n wi t h r es p ec t t o ti m e ):
wh e r e D is t he di f fu s i o n c o ef f ic ie n t o f t h e s ol ut e , A i s t he su r f ac e a r ea of th e s o li d u n d er g oi n g di s s o lu t io n , δ is t he th ic k n es s o f th e d i f fu s i o n l a y e r, C s i s t h e c o nc en t r at i on of t he s o l va t e a t s a tu r a ti on , an d C b i s t h e co nc e nt r a ti o n o f th e d ru g i n t h e b u lk s ol u ti o n p ha s e a t ti m e t . 2 . D r u g s o lu b i li t y i n a s a t u r at e d so l ut i on (s e e Ch a p te r 3, I V ) is a s ta t ic ( e q ui l ib r iu m ) p ro p e rt y . Th e di s s ol u ti o n r a te of a dr u g i s a d y na m i c p r op e r ty r e l a te d t o t he ra t e o f a bs o r pt i on . 3 . P a r ti c le s iz e a nd su r fa c e a r e a a r e i n v er s el y re l a te d . A s s ol id d ru g p a rt i c l e s i ze d e c re as es , p a r ti c l e s u rf ac e a r e a i nc r ea se s . a . A s d es c r ib e d b y t he No y e s -W hi tn e y eq u at i on , th e di s s ol u ti o n r a te is d i re c tl y p r o po r t io n al to th e s u r fac e a r e a. A n i nc r ea s e in su r f ac e a r e a al l o ws fo r m o r e c o nt ac t be t we e n th e s ol id d r ug pa r ti c l es an d th e s o l v en t , r e s u lt i ng in a f as t e r d i ss ol u ti on r a te (s ee I I I.A . 1 ) . b . W ith c e rt a in h yd r o p h o b i c d r u g s, e xc e s s i v e pa r t ic le s i z e r ed uc t io n d oe s n o t a l wa ys i nc r ea s e t he di s s o l u ti on r at e . Sm al l p a rt icl e s t en d to re a gg r e ga t e in t o l a r ge r p a r ti c l e s t o r e du c e th e h ig h s u r fa c e f re e e n e rg y pr o d uc ed b y pa r t ic le s i z e r e d uc t io n .
c . To p re v e n t t he f or m a t io n of ag g r eg a te s , sm al l d r u g p a rt ic l es a r e m ol ec u l a rl y d i sp e rs ed in po l y e th y l e ne g l yc o l ( P E G ) , p o l yv i n y lp y r r o l id o ne ( P V P; po v i d on e ) , d e xt r o s e , o r o t he r ag e nts . Fo r e xa m pl e , a m ol ec u l a r d is pe r s i o n o f g r is eo fu l vi n i n a wa t e r - s o lu bl e c a r ri e r s uc h as P E G 40 0 0 ( e .g . , G ris - P E G ) en h an c e s i ts di s s o lu t io n a n d b io a v a il a bi li t y . 4 . P a r ti t i o n c oe f f i ci e n t a n d e x t en t o f i o ni za t i on a . Th e pa r t i t io n co e f fi c ie n t of a d r ug is th e ra ti o o f th e s ol u bi li t y o f t he dr u g , a t e q ui l ib r iu m , in a n o na que o us s o l v en t (e . g ., n -o c ta n ol ) t o t ha t i n a n a q ue ou s s ol ve n t ( e . g ., wa t e r ; p H 7 .4 bu f fe r s o l ut i on ) . H y d ro ph i li c d r u gs wi t h h i gh e r wa t e r s o lu bi l it y h a ve a f as t e r d is s o lu t io n r a t e t ha n d o h y d r o ph o bic o r l ip o ph il ic d ru gs , wh ic h h a ve p o o r wa t e r s o l ub il i t y . b . E x te n t o f i on i z a t i on . D r u g s t ha t ar e we a k e le c t r o l yt es (a c i ds o r b as es ) e xi s t i n b o t h a n i on i z e d f o rm a n d a no n io ni ze d fo r m i n s o lu t i on . Th e e xt e n t of io n i za t i on d e p en ds on th e p K a o f the we a k el ec t ro l y t e a nd th e p H o f t h e so l ut i on . The i on i z ed f o r m is m o r e p ol a r , a nd th e r e fo r e m o r e wa t e r s olu b le , th a n t he no n io ni z e d f o rm . Th e H e n d e r so n - H as s el b al c h e q ua t i o n d es c r i be s t he r e l at i on be t we e n th e i on ize d a nd t h e n o ni o ni z e d f o rm s o f a d r ug as a f un ct i on of pH a n d p K a . W hen t h e p H o f t he m e di um eq u al s t he p K a of t h e d ru g , 5 0% o f t he d ru g in s o lu t io n i s n on io n i ze d an d 5 0 % i s i on i z ed , as c an be s h o wn f r om th e fo ll o wi n g eq u at i on s : ( 1 ) F o r w ea k a ci d s :
( 2 ) F o r w ea k b as e s :
5 . S al t f o rm a t io n a . Th e c h oi c e of s a lt f o rm f or a d r ug de p en ds on t h e d es i re d p h y s i c a l , c he m ic al , o r p h a rm ac ol o gi c p r op e r ti es . C e rt a in s a lt s a r e d es ig n e d t o p r o vid e s lo we r di s s o lu t io n , s l o we r bi oa v a i la b il it y , a nd l on ge r du r a ti o n o f ac t i o n . O th e r s al t s a re s e le ct e d fo r g r e a te r s t ab il i t y , l es s l oc a l ir r i ta t io n a t th e a bs o rpt i o n si t e, o r l es s s ys t em ic t o xi c it y. ( 1 ) S om e s ol ub l e s a l t f o rm s a r e l es s s t a bl e t h an th e no ni o ni z e d fo rm . Fo r e xa m p l e , s o di um as pi r in is le s s s ta b le t ha n a s p i ri n i n t h e ac i d f o rm . ( 2 ) A s o li d d os ag e fo rm c o nt a in in g bu f fe r in g a g en t s m a y b e fo rm u la t ed wi t h t h e f r ee a c id fo r m o f t h e d r ug (e .g . , bu f fe r ed as pi r i n) . P.88
( a ) Th e bu f fe r in g a g en t fo r m s an al k a l in e m ed iu m i n t h e g as t ro i nt es t in a l t ra c t , a nd t h e d r u g d is s o l v es i n s i tu . ( b ) Th e di s s ol v e d s al t for m of t he dr u g d if f us es in t o th e b ul k f l ui d o f t h e g a st r o in t es ti n al t ra c t , fo rm s a fi n e p re c i p it a te t ha t r e di ss o l v es ra p id l y , a n d b ec om e s a va i la b le fo r ab s o r p ti o n. b . E f f e r ve sc e n t g r an u l es o r ta b le t s c on t ai ni n g th e ac id d ru g i n a dd i ti o n to s o d iu m b i ca r bo n at e , t a r ta r ic ac id , c i t ri c a c i d , o r o t he r i ng r e di e nt s a r e a dd e d t o wa t e r j us t b e f o re or a l a dm in is t r at i on . Th e e xc es s s od iu m b ic a r bo na t e f o rm s a n a lk ali n e
s o lu t io n i n wh ic h t h e d r ug d is s o l v es . Ca r b on di o xi d e i s a ls o f o rm ed b y th e d e co m p os i ti o n o f c ar b oni c a c i d . c . Fo r we a k l y a c i di c d r ugs , po t as s i um a n d s o d iu m s al t s a re m o r e s ol ub l e th a n d i va le n t c at i on s a lt s ( e . g. , c a lc i um , m a g ne si um ) o r t r i v al en t c a ti o n sa l ts (e . g . , a l um in um ) . d . F o r we a k b as e s, c om m o n wa t e r - s o l ub le s a l ts in c lu d e t he h yd ro c h l or i de, s ul f at e , c i t ra t e, an d g l uc on a te s al t s . Th e es to l at e , n ap s y la t e , a nd s t e a ra t e s a l ts ar e le s s wa t e r s ol u bl e . 6 . P o l ym o r p h i s m i s t h e a b il i t y of a d r ug to e xi s t i n m o r e t ha n o n e c r ys t al li n e f o rm . a . D i ff e re n t p ol y m o rp hs h a v e di f fe r e nt ph y s ic al pr o p e rt i es , i nc lu d in g m el t in g po in t a n d d is s o l ut i on ra t e . b . Am o r p h o us , o r n on c rys t a l l i n e , f o rm s o f a d rug h a ve f as t e r d is s o lu t io n r a t es t h a n d o c r y s t a ll in e f o rm s . 7 . C h i ra l i t y i s t h e a b il i t y o f a d ru g to e xi s t a s o p ti c a l l y a c t i ve s t e r eo i s om e r s o r e n a n ti o me r s . I n di v i du a l e n a nt io m er s m a y n o t h ave t h e s am e p ha r m a c o k in e t ic a n d p h a rm ac o d y na m i c ac t i v ity . B e c au s e m os t c h ir a l dr u g s a re us e d as r ac em ic m i xt u r e s , t h e re su l ts o f s t ud i es wi th s u c h m i xt u r e s m a y be m is l ea di n g b ec au s e t he d r u g i s a ss u m e d t o b e ha v e as a s i ng le en t i t y . F o r e xa m p le , ib u p ro f en e xi s ts as t he R - an d S - e n an t io m e r s ; on l y t he S - e n an t io m e r is p h a rm ac o l og ic a ll y ac t i v e . W hen th e r a c em ic m i xt u r e o f ib up ro f e n is t ak en o ra ll y , t he R - e n a nt io m er un d e rg oe s p r e s ys t em ic in v e r s i on in t h e g u t t o t h e S - e na n ti om e r . B ec a us e t h e r a te an d e xt e n t o f i n ve r si on a re s i te s p ec i fic an d fo r m u la t io n d e pe nd e n t, ib u p ro f en ac ti v i t y m a y va r y c o ns id e ra b l y . 8 . H yd r a t e s . D r ug s m a y e xi s t i n a h yd r a t e d , o r so l va t e d , f o r m o r as a n an h yd r o u s m o l ec u le . D is s o lu t io n rat e s d i ff e r f o r h y d r a te d a nd a nh y d r ou s f o rm s . F o r e xa m p l e , t h e a n h y d ro us fo r m o f am p ic il li n d is s o l v es f as te r a n d is m o r e r a pi dl y a bs o r b ed t ha n t h e h yd r a te d fo rm . 9 . C o mp l ex f o rm a t io n . A c o mp l ex is a sp ec i es fo r m ed b y th e r e v e rs i bl e o r i r r e ve rs i bl e a s s oc ia t io n o f t wo o r m o re in t er a c t ing m o l ec ul es o r i on s . C h el a t e s a re c om p le xe s t h at t y pi c a l l y i n v o l v e a r in g -l ik e s t ru c tu r e fo r m e d b y t he in t e rac t io n b e t we e n a pa r t ia l r i ng of a t om s a nd a m e t al . Ma n y b i o lo gi c a l l y i m p o r ta n t m o le cu l es ( e . g ., he m o g lo b in , i ns u lin , c y an oc o ba la m i n ) a r e c h e l a te s. D r ug s s uc h a s t e t r ac yc li ne f o r m ch e la t es wi t h d i v a len t ( e. g . , C a
++
, Mg
++
) a n d t r i v a le n t ( e .g . , Al
+++
, Bi
+++
) m e ta l
i o ns . Ma n y d r ug s a ds o rb s t ro n gl y o n c ha rc o al o r c l a y (e . g. , k a ol in , be n to ni t e ) p a r ti c l e s b y fo r m i n g c o m p l e xe s . D ru g c om pl e xe s wi t h p r o te i ns , s uc h as alb u m i n o r α 1 - a c id gl y c op r o te in , of te n oc c u r . a . C om pl e x f o r m at i on us u a ll y a l te r s t he ph ys ic al a n d c he m i c a l c ha r ac t e ri st i c s of th e d r u g . F o r e xa m p le : ( 1 ) Th e c h el a te of te t r ac y c l i ne wi t h c al c i um is le s s wa t e r s o lu bl e a n d is poo r l y a b so r be d . ( 2 ) Th e op h y l li ne c o m p l exe d wi t h e th y l e ne di am i ne t o f o rm am in op h y l li n e is m o r e wa t e r s ol u bl e a n d is us ed f o r p a re n te r al an d re c ta l ad m i ni s tr a ti o n. ( 3 ) C yc lo d e xt r i ns a re us e d to f or m c om pl e xe s wi t h m a n y d ru gs t o i nc re a se t he i r wa t e r s ol u bi li t y .
b . L ar g e d r ug c om p le xe s , s uc h as d ru g -p r o te i n com p le xe s , do n ot c r os s c el l m em b r an es ea s i l y . Th es e c o m p l e xe s m us t d is s oci a t e t o f r ee t he dr u g f o r a b s o r p ti on a t t he ab s o r p ti on s i t e o r t o pe r m i t tr a ns po r t a c ro s s ce ll m e m b r an es o r g lom e r ul a r f i l t ra t io n b e fo r e t h e d ru g i s e xc r e t e d in t o t h e u r ine . B . D r u g p r od u c t a nd d el i ve r y s ys t e m f o r m u l at io n 1 . G e ne r a l c o ns i de r a t i on s a . D es i g n o f th e a p p r o pr i a t e do s ag e fo r m o r del i ve r y s ys t e m d e p en ds o n th e ( 1 ) P h ys i c a l a nd c h em ic a l pr o pe r t ie s o f t h e d r ug ( 2 ) D os e o f th e d r ug ( 3 ) R o ut e o f a dm i ni s t r a tio n ( 4 ) Ty p e o f d r ug de li v e r y s y s te m d es i re d ( 5 ) D es i re d th e ra p eu t ic ef f e c t ( 6 ) P h ys i ol o gi c r e le as e of t h e d ru g fr o m t he de li v e r y s y s te m ( 7 ) B io a v a il ab i li t y o f t he d r u g a t t h e a bs o rp t io n s it e ( 8 ) P ha r m a c o k i n et ic s a nd p ha r m a co d y n am ics o f th e d ru g P.89
b . B i oa va i l a bi l i t y. Th e m o r e c o m p l ic at e d t he f orm u la t io n o f t h e f in is h ed d r u g p r o du c t ( e .g . , c on t ro l le d -r e l ea s e t ab le t , e n te r ic - c o a t ed ta b le t , t r an s de rm al p at c h ) , t h e g r e at e r t h e p ot e nt i al f o r a b io a va il ab i li t y p ro ble m . F o r e xa m p le , th e r ele a s e o f a d r u g f r om a p e ro r al do s ag e fo r m a nd it s s ub s e q ue n t b i oa v a il a bi li t y d ep e nd o n a s uc c ess i on of r at e p r oc es s e s (F ig u r e 4 - 2) . Th es e p r oc es s e s m a y i nc l ud e th e f o l lo wi n g : ( 1 ) At t r i t i o n , d i si n t eg r at i o n , o r di s ag g r e ga t i on o f t he dr u g p r od uc t ( 2 ) D i ss o l ut i o n o f t h e d ru g in an aq u eo us en v i r on m en t ( 3 ) C o n ve c ti o n a nd d i ffu s i o n o f t h e d ru g m ol ecu l es to t he ab so r bi n g su rf a c e ( 4 ) Ab s o r p t i on of t he d ru g ac r os s c e ll m e m b r an es in t o t h e s ys t em ic c i rc u la t i on c . Th e ra t e - li m i ti n g s t ep i n t he bi o a vai l ab il i t y o f a d ru g f r om a d r ug p ro du c t i s t he s l o we s t s t e p i n a s e ri es o f k i ne t ic pr oc e ss es . ( 1 ) F or m o s t c o n v e nt io na l s o li d d r ug p ro d uc ts (e. g . , c ap s u l es , t a bl e ts ) , th e d i ss ol u ti on r a te is t h e s lo we s t , o r r a te - li m i t in g , s t e p fo r b i oa va i la bi l it y. ( 2 ) F or a c on t r ol le d - o r s u s ta i ne d - re l ea se d ru g p ro d uc t , t h e r el e as e o f t h e d r u g f r om t h e d e li v e r y s y s t em is the r a te - li m i t in g s te p . 2 . S o lu t i on s a r e h om o ge n e ou s m i xt u r e s o f on e o r m o r e s ol u te s d i s pe r s ed m o le cu l ar l y in a d is s o l v in g m e di um (s o l ven t ) . a . C om p ar e d wi t h o th e r o r a l a nd pe r o ra l d r u g f o rm u la t io ns , a d ru g d is s o l ve d in an a q u eo us s o lu t io n i s i n t he m o s t b io a vai l ab l e a nd c o ns is te n t f o rm . Be c a u se t he d ru g i s a l re a d y in P.90
s o lu t io n , n o d is s o lu t io n s t e p i s n ec es s a r y b ef o r e s y s t em ic a bs o r pt i on oc c u r s . P e r o r al dr u g s ol u ti on s a re o f te n u s e d a s t he r ef e re n ce p re pa r a ti o n f o r so l id p e ro r al f o r m u l at io n s .
Figure 4-2. The processes involved in drug release from peroral dosage forms. GI, gastrointestinal.
b . A dr u g d is s o l v ed in a h y d r o al co h ol ic s o lu t io n (e . g . , el i xi r ) a ls o h as go od b i oa va i la b il it y . A lc o ho l ai d s d r ug s o lu bi l it y . H o we ve r , wh e n t he dr u g i s di lu t e d b y g a st r o in t es ti n al t ra c t fl u id a nd ot h e r g ut co n te n ts ( e . g. , fo o d) , it m a y f o rm a fi n el y d i vi de d p r ec i pi t at e i n t h e l um e n o f t h e g as t ro in t es t i n al t ra ct . Be c au se of t he e xt e n s i v e di s p e rs io n a n d l a rg e s u r fa c e a re a o f s uc h fi ne l y di v i d ed p re ci pi ta t es , r e d is so lu t io n a n d s u b s e qu e n t a bs o rp t io n o c c u r r ap i d l y. c . A visc o us dr u g s ol ut i on ( e .g . , s yr u p) m a y i nt e r fe r e wi t h d i lu ti o n a nd m i x i n g wi t h g a st r o in t es ti n al t ra c t c o nt e n ts . Th e s ol ut i on de c rea s es th e g as t r ic e m p t y i ng r a te an d t h e ra t e o f t r a ns fe r of d ru g s o lu t io n t o th e d uo d en a l r e gi o n, wh e r e a bs o r pt i o n is m os t ef f ic ie n t. 3 . S us p e ns i on s a r e d is pe r s io ns of fi n el y d i vid e d s o li d p a r ti c l es of a d r ug in a l i qu id m e di um in wh i c h th e dr ug is no t re a di l y s o lu b le . Th e l i qu id m e di um o f a su s pe ns i on c om p r is es a s a t u ra t ed s o l u ti on o f t he d ru g i n e qu i l i b ri u m wi t h th e s ol i d dr u g . a . Th e bi oa v a i la bi l it y o f th e d ru g f r om s us p en si o ns m a y b e s i m i l ar t o t ha t o f a s o lu t io n b ec a us e t he fi ne l y d i v id ed p ar t ic le s a r e d i sp e rs ed an d pr o v i de a l a r ge s u r fa ce a re a f o r ra pi d d is s o l ut i on . O n t he o th e r ha n d , a s lo w d i ss o lu ti o n ra t e d e c re as es th e a b s o r pt i on r a te . b . S u sp e nd i n g a ge n t s ar e o ft e n h yd r op hi l ic c ol l oi d s ( e .g . , c el lu l os e d e ri va t i v es , a c ac ia , xa n t h an gu m ) add e d t o s us p en s i on s t o i nc r e as e v i s c os i t y , i nh i bi t a g gl o m e r at i on , a n d d ec re a s e th e ra t e a t wh ic h pa r t i c le s s et t le . H ig hl y vi sc o us s us p en s i o ns m a y p ro lo ng g as t ri c e m p t y i ng ti m e , s l o w d r ug di ss ol u ti o n, and d e c re as e t h e a bs o rp t io n r a t e . 4 . C a ps u le s a r e s ol id d os a ge fo r m s wi t h h a r d o r s o f t g el a ti n s he ll s t h at c o n t ai n d r u gs , u s u a ll y a dm i xe d wi t h e xc i p i en t s. C oa t i n g t h e c ap su le s h el l o r t he d r u g p a r ti c l e s wi t h i n t he c a ps u l e c an af f ec t b i oa v a il a bi l it y. a . H a r d g e la t i n c ap s ul es a r e us u al l y fi ll e d wi t h a p o wd e r b le n d t h at c o nta i ns th e d r u g . Ty p i c al l y , th e p o wd e r bl en d i s s im pl e r a nd l e ss c om p ac te d t h an t he b l en d i n a c om p r es s e d t ab l et . A ft e r i n ge s t i on , th e g el a ti n s of t e ns , s we l ls , an d b eg i ns t o d i ss ol ve in th e g as t r oi n te s ti n al t ra ct . E nc ap s u la te d d ru gs a re re l ea s e d rap i dl y a nd d i sp e rs ed ea s i l y , an d b ioa v a i la b il i t y i s g oo d . Ha r d g e la t in c a ps ul es a re th e p r e fe r r ed d o sa g e f o rm fo r e a r l y c lin i c a l t r ia ls o f n e w d r ug s .
b . S o f t g e la t i n c ap s ul es m a y c on t ai n a no n aq ue o us s o lu t io n , a p o wd e r , o r a d r ug s us p en s i o n. Th e v e hi c l e m a y be wa t e r m is c i b le ( e. g . , P E G ). Th e c a r di ac glyc o si d e d i go xi n , d is p er s e d i n a wa t e r -m is ci bl e veh ic l e ( L an o xi c a ps ) , h as be t t e r b i oa va i la b il it y t h an a c om p r es s e d t ab l et f or m u l ati o n ( L an o xi n ) . H o we ve r , a s o f t g e la t in ca ps u le th a t c o n ta i ns th e d r u g d is s o l ved in a h yd r o p h o b i c v eh ic l e ( e . g. , ve g e t ab l e o il ) m a y ha v e p o o re r bi o a vai la b il i t y t h an a c om p re s s ed t ab le t for m u la ti o n o f t he dr u g. c . Ag i n g a n d s t o ra g e c on d i t i on s c an a ff ec t th e m o is tu r e c on t en t of th e ge l a ti n c om p on e nt o f t he c a ps ule s h e ll an d t h e b io a v a il ab i l i t y o f t he d ru g . ( 1 ) A t l o w m oi s t u r e l e v els , th e c ap s u l e sh e ll be com es b ri t tl e a n d is ea s i l y r u p t ur e d. ( 2 ) A t h ig h m oi s tu r e l e v el s , t h e c a ps u le s h el l b ec o m es m oi s t, so f t, an d d is t o rt e d. Mo i s t u r e m a y be t ra ns f e rr e d to th e c a ps ul e c on t en t s , p ar t ic ul a r l y i f th e c on t e nt s a r e h yg r o sc op ic . 5 . C o mp r e ss e d t a bl e t s a r e s o li d d os ag e fo r m s in wh i c h h ig h p r es su r e i s u s ed to c om p r es s a p o wd e r b l end o r g r an u la t io n t h at co nt a i n s th e d r ug an d o t he r i n g re d ie n ts , o r e xc i p i en ts , in t o a s ol i d m a ss . a . E xc i p ie n ts , in c l ud i ng d i lu e nt s (f il l e rs ) , b in de r s , d is in t eg r a n t s, lu b r ic an ts , g l id a nt s , s u r f ac t an ts , d y e , an d fl a v o ri n g a ge n ts , h a ve th e fo ll o wi n g p r op er t i es . ( 1 ) Th e y p e rm i t th e e f fi c ie n t m an u fa c tu r e o f c om pr e s s e d t ab l et s . ( 2 ) Th e y a ff e c t th e p h y s ic a l a nd c h em ic al ch a ra c te r i s t ic s o f t h e d r ug . ( 3 ) Th e y a ff e c t bi o a v ai lab i li t y . Th e h i gh e r t h e r a tio o f e xc i p ie n t t o a c ti v e dr u g , t h e g r e a te r th e l ik el i ho o d t ha t t he e xc i pi en t s a f fe c t bi o a vai l ab il i t y . b . E xa m p le s ( 1 ) D i si n t eg r a n ts ( e. g . , s t a rc h , c ro s c a rm el lo s e , s o di um s t a rc h g l y c o la t e ) v a r y i n a c ti o n, de p en d in g o n t h ei r c o nc e nt r a ti on , th e m e th o d b y wh i c h t h e y a r e m ixe d wi t h t h e p o wd e r fo r m u l at i on or g r an u la t io n , a nd th e d eg r e e o f t a bl e t c o m pa ct i on . A l t h ou gh t ab le t di s i n te g ra t i on is u su a ll y n ot a p r o b l em be c a us e i t o f t en occ u rs m o r e r a p id l y t ha n d r ug di s s ol ut i o n, it is ne ce s s a r y fo r di s s o lu t io n i n i m m ed ia t e - re l ea s e f o r m u l at io n s . In a bi li t y t o d i s i n te g ra t e m a y i n te r f e re wi t h bi o a v ai l ab il i t y . P.91
( 2 ) L ub r i c an t s a r e us u all y h y d r o ph ob ic , wa t e r -i ns o lu bl e s u bs ta nc e s s u ch a s s te a ri c a c id , m ag n es iu m s te a ra te , h y d ro g en a te d v eg e ta bl e oi l , a nd ta lc . Th e y m ay r e d uc e we t t i n g o f th e s u rf ac e of t h e s ol i d d r ug pa r ti cl es , s l o wi n g t he di s s ol u ti o n an d b i oa va i la b il it y r a t es o f the d r ug . W ate r - s o lu b le lub r i c a n ts , s uc h as L -l e uc in e , d o n o t i n t er f e re wi t h di s s ol u ti on o r bi o a v ai la b il it y. ( 3 ) G l i da n t s ( e .g . , c ol lo id a l s il ic on di o xi d e ) im pro v e t he f lo w p r o pe r t ie s of a dr y p o wd e r bl e nd be f o re it is c om p re ss ed . R at h e r t han p os in g a po t en t ia l p r obl e m wi t h b i oa va i la b il it y , g li da n ts m a y r ed uc e ta bl e t -t o - ta bl e t v a ri a bi li t y an d i m p r o ve p r od uc t e f f ic ac y . ( 4 ) S u r fa c t an t s e n ha nc e d r u g d iss o lu t io n r a te s an d bi oa v a i la b il it y b y r e du c in g i n t er f ac i al te ns i on at th e b o un d ar y b e t we e n s o l id d r u g a nd li qu i d a nd b y im p r o v in g t h e we t t ab il i t y (c o nt ac t ) o f s o li d d r u g p ar t ic le s b y t h e s ol v e n t.
c . C oa t e d c om p r es s ed ta b l e ts ha v e a s ug a r c oat , a f i lm c oa t , o r an en t e ri c c oa t wi t h t h e f o ll o wi n g p r op e rt i es : ( 1 ) I t p r ot ec t s t he d ru g f ro m m oi s tu r e, li g ht , an d ai r . ( 2 ) I t m a s k s t h e t as te o r o d o r o f t h e d r ug . ( 3 ) I t im p r o v es th e a pp ea r a nc e o f t h e t a bl e t. ( 4 ) I t m a y a f fe c t t he r el ea s e r a te of t he d ru g . d . I n a dd i ti on , en t e r ic co a t i ng s m in im i z e c o nt ac t b e t we e n t he d ru g a nd th e ga st r ic r e g io n b y r e s i s t in g d is s ol u t io n o r a t t ri t io n a n d p r ev e n t i ng c o nt a c t be t we e n t h e u n d er l yi ng d ru g a nd t he g a s t r ic c o n te n ts o r ga s t r ic m u c o sa . So m e en t e ri c c o at i ng s m i ni m i ze ga s t r ic c o n ta c t b e c a us e th e y ar e i ns o lub l e a t a c i d ic p H s . O t h e r c o at i ng s r e s is t a t tr i ti o n a nd r em ain wh o l e l o ng en ou g h f o r t h e ta bl e t t o l e a v e t he ga s t ri c a r e a . B y r es is t in g d is s o lu t i on o r a tt r i ti on , en t e ri c c oa t in gs m a y d ec r ea se b i oa va i la b il it y . E n te r ic c o a t in gs a re us ed to ( 1 ) Mi n i m i z e i r ri ta t io n o f t h e g as t r ic m uc os a b y t he d r ug ( 2 ) P r e v en t i n ac ti v a t io n o r d eg r ad a ti o n o f t he d rug i n t he s t om ac h ( 3 ) D el a y r el e as e o f t h e d r u g u n ti l t h e t ab le t r ea ch e s t he s m al l i n te s t i ne , wh e r e c o nd i ti on s f o r a bs o r pt i on m a y be op t im al 6 . M o d i fi e d - re l ea s e d o sa g e fo r m s a r e d r ug pr o du c ts th a t a lt e r th e r a te or t im i ng of d r u g r e le as e . B ec a us e m o d i fi ed - r el e as e d os ag e fo r m s a re m o r e co m p l e x t h a n c o n ven t io n al im m e di a te -r e l ea s e do s a g e f o rm s , m o r e s t r in ge n t q ua l it y c on tr o l a n d b i oa va i la b il it y t es t s a r e re q ui r e d. D o se du m p in g , o r th e a b r up t , u nc on t r ol le d r e l ea se o f a l a rg e a m o u nt o f d r ug , is a p ro bl em . a . E x te n de d - r el e as e d os a g e f o r ms in cl u de co n tr o l l e d - re l ea s e, s us t ai ne d - a ct i o n, a n d l o n g -a c ti n g d r u g de l i ve r y s ys t e m s . Th es e d e li ve r y s y s te m s a l lo w a t l ea s t a t wo f o l d re d uc ti o n i n d os in g f re q ue nc y co m pa r ed wi t h c on v e n t io na l i m m edi a t er e l ea se f or m u l at i on s . ( 1 ) Th e e xt e n de d , s l o w r e l ea s e o f c o n t ro l le d - re lea s e d r ug p ro du c ts p r o duc es a r e l at i ve l y fl a t, s u s t a in ed p l as m a d ru g c on c e n t ra t io n th a t a v o id s t o xi c i t y ( fro m h i gh d r u g c on c e n t ra t io ns ) o r la c k o f e f fi c a c y (f r om lo w d r u g co nc e nt r a ti o ns ) . ( 2 ) E xt e n d ed - r el e as e d os a ge fo r m s pr o v i de an im m e d ia t e ( i ni ti a l ) r el e ase o f t h e d r u g , f ol lo we d b y a s lo we r s u s ta in e d r el e as e . b . D e la ye d - r e l e a se do sa g e fo r m s r e le as e a c t i ve d r ug at a t im e o t he r tha n i m m e di a te l y af t e r a dm in is t r at i on at a d es i re d s i te i n t h e g as t ro i nt es t in a l t ra c t . F o r e xa m p l e , a n e nt e r ic -c o ate d d ru g p r od uc t do es not a l l o w f o r d is so l ut i on in t h e a c i d e n vi r on m e n t o f t h e s to m a c h b ut , ra t h er , in th e l es s a c i di c e n vi ro nm e nt o f t h e s m a ll i n t es ti n e. 7 . T r an s de r m al d r u g d el i ve r y s ys t e m s , o r p a t ch e s , a r e c o n t ro l le d - re le as e d e v ic e s t h a t c on t ai n t h e d r ug fo r s y s t em ic a bs o r pt i on af t er t o pi c a l a p pl ic a ti on to t he s k in s u r fa ce . Tr a ns de r m a l d ru g de li v e r y s ys te m s a r e a va i la b le fo r a n um be r of d r u gs ( n i t ro g l yc e r in , n ic o ti n e, s c o po l am in e , c l o ni di n e, fen t a n y l, 17 - β - es t r ad io l , an d t e s to st e r on e ). A lt h ou g h th e fo r m u l at i on m a t ri ce s o f t he se de li ve r y s y s te m s di f f er s om e wh a t , t h e y al l d if f e r f r om c o n ve nt i on al t op ic a l fo r m u la t io n s in t he fo l lo wi n g wa ys : a . Th e y h a v e a n im p e rm e a bl e oc c lu s i ve b a ck i ng f i l m t ha t p r e v e nt s i ns en s ib le wa t e r l os s f r om th e s k i n b e n ea t h t he pa t c h . Th is f i lm c a us es in c re as ed h yd r a ti o n
a n d sk i n t em p er a tu r e u nd e r th e p a tc h a nd en h anc e d p e rm ea t io n o f th e sk i n b y th e drug. b . Th e fo r m u l at io n m a t rix o f t h e pa t c h m a in t ai ns t h e d r u g c o nc e nt r a ti o n gr a d ie n t wi t h i n th e d e v ic e a f t e r ap p li c a t io n s o t h at d ru g de l i ve r y to th e i n te r f ac e be t we e n t he p a tc h a n d t he s k in is s us t a i ne d . A s a re su l t , d ru g p a r ti t io n in g a n d d if f us io n i n to th e s ki n p e rs is t , a n d s y s t em ic ab s o r p ti o n is m a in t ai ne d th r o ug ho u t t h e d os in g i n te r v a l . c . Tr a ns d er m a l d r u g d el iv e r y s y s t em s a re k e p t i n p l ac e o n t he s k in s u r fa ce b y an a d h es i ve l a ye r , e n s u ri ng d r ug c o nt ac t wi t h t h e s k i n a nd c o nt i nu e d d ru g de l i v e r y . 8 . T a rg e t ed ( si t e -s p ec i fi c ) d r ug de l i ve r y s ys t e m s a re dr u g c ar r i er s ys te m s t ha t p l ac e t h e d r ug at o r n ea r t h e r ec e pt o r s i te . E xa m p l es in cl ud e m ac r om ol e c u l a r d r ug c a r ri e rs ( p ro t ei n d r ug P.92
c a r ri e rs ) , p a r ti c u l at e d r ug d el i v e r y s y s t em s ( e. g . , l i po s o m e s , na n op a r ti cl es ) , a n d m o no cl o na l a n ti bo d ie s . W ith t a rg e te d d r u g d el i ve r y , t he d ru g m a y be de liv e r e d to a . Th e c a pi ll a r y be d o f th e ac ti v e s i t e b . A s p ec ia l t y p e o f c e ll ( e . g ., t um or c e ll s ) b u t n ot t o n o rm al c e ll s c . A s pe c i f ic o r g an o r t is s u e b y co m p l e xi n g wi t h a c a r r ie r th a t re c o gn i z e s t h e t a rg e t 9 . I ns e r t s, im p l an t s , a nd d e vi ce s a r e u s e d to c o n t r ol dr u g d el i ve r y fo r lo c al i z e d o r s ys t em ic d r u g e ff e c t s . Th e d ru g i s im p re g na t ed in t o a bi o de g ra d ab l e o r n o n bi od e g ra da b le m a te r ia l an d i s r el e as ed s l o wl y. Th e in s er t s , im pl a nt s, an d d e vi ce s a r e i ns e rt e d i nt o a v a r ie t y o f c a vi t ie s ( e .g. , v a g in a , b ucc a l c a v i t y ) o r t iss u es ( e . g ., sk in ) . F o r e xa m p l e, t h e le u p ro li d e a ce t at e im p la n t, V ia d ur , is i ns e r te d be n ea t h t h e s ki n o f t h e u pp e r a rm . It p ro vi d es p a ll ia t i v e tr e a tm e nt of ad v a n ce d p ro s ta t e c a nc e r f o r 1 y ea r . P.93
STUDY QUESTIONS D i r e c t i on s : E a c h qu es t io n , s t at em e nt , or in co m pl e t e s ta t em en t i n t h is s ec t io n c an b e c o r re c tl y a ns we r e d o r c om pl e te d b y o n e o f t h e s ug g es t ed an s we r s o r ph r a se s . C h o os e th e b e st an s we r . 1 . W hi c h s t a te me n t be st d e sc r i b es bi o a va i la b ili t y? ( A ) r e la t io n b e t we e n t he p h y s ic al an d t h e c he m i c a l pr o pe r t ie s o f a dr u g an d it s s ys t em ic a bs o r pt i on ( B ) m ea s u r em en t of th e r a t e a n d am o un t o f th e rap e u ti c a ll y a c t i ve d r u g t ha t r ea ch es t h e s ys te m i c c ir c ul at i on ( C ) m o vem en t of th e d r ug i nt o b o d y ti ss ue s o v e r t i m e ( D ) d is so l ut io n of th e d r ug i n t he ga s tr o in t es ti n al t r a c t ( E ) a m o un t of d ru g d es t ro y e d b y th e l i v e r b e fo r e s y s t em ic a bs o r pt i on f rom t he g a st r o in t es ti n al t ra c t oc c u r s V i e w A n s we r 1 . T h e a n sw e r i s B [ se e] . 2 . T h e r ou t e o f d r u g a dm i n is t r a ti o n t h a t gi ve s t he mo s t ra pi d o ns e t o f t he ph a r mac o l o gi c e f f ec t is ( A ) i nt r am us c u l a r i nj ec t io n .
( B ) i nt r a v e no us in j ec ti o n. ( C ) i n tr a de r m a l i nj ec t io n . ( D ) p e ro r a l a dm in is t ra t ion . ( E ) s ub c u t an e ou s i nj ec tio n . V i e w A n s we r 2 . T h e a n sw e r i s B [ se e] . 3 . T h e r ou t e o f d r u g a dm i n is t r a ti o n t h a t p ro vi d e s c o mp l e te ( 1 0 0 %) b i o a va i l a b il i t y i s ( A ) i nt r am us c u l a r i nj ec t io n . ( B ) i nt r a v e no us in j ec ti o n. ( C ) i n tr a de r m a l i nj ec t io n . ( D ) p e ro r a l a dm in is t ra t ion . ( E ) s ub c u t an e ou s i nj ec tio n . V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . 4 . Af t e r pe r o r a l a d mi n i st r a t i on , d r u g s g e ne r a l l y a r e a b s o r b e d b es t f r om t he ( A ) b uc c a l c a v it y . ( B ) s to m a c h . ( C ) d u od en um . ( D ) i le um . ( E ) r ec t um . V i e w A n s we r 4 . T h e a n sw e r i s C [ se e] . 5 . T h e c ha r a c t e ri s t ic s o f an ac t ive t r a n s po r t p r oc e ss i nc l ud e a ll o f t h e f o l low i n g e x c ep t f o r w h i c h o ne ? ( A ) A c ti v e t ra ns p or t m o ve s d r u g m o l ec ul es ag a ins t a c o nc e nt r a ti o n g ra d ien t . ( B ) A c ti v e t ra ns p or t fo l lows F i c k ' s l a w o f di f fu s i on . ( C ) A c ti v e t ra ns p o rt is a c a r ri e r -m e di at e d t r an s p or t s y st em . ( D ) A c ti v e t ra ns p o rt r eq ui r e s e ne r g y . ( E ) A c ti v e t ra ns p or t of d ru g m o le cu l es m a y be s a tu r a t ed at hi g h d ru g c o nc en t r at i on s . V i e w A n s we r 5 . T h e a n sw e r i s B [ se ea n d] .6 . T h e p a ss a ge o f d r u g m o l ec u le s f r om a r e g ion o f hi g h d r u g c o nc e n tr a t i o n to a r e g io n of l ow d r ug c o n ce n t r a ti o n i s k n ow n a s ( A ) a ct i v e t r a ns po r t . ( B ) b io a v a il ab i li t y . ( C ) b io p ha r m a c e u ti c s . ( D ) s im pl e d i ff us i on . ( E ) p in oc y t o s i s . V i e w A n s we r 6 . T h e a n sw e r i s D [ se e] . 7 . W h ic h e q u a ti o n d e sc r i be s th e r a t e o f d r u g d i ss o lu t i o n f r om a ta b le t ? ( A ) F ic k 's la w ( B ) H e nd e rs o n - Ha s s el b al c h e qu a ti o n ( C ) L a w o f m as s a c t i on ( D ) Mi c h a e li s - Me n t e n e qu a t io n ( E ) N o y e s -W hit n e y e q ua ti o n V i e w A n s we r 7 . T h e a n sw e r i s E [s e e] . 8 . W h ic h c o n d it i o n u s ua l l y i n c r e a s e s t h e r a te o f d r u g d i ss o lut i o n f r om a t a bl e t ? ( A ) i nc r ea s e in th e p a r ti c l e s i z e o f th e d r ug ( B ) d ec r ea s e in th e s u r fac e a r e a o f t h e d ru g
( C ) u se of t he f re e a c i d o r f r ee ba se fo r m o f t h e d r u g ( D ) u se of t he io ni z e d , or s al t , f o rm of t he dr u g ( E ) u se of s u ga r c o at i ng a r o un d th e t a bl e t V i e w A n s we r 8 . T h e a n sw e r i s D [ se ea n d] .9 . Dos e du m p in g is a p r o bl em i n t h e f o rm u la t i o n o f ( A ) c om pr e s s ed ta b le ts . ( B ) m od if i ed - r el e as e d r ug p r od uc ts . ( C ) h a rd ge l at i n c a ps u les . ( D ) s of t ge la t in c a ps ul e s . ( E ) s up po s i t o ri es . V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . 1 0. T he ra t e - l im i t in g s t e p i n th e b i o a va i la b i li t y o f a l i pid - s o lu b l e d r u g f o r mu l at e d as an i mm ed i a te - r e le a s e c o m p re s se d ta b le t i s t he r a t e o f ( A ) d is in t eg r a ti on o f t he t a b le t a n d r e le as e o f t h e d r u g. ( B ) d is s o lu t io n o f th e d r ug . ( C ) t r a ns po r t o f th e d r ug m ol ec u le s ac r os s t h e i nte s ti n al m uc os a l c el ls . ( D ) b lo o d f lo w t o t he ga s t r o in t es t in al t r ac t. ( E ) b io t r an s f o rm a ti o n, o r m e ta bo l ism , of th e d r u g b y t h e l i ve r b ef o r e s y st em ic a b so r p ti on oc c u r s . V i e w A n s we r 1 0 . T he a nsw e r i s B [ se e] . P . 94
1 1 . Th e e x te n t of i on i z at i o n o f a w ea k e l ec t r o l yt e d r u g d ep e n ds on t he ( A ) p H of th e m e di a a nd p K a of t he d ru g . ( B ) o il to wa t e r pa r ti t io n c o ef f ic ie n t o f t h e d r ug . ( C ) p a r ti c l e s i z e a nd s u r fa c e a r ea of t he dr u g. ( D ) N o y e s -W hit n e y e q uat i o n f o r t he d ru g . ( E ) p ol ym o rp h ic f o rm o f th e d ru g . V i e w A n s we r 1 1 . T he a nsw e r i s A [ se e] . 1 2. T he ra t e o f d r u g b i oa va i l ab i li t y i s mo s t r ap i d w h e n t h e d r u g is f o r mu l a te d a s a ( A ) c on t ro l le d - re l ea s e pro d uc t . ( B ) h a rd ge l at in c a ps u le . ( C ) c om p re s s ed ta b le t . ( D ) s ol u ti on . ( E ) s us pe ns io n . V i e w A n s we r 1 2 . T he a nsw e r i s D [ se e] . 1 3. T he am o u n t o f d ru g t ha t a t r a n s de r m al p at c h ( i . e. , t r a n sd e r ma l d r ug de l i ve r y s ys t e m ) d e l i ve r s w it h i n a 2 4h r p e r i od de p e nd s o n th e ( A ) p a tc h c o m p os i ti o n, wh i c h in cl ud e s a n oc c l us i ve b ac k i ng an d a n a d he s iv e f i lm i n c o nt ac t wi t h th e s k i n. ( B ) a f fi ni t y o f t h e d ru g for t h e f o rm ul a ti o n m a t r i x r e l a ti ve to it s a f fi n it y f o r th e s t r at um c o r ne um . ( C ) r a t e o f d r ug pa r ti t io ni n g a nd / o r d i ff us i on th r ou g h t h e p at c h t o t he sk in s u rf a c e . ( D ) s u rf ac e a r e a o f t he pa t c h . ( E ) A l l o f t h e a bo v e
V i e w A n s we r 1 3 . T he a nsw e r i s E [s e e] . P . 95
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee I . A . 3] . B i o a vai l ab il i t y is t h e m ea s u re m e n t o f t h e r a te and e xt e n t (a m ou n t) o f t he ra p e ut ic al l y a c ti ve d ru g t h a t r ea c h e s t h e s y s te m i c c ir c ul at i on . Th e r e la t io n o f th e p h ys ic a l a nd t h e c he m i c a l p r o pe r ti e s o f a d r ug to i ts s y s te m i c a b s o r p ti on ( i. e . , b io a vai la b il i t y ) i s k n o wn as it s b io p ha r m a c e u t ic s . Th e m o v em en t of a d ru g i n to bo d y ti ss u es i s a n a s pe ct o f p ha r m a c o k i n eti c s , wh i c h is th e s tu d y o f d r u g m o v e m e n t i n t h e bo d y o v e r t i m e . Th e d is s o l ut io n of a d r ug in th e g as t r oi n te st i n al t ra ct is a p h ys ic oc he m ic al p r o ce s s th a t a ff e c t s b io av a i l ab i li t y . Si g ni f ic an t d es t r uc ti o n o f a d ru g b y t he l i v er b e f o re it is s y s te m i c a l l y a b s o r be d (k no wn a s t h e f i r st - p as s e ff ec t b e ca us e i t o c c u rs d u r in g th e f i rs t p as s a g e o f t he dr u g t h ro u gh th e l iv e r ) d ec r ea se s b i oa v a il ab i li t y . 2 . T he an sw e r is B [ s ee I I . B .1 . a] . W hen t he ac t i v e f o rm o f t h e d r u g is gi ve n i n t ra ven o us l y, i t en t er s t h e s y ste m ic c i rc u la ti o n d i re c t l y . Th e d r u g i s d el i ve re d ra pi d l y t o al l t is s ue s, in c l u di ng th e d ru g r e c ep t or s i t es . F o r a ll o th e r ro u te s o f d r u g a dm ini s t ra t io n , e xc e p t i n t ra - a rte r i al i n je c ti on , th e d r u g m u s t b e s y s t em ic al l y ab s o r b ed b ef o r e i t is di s tr i bu t ed t o t he dr u g r e c ep t or s i t es . F o r t h is re a s o n , t he on s et of ph a rm ac o lo g ic e f fe c ts i s s lo we r . I f t he d r u g i s a p r od r u g t ha t m u s t b e c on ve r t ed to an ac t i v e d r ug , o r a l a dm in is t ra t i on , n o t i n t ra ve n ou s i nj ec t io n , m a y n o t p r o vid e th e m os t ra p id on s et of ac t i v it y i f co n v e r s i on t o t he ac ti v e f or m t ak es p l ac e i n t h e g as t ro i nt es t in a l t r ac t o r li v e r . 3 . T he an sw e r is B [ s ee I I . C .2 ] . W hen a d r u g is gi v e n b y i n t ra v e n ou s i nj ec t io n , t he e nt i r e d os e e nt e rs th e s ys t em ic c i rc u la ti o n . W ith o t he r r ou t es o f a dm in is t ra t io n , t he d r ug m a y be lo s t b ef o re i t r e a ch es th e s y s te m i c c irc u la t io n . F o r e xa m p le , wi t h f i rs t - pa s s ef f ec ts , a po r t io n of a n o ra ll y a dm in is t e re d d ru g is e l im in a te d , us u al l y t h r o ug h d eg r a da t io n b y li ve r e n zym e s , be f o re th e d r ug r e ac he s i ts re c e p t or si te s . 4 . T he an sw e r is C [ s ee I I . B .2 . b. ( 4 ) ]. D r u g s g i v en o ra ll y a r e w e l l a bs o rb e d f r om th e d uo d e nu m . Th e d u od e nu m h a s a l a r ge s u r fa ce a re a b ec a us e o f t h e p r es e nc e o f vil li an d m ic r o vi ll i. I n a dd i ti on , bec a us e t h e d u o de nu m i s we l l pe r f us e d b y th e m es en t e ri c b loo d v es s el s , a c o n ce n tr a tio n g r a di e nt is m a in t ai ne d be t we e n t he l u m e n o f t h e d u o de nu m a nd t he bl oo d. 5 . T he an sw e r is B [ s ee I I . A .2 an d 3 ] . F i ck ' s l a w o f d i ff u s i on des c ri b es p as s i ve di f f us io n o f dr u g m o l ec ul es m o vin g f ro m a h i gh co nc e nt r a ti on t o a lo w c o n c e n tr a ti o n. Th i s pr o c es s is no t s a tu r ab l e an d do es n o t re q ui r e e ne r g y . 6 . T he an sw e r is D [ s ee I I . A .2 ] . Th e t r a ns po r t o f a d ru g ac r os s a c e ll m em b ra n e by p a s s i v e d i ff us i on fo l lows F i c k ' s l a w o f di f f us io n : Th e d rug m o v e s wi t h a c o nc en t ra t i on g ra di e nt ( i. e . , f r om a n a r e a o f h i gh co nc e nt r a ti on t o a n a r e a o f l o w c on c e n t ra t ion ) . In c o n t ra s t , d r u gs th at a r e a c ti ve l y t ra n s p o rt e d m o v e a ga in s t a c on c en t ra t ion g r ad ie n t . 7 . T he an sw e r is E [ s e e I I I . A. 1 ] .
Th e N o ye s -W hi tn e y eq uat i o n d esc r i be s t he r at e at wh i c h a s o li d d r ug di s s o l v e s. F i ck ' s l a w i s s i m i l ar t o t he N o y e s -W hit ne y e qu a ti on i n t ha t bo t h e qu a ti on s d e s c r ib e d r u g m o v em en t c au s ed by a c on c e n t ra t io n g r ad i en t . Fi c k ' s l a w g en e r al l y re f e rs to p a ss i ve d if f us io n , o r pa s s i v e tr a ns po r t , o f d r ug s . Th e l a w o f m as s a c t i on de sc r i be s t h e ra t e o f a c h em ic al r ea c ti o n, t he Mi c h ae li s - Me n t e n e qu a ti o n i n v ol ve s en z ym e k i ne t ics , an d t h e H e nd e rs o n - Ha s s el b al c h eq u at ion g i v es th e p H of a b u ff er s ol u ti o n. 8 . T he an sw e r is D [ s ee I I I . A. 1 a n d 3 ] . Th e i o ni z e d , o r s al t , f o rm o f a d r ug ha s a c h a rge a nd is g e ne r al l y m o r e wa t e r s o lu bl e a n d , t he r e fo r e, di s s o l v es m o re r ap i dl y t han t he no n io ni ze d ( fr e e ac i d o r f r e e b a se ) fo r m o f t h e d ru g . Th e di s s ol u ti o n r a te is d i re c tl y p r op o r ti on a l t o t h e s u r fa ce a r e a a nd in v e r s e l y p ro p or t i on a l t o t h e p a rt ic l e s i z e . A n i nc r ea s e in th e p a rt i c l e s i z e o r a d ec r e as e i n t he s u r fa c e a r ea s l o ws th e d is sol u t io n r a te . 9 . T he an sw e r is B [ s ee I I I . B. 6 ] . A m od i fi e d- r e le as e , o r c o n t r ol le d - re l ea se , d r u g pr o d uc t c on t ai ns t wo o r m o r e c o n ven t io n al do s e s o f t he d r ug . An ab r up t re l ea se o f t h e d ru g , k no wn a s d o se d u m p i ng , m a y c a us e i nt oxi c a t i o n. P.96
1 0 . Th e a n sw e r i s B [ s ee I I I. B . 1. c ]. F o r li pi d -s o lu bl e d r u gs , th e r at e o f d is s ol ut i on is th e s l o we s t ( i .e . , r a te - li m it i n g) st e p i n dr u g a bs o rp t io n a n d th u s i n b io a v a il ab i li t y. The d is in t eg r a ti on r at e o f an i m m e di a te - r el e as e o r c on v e n t io n al c om p re s s e d ta b le t is u s u a ll y m o r e ra pi d th a n t he r a t e o f d r u g d is s o lu t io n . B e c au s e th e c el l m em b ra n e i s a l i po p ro t ei n s t ru c t u r e , t r a ns p or t of a l ip i d- s o l ubl e dr u g a c r o s s t h e c el l m e m b ra ne is us ua ll y r a pi d. 1 1 . Th e a n sw e r i s A [ s ee I I I. A . 4. b ] . Th e e xt e n t o f i on i z a ti o n o f a we ak el ec t r ol y t e i s d e sc r ib ed b y th e H en de rs o n H a s se lb a lc h e qu a ti o n, wh i c h r el a te s t he p H o f t he s o l ut i on to t he p K a of th e d ru g . 1 2 . Th e a n sw e r i s D [ s ee I I I. B . 2. a ] . B e c au se a d r ug in s o lu t io n is a l r ea d y di s s ol v e d , n o di s s ol u ti o n is ne e de d b e fo r e a b so r p ti on . C on s e q ue n tly , c om p a re d wi t h o th e r dr u g fo r m u la t io ns , a d r ug i n s o lu t io n h a s a h i gh r at e o f bi oa v ai l ab i li t y . A d r ug in aq u eo u s s ol u ti o n h as th e h ig he s t b i oa va i la b il it y r a t e a nd is o ft e n us e d as t he r ef e re n c e p re pa r a ti o n f o r o the r f o r m u l at io n s . D r ug s i n hy d r o a lc oh o li c s o l ut i on ( e. g . , e li xi r s ) a ls o h a v e g oo d b i oa va i la b il it y . Th e r at e o f d ru g b i oa v a il a bi li t y f r om a h a rd ge l at i n c a ps u le, c om p r es s e d t ab l et , or s us p en s i o n m a y b e e qu a l to t ha t of a s ol ut i on if an o p t im al f o r m u l at io n i s m an u fa c t ur e d an d t h e d ru g i s i nh e re n t l y ra p id l y ab s o r be d . 1 3 . Th e a n sw e r i s E [s ee I I I. B . 7] . D r u g de li v e r y f r om a t r ans d e rm al dr u g d el i ve r y s y s t em de pe n ds on al l o f th e fa c to r s c i te d — th a t is , on th e p r es e nc e o f a n o cc lu s i v e bac k i n g ( t o m ai nt a in s ki n hy d r a t i on a n d e le v a t e s k i n t em p era t u r e s l i gh tl y) a nd an adh e s i v e fi lm t o m a i nt ai n co n t ac t o f t h e fo rm u la t io n m at r i x wi t h t he s ki n t o en ab l e d r ug t r an sf e r fr om t he pa tc h i n to th e s ki n . I f th e d r ug ' s a f f in i ty f o r t he fo r m u l at io n m a tr i x i s g r ea t er t ha n i ts a ff in i t y f or t he s t r at um c o r ne um , th e d ru g ' s e s c ap i ng te n de nc y fr o m t h e p at c h wi l l b e re du c ed , m i ni m i zi ng t he gr a di e nt fo r d ru g tr a ns f er in t o t h e s k i n . Th e m i c ro vi sc os it y o f t he
f o r m u l at io n m a t ri x, t h e pr e s en c e of a m em br a ne b e t we e n th e d r ug r es e r vo i r i n th e p a tc h a n d t he s k in s u r fac e , a nd in t e ra c ti on o f t he d r ug wi t h t h e f o rm ul a tio n m a t ri x a f f ec t t h e r a te an d e xt e n t o f d i ff us i on an d /o r pa r tit i o ni ng o f t he d ru g t h r oug h th e p a tc h to th e s k i n s ur f ac e. F in a ll y, t he e xt e n t o f d ru g de li ve r y f r om th e p a tch is d i r ec tl y p r op o r ti o na l t o th e s u r fa c e a re a o f th e pa t c h in co n ta c t wi t h th e s k i n s u r fa ce .
5 Extemporaneous Prescription Compounding L o yd V . Al l e n J r .
I. INTRODUCTION A. D e f i n i t i o ns 1 . C o mp o u nd i ng vs man u f a c tu r i n g 2 . I t is im po r t an t , b u t o f te n t im es d i f fi c u lt , to di s tin g ui s h b et we e n c om p oun d in g a n d m a nu f ac tu r i ng . 3 . C o mp o u nd i ng ha s b ee n de f in e d b y th e N at i ona l As so c i a ti o n o f B o a rd s o f P h a r m a c y a s t h e p re p a ra t i on , m i xi n g , a s s em bl ing , pa c k a gi ng , o r la b el in g o f a d ru g o r d e vic e ( i ) a s t he r es ult o f a p ra c t i ti o ne r ' s p r es c r i pt io n dr u g o r de r o r in it i a ti v e b a se d o n t h e p ha r m a c i s t/ p a ti e nt / p re sc r ib e r r e la t io n s h i p in t he c o u rs e o f pr o f es s i o na l p r a ct ic e o r (i i ) f o r th e p ur p o s e of , a s a n i nc i de n t to r es e ar c h, te ac h in g , o r c h em ic al a n al ys is an d n o t f o r s al e o r di s p e ns in g . C om p ou nd i n g al s o in cl u de s t h e p re p a ra t io n o f d ru gs an d d e v ic es in a n t ic ip a ti on o f p r esc r ip t io n d ru g o r de r s b as ed on r o u ti n e, r e g ul a rl y o bs e r v e d p at t er n s . 4 . M a n u fa c tu r i n g h as be e n d e fi n ed as t h e p r od uc t io n , p r ep a ra t io n , p r op ag a t io n , c o n ve rs io n o r pr o c e s s ing o f a dr u g o r d e v ic e , e i th e r di r ec tl y o r i n di r ec t l y , b y e xt r a c t i on f ro m s ub s t a nc e s o f na t ur a l o r ig in o r i nd e p en de n tl y b y m e a ns o f c he m i ca l o r bi o lo g ic al s y n t he s i s , an d in c l ud e s a n y p ac ka g in g o r r ep a ck ag in g o f th e s u bs ta n c e (s ) o r l ab el i ng o r r el a be li n g o f i ts c o n ta i n e r, a nd th e p r om o ti on a n d m a rk e ti n g o f s uc h d ru g s o r d e v ic es . Ma n u fa c t u ri ng a ls o i nc lu d es t h e p r epa r a ti o n a n d p r om o ti on o f c o m m er c i al l y a va i la b le pr o du c ts f r om bu lk c o m p o un ds for r e sa le b y p h a rm ac ie s , p ra c ti ti on e r s , o r o th e r p e rs o ns . 5 . Th e pu r po s e o f p ha rm a c eu t ic al c om p ou n di ng is t o p re p a re an in di vi d ual i z e d d r ug t r e a tm en t fo r a p at ie n t ba s ed on an o rd e r f r om a d u l y li c e ns e d p re sc r ib e r . Th e f u n da m e n ta l d i ff e r en c e be t we e n c o m p ou n di n g a nd m a n u f ac t u ri n g is t he exi s t e n c e o f a p ha r m a c i s t / p re s c r ib e r /p a t ie n t r el a ti o ns hi p t h a t c o nt r o ls t h e c om po un d ing o f t h e d r u g p r ep a ra t io n . Co m p ou n d ed dr u gs ar e n o t f o r re s al e b u t, r at h e r, a re per s o na l a n d re sp on s i v e t o t he pat i e nt ' s i m m ed i at e n e ed s . Th e y a r e p r e pa r ed an d a d m i ni s te r ed b y th e p a tie n t , c ar e gi ve r o r p at i en t 's he a lt hc a r e p r of es s i o nal s , wh ic h a l lo ws f o r t h e m on it o r in g o f pa ti e n t o ut co m e s . O n t h e o t he r h a nd , dr u g m a nu f ac tu r e rs p ro d uc e ba t c h es c o ns is t in g o f te ns o r hu n dr e ds of th o us and s o f d o sa g e u ni ts , s uc h a s t ab l e ts o r c a ps ul es , fo r re s a l e , us i ng m a n y p e rs o nne l an d l a r ge - sc al e m an u fa c tu r ing e qu ip m en t . Th e se p ro du c ts a re di s t r ib u te d th r ou g h t h e n o r m a l c ha nn e ls o f in t ers t a te c om m e r c e t o in d i v id u al s u nk n o wn to t he c om p an y . Ma n u f a c tu r e rs a re no t req u i re d to , a n d d o n ot , p ro v i d e o v e r si gh t of in d i vid u al p a t ie n ts . I t i s a ls o a c c ept a b le an d ro u ti ne p ra c t ic e f o r p ha r m a ci st s t o c om p o u nd fo r “ o f f ic e us e ” th os e p r ep a ra t i on s t ha t ar e n o t c om m e r c ia ll y a va il a bl e . Th e s e p r e pa r a ti o ns a r e “F o r O ffi c e U s e O n l y ” a n d a r e n ot f o r r es a le o r t o b e g i v en t o t h e p a t ie n ts to ta k e ho m e ; the y a r e t o b e ad m i ni s te r ed a t t h e o ff ic e . 6 . Th e U ni t ed S ta t es Pha r m a c op ei a ( U S P ) us es th e te r m p r ep a ra t io n to ref e r to c om p ou n de d p r es c ri pt i on s a n d t he t e rm p r od u ct s t o re f e r t o m an u fa c t u r ed p h a rm ac e ut ic al s . A ls o , fo r s t a bi li t y p u rp os es , c om p ou n de d p r ep a r at io n s a r e
a ss i gn e d a “b e y o nd - us e ” d a te an d m an u fa c tu r ed p r o du c ts a r e a ss ig n ed an “ e xp i r a t i on da t e. ” B . R e g u la t i on 1 . C u r r e nt g oo d m a n uf ac t u r i n g p r ac t i ce s (c G M P s ) a re t he s t an d a rd s o f p r a c t ic e u s ed in th e p h a rm ac eu t ic a l i nd us t r y an d a r e re gul a t ed b y th e F o od an d D ru g A d m in is t ra t io n (F D A ) . P.98
2 . G o o d c om p o un d in g p r a c t ic e s ( G C P s ) a r e the s ta nd a r ds o f pr a c t ic e de t a il ed in t h e U S P , c h a pt e r < 1 07 5> . C om m u n it y p ha r m a ci st s m us t c om p l y wi t h s ta te b oa r d o f p h a rm ac y l a ws , re gu l at i on s , a nd gu i de li n es to ens u r e a q u al i t y p r ep a r at i on , wh i c h i n cl ud e s us i ng pr o pe r m a t e ri a ls , we i gh in g e q ui pm e nt , do cu m e n te d t ec h ni q ue s , a nd d i sp e ns in g a nd s t o r ag e in s t ru c ti on s . 3 . L eg a l c on s i de r a t io n s a . E xt e m p or a ne o us c om p o u nd in g b y t h e p ha r m ac is t or a p r es c r i pt i on o rde r f r om a l i ce ns e d p ra c ti t io ne r , a s wi t h t h e d is pe n si ng o f an y o t he r p re s c r ip t io n , is c o nt r o ll ed b y t h e s ta t e b oa r ds o f ph a r m a c y . b . Th e le ga l ri s k (l i ab il i ty ) o f c o m p o un di n g is no g r e a te r th an t he ri s k of f il l in g a p r e sc ri p ti o n f o r a m a nu fa c tu r e d p r od uc t b ec a us e t h e p ha r m a c i s t m u s t e ns u r e t ha t t h e c o r re c t d ru g , d os e , an d di r ec t io ns ar e p r o v i ded . Th e ph a rm ac is t i s a lso r e s po ns ib l e f o r p r ep a ri ng a q u al i t y p h a rm ac eu t ica l pr e pa r a ti o n, p ro vi di n g p r o pe r i n st r uc t io ns r eg a rd i ng it s s t or a ge , a n d a d vis in g the p at i en t o f an y a d v e rs e e f f ec ts . 4 . F oo d a n d D r ug Ad m in i s t r a ti o n . Th e F D A h as d e ve lo p ed a li s t o f p r epa r a ti o ns t h a t s ho ul d n o t b e e xt e m p o r an e ou sl y c om po un d ed . Th i s li s t wa s d e vel op ed p ri m ar i l y f r o m co m m e rc ia l p r o du c ts t ha t h a v e b e en r em o ved f r om th e m a rk et o wi n g t o s a f et y a n d /o r ef f ic ac y c o nc e r ns . Th i s i s a l e ng t h y l is t and m u s t b e r e ad c a re f ul l y b e c a us e , i n s om e c as es , o n l y c e r ta i n d os a ge fo r m s o f a s pe c if ic d ru g a r e i nc lu d ed o n th e l is t a n d o t he r s a r e n ot . Th e li s t i s t oo e xt e n s i v e to inc l ud e h e re bu t c a n b e acc es s ed at w w w. f d a . g o v / c d e r /p ha r m c om p /p c wd . t xt . C . S t a b il i t y a n d q u a l i t y c o n t r o l o f c o mp o u nd e d p r e p a ra t i on s 1 . B e yo n d - u s e d a te s . Th e as s i gn m e n t o f a be yon d - us e d a te is o n e o f t he m o s t d i f fi cu l t t as k s re q ui r ed o f a c o m p ou n di n g p ha r m a ci s t . C h ap t e rs < 7 95 > a n d < 7 9 7> of t h e U S P p r o v id e g u id el i ne s fo r th is ta sk . Ch a pt e r < 7 9 5> in vo l ves no ns t e ri le p r e pa r a ti o ns , a nd c h ap t er < 7 97 > i n vo l ves s t e ri le p r e pa r a ti o ns . F o r n on s ter i l e p r e pa r a ti o ns , c ur r e nt U SP c r it e ri a fo r no na q ue o us l i q ui ds an d s ol id f o rm ul a t io ns ( fo r wh i c h a m an u fa c t u r ed dru g p ro du c t is t he s o ur c e o f ac t i ve i ng r ed i en ts ) in c l u de a b e yo n d- u s e da t e n ot la t er t h an 25 % o f th e t im e rem a in in g u n ti l th e p r od uc t' s e xp i r a t i on da t e o r 6 m o nt h s , wh i c he ve r is e a rl i e r. W hen a U SP o r Na t io na l F o r m u l ar y ( N F ) s u bs ta nc e is t he s o ur c e o f ac t i ve i n g re d ie n t, t he be yo nd - us e d a te is n o t l a te r th a n 6 m on t hs . F o r wa t e r -c o nt a in in g fo rm u la t io ns ( pr e pa r ed f r om i n g re d ie n ts i n s ol i d f o rm ), t h e b e y on d -u s e da t e i s n o t l a te r th a n 1 4 d a y s wh e n s t o re d a t c ol d te m p e ra t ur e s . F o r a ll ot h e r f o rm ul at i o ns , t h e b e yon d -u s e dat e is no t l a t er t ha n t h e i nt e nd e d du r a ti o n o f t h e ra p y o r 3 0 d a y s , wh ic h e ve r is ea r li er . Th e se
b e yo n d- u s e da t es m a y be e xc e e de d wh e n t h er e is su pp o r ti n g v a l id s ci e nt if i c s t ab i li t y in f o rm at i on th a t i s d i re c tl y a pp li c ab le t o th e s p ec if ic p re p a ra ti o n . F o r s t e ri l e p re p a ra t io ns , i f a s te r il i t y te s t i ng p ro g ra m i s n o t i n pl a ce , t h e f ol l o wi n g c a n b e u s e d p r o v id e d t he p r ep a ra t io n i s p r op e rl y p a c k a g ed an d s t or e d . L o w- R i s k L e v el C om p oun d e d S t e ri le P r ep a ra t io ns : N ot m o r e t ha n 48 ho u rs a t c o nt r o ll ed r oo m t em p er at u r e , n ot m o r e t h an 14 da ys a t a c ol d te m p e ra t u re ( r e f r ig e ra t o r ) a nd fo r 45 d a y s f ro ze n a t -2 0 ° C o r c o ld e r . Me d i u m - R is k L e v el C om p o u nd ed S t er i le P re p a rat i o ns : No t m o re th a n 3 0 h o u rs at c o nt r o ll ed r oo m t em p er at u r e , n ot m o r e t h an 9 d ays a t c ol d te m p e ra t u re ( re f r ig e r at o r ) a n d f o r 4 5 d a y s f r o z e n at - 2 0 ° C o r c ol d er . H i g h - Ri s k Le v e l Co m p o un d e d S t e ri le P r ep a ra t io ns : N o t m o r e t ha n 24 ho u rs a t c o nt r o ll ed r oo m t em p er at u r e , n ot m o r e t h an 3 d ays a t c ol d te m p e ra t u re ( re f r ig e r at o r ) a n d f o r 4 5 d a y s f r o z e n at - 2 0 ° C o r c ol d er . I f a s te r i li t y te s ti ng p ro g ra m i s i n p la c e , th e b e y on d - us e d a te s f o r n on s te ri l e p r e pa r a ti o ns a p pl y . As in n o ns te r i le c om p ou n di ng, t h es e b e y on d -u s e d at es f or s t e ri le c o m p o un di n g m a y b e e xc e e d ed wh e n th e re is s u pp o r ti n g v a l id s c i en t i fi c s t ab i li t y in f o rm at i on th a t i s d i re c tl y a pp li c ab le t o th e s p ec if ic p re p a ra ti o n . 2 . Q u a li t y c o n t r o l . Q ua li t y c on t ro l i s b ec om in g on e of t he fa s te st g ro wi n g a s p ec t s o f ph a rm ac y c om po u nd ing . P ha r m a c i s t s a r e b ec om i ng m o r e i n v ol ve d i n t he f in a l t e s ti ng o f c o m p o un d ed pr e p a ra t io ns o r a r e s e n din g th em t o co n t ra c t la b or a t o ri es f or t e s ti ng . Fo r e xa m pl e , t he f o ll o wi n g q u al it y c on t r ol t e s t s c an be c o ns id e re d f o r th e r e s pe c t i v e c om po u nd e d d o s a g e f o rm s : P.99
a . O i n tm e n ts , c r e am s , a n d ge l s. Th e o re t ic al we i gh t c om p a re d t o a c tu al we i g h t , p H , s p ec if ic g ra v i t y , ac ti v e dr u g as s a y , ph y s ic al ob s er va t i o ns (c ol o r , c l a ri t y , te xt u r e s u r fa ce , te xt u r e - s pa t ul a s p r ea d , a pp e ar a nc e, f ee l) , a nd r he ol o gi ca l p r op e rt i es . b . H a r d g e la t i n c ap s u les . W ei gh t o ve r a ll , a ve r ag e we i g ht , i n di v i d ua l we ig h t va r i a ti o n , di s s o lu t io n o f c a ps ul e s he l l, di s i n te g ra t i o n o f c ap su le c o n te n ts , a c ti v e d r u g a ss a y , p h y s i c a l a p pe a r an c e ( c o lo r , u n if o rm i ty , e xt e n t o f f i ll , l oc ke d ) , a n d p h ys ic al s t a bi li t y ( di s c olo r a ti o n , c h a ng es in ap p ea r a nc e ). c . S pe c ia l ha r d g e la t i n c a p su l es . W eig h t o ve r all , a ve ra g e we i g h t, in d i vid u al we i g h t va r i a ti o n , di s s o lu t io n o f c a ps ul e s he l l, di s i n te g ra t i o n o f c ap su le c o n te n ts , a c ti v e d r u g a ss a y , p h y s i c a l a p pe a r an c e ( c o lo r , u n if o rm i ty o f a pp ea r a nc e, un i fo r m i t y o f e xt e n t o f f i ll , c lo s u r es ) , a n d p h y s i c a l s t ab il i t y (d is c o l o ra t io n o r o t he r c h ang e s ). d . S u pp o s it o r i es , t r oc he s , lo l l ip o ps , an d s t i cks . W ei gh t , s pe c i f ic g r a vi ty , a c ti v e d r u g a ss a y , p h y s i c a l o bs e r v a t i on s ( c o l or , c l ar i t y , t e xt u r e o f s u rf ac e , a pp ea r a nc e , f e e l) , m e lt i ng te s t, di s s olu t i on te s t, ph y s ic al s t a bil i t y. e . O r a l a n d t o p ic a l l i qu id s . W eig h t t o v ol um e , pH , s pe c i f ic g r a vi t y , a c t i ve d r ug a ss a y, gl o bu le s i z e ra n ge , r he o lo gi ca l p r o pe r ti es/ p o u ra bi l it y , p h ys ic a l o bs e r va t i on s ( c o lo r , c la r it y ) , a nd ph y s i c al s t ab i li t y ( di s c ol o ra t io n , fo r ei g n m a t e ri al s , g as f o r m a t io n , m o l d g r o wt h ) .
f . P a r en t e r al p r ep a r a ti on s . W eig h t o r vol u m e , pH , s pe c i f ic g r a v i t y, o sm ol a li t y , a ss a y, ph y s ic al ob s e r v a ti o ns (c o lo r , c la r it y ) , p ar t ic u la t e m a t t er , s t e ri li t y, an d p yr o g en ic i t y . 3 . Q u a li t y c o n t r o l te s t in g . P ha rm a c i s t s h a ve t he o pt i on of do i ng te s ti ng i n - ho us e o r o u ts o u rc in g i t t o l a bo r a to r i es . a . I n -h o us e te s t in g c an i n c l ud e m e as ur em e n ts s u c h as we i g h t, v o lu m e , pH , s pe c i f ic g r a vi t y, o s m o la li t y , ph y s ic a l o bs e r v at i on s, st e ri l i ty a n d e n do t o xi n s . b . O u t - so u r ce d t es t i ng c a n i nc lu d e st e r il i t y, e ndo t o xi n s , p o te nc y , an d d i s s o lu t io n . c . Te s t re s ul t s s ho u ld be k e p t o n f i le wi t h t h e c om p ou n di ng r ec o rd s f o r th e i n di vi d ua l c om po u nd e d pr e p a ra t io ns .
II. REQUIREMENTS FOR COMPOUNDING A. S o u r c e s fo r c he m ic al s a nd d r ug s . P h a rm ac is t s c a n o b ta i n s m al l q u an t i ti es of t h e a p p ro p ri a te c h em ic als o r d r ug s f r om wh o le s a le r s o r c h em ic al s u pp l y ho u s e s . Th e s e s up p li e rs th e n m ay a l s o s e r v e as c om po u nd i ng c o ns u lt a nt s t o t h e p h a rm ac is ts t o a id i n ens u r in g t h ei r p r o du c t ' s p ur i t y a nd qu a li t y . B . E q u ip m en t . Th e c o rre c t e qu i pm en t i s i m p o rt an t wh e n c om p ou nd i ng . Ma n y s ta t e b o a rd s o f p h a rm ac y ha v e a re q ui r ed m i ni m u m l is t o f e q ui pm en t fo r c om p ou n di n g p r e sc ri p ti o ns . Su gg e s t e d e q ui pm e nt , wh i ch v a ri es a c c o rd i ng to t he am ou n t o f m a te r i al n e ed e d a nd th e t y p e o f c o m p o un d ed pr es c ri p ti o n ( e .g . , p a re n te r al ) , i n cl ud e s t he fo l lo wi n g : 1 . E le ct r o ni c b al an c e a nd / o r c la ss A p r es c r i pt i on b a l a nc e 2 . H o t p la t e 3 . Ma g n e ti c s ti r r e r 4 . E le ct r ic m i xe r 5 . S pe ci a l c o n ta i ne r s f o r p ac k a g in g (e . g. , ap pl ic at o r ti p b o t tl es , i ns u ff l at o rs ) 6 . G r a du a te d c y l in de r s f ro m 1 0 m L t o 1 0 00 m L 7 . G l ass , W ed g wo o d, and p o rc el ai n m o rt a rs an d p e s t l es o f v a ri o us s i z es 8 . F un ne ls o f v a r io u s s i z e s 9 . S pa t ul as o f v a r io us s iz e s , in c l ud i ng s e ve r al pla s ti c s pa t ul as 1 0 . W eig h in g a nd f il t er pa p e rs 1 1 . St i r ri n g r o ds (g l as s ) 1 2 . O in tm e nt / pi l l t il e 1 3 . Ca p s u le - f il li n g m a c h in e 1 4 . O in tm e nt - f il li n g m a c h i ne 1 5 . Au t oc la v e 1 6 . L am i na r fl o w c le a n be n c h 1 7 . Sp ec i al s u pp os i to r y , t r o c h e a n d m e d ic at i on - s ti ck m o ld s P.100
1 8 . Re c or d -k e ep in g s y s te m (c om po u nd in g l o g b oo k ) 1 9 . G la s s b e ak e rs f ro m 5 0 m L to 10 00 m L C . L o ca t i on o f c o mp o un d i n g a r ea . Ma n y p h a rm a c ie s ac t i vel y i n v ol ve d in c om p ou n di ng ha v e d ed ic a t e d a s ep a r at e a r e a i n th e p h a rm ac y t o t h is p r oc e s s . Th e
i d ea l l oc a ti o n is a wa y f r om he a vy f o ot t ra f f ic a n d is ne a r a s i nk wh e r e t h ere is s u f fi ci en t s p ac e t o wo r k a n d s to r e a l l c h em ic a ls an d eq ui p m e n t. Fo r c o m po u n di ng o f s t e ri le p re p a ra t io ns , a lam i na r ai r - fl o w h o od (m in i m a l ) a nd a c l e an ro o m ar e cu r r en t p r a ct ic e , o r i s o l at i on ba rr i e r te c h no l og y e qu i pm en t . D . S o u r ce s o f i n fo r m a tio n 1 . Li b r ar y a t a c o ll e ge of p h a rm ac y 2 . R e fe r e nc e s a . A ll e n J r L V . T he A r t , S c i en c e an d T ec h no l og y o f Ph a r m ac e ut ic a l C o mp o u nd in g . 3 r d ed . W as h in g to n , D C : A m e ri c a n Ph a rm ac eu t ic a l As s o ci a ti o n, 20 0 8. b . A no n . Re m i n gt o n: Th e S c ie nc e a n d P r ac t ic e o f P h a r m ac y . 2 1s t e d. P hi la d el p hi a : L i pp i nc ot t W ill i am s & W ilk i ns ; 2 00 6 . c . Sm i th A , H e c k el m a n PE , O ' N e i l M, B u da v a r i S, e ds . Me r c k I nd e x . 13 t h e d . W hite h ou s e S ta t io n , N J : Me r c k & C o , 2 00 1 . d . T he U S P Ph a r m ac is ts ' P h a r m ac o pe ia . 2n d Ed iti o n Ro c k v i ll e , MD : U . S . P h a r m a c o pe i al C on v e n tio n , In c . , 2 0 08 . e . A ll e n L V J r , P o po v i c h N G , A n se l H C . A ns e l 's Ph a r m a c e u ti ca l Do s a g e Fo r m s an d D r u g D el iv e ry Sy s te m s . 9 t h Ed i ti o n Me d i a , P A: Lip p in c ot t W ill ia m s & W ilk in s , 2 00 8 . 3 . J ou r n al s a . I nt e rn a ti o na l J ou r na l o f P ha r m a ce u ti c a l Co mpo u n di ng b . U . S . P h a r m ac is t c . P ha r m ac y T i m es d . Li p pi nc o tt ' s H os pi t al P h a r m a cy e . A m e r ic an J o u rn al o f He a l th - Sy s te m P h a r m ac is ts 4 . Ma n u f ac t u re rs ' d r ug pr o d uc t i n fo r m a t io n i ns e r ts ; c om p ou n di ng sp ec ia l ty s u pp l ie r s 5 . We b si t e s a . C om p ou nd i ng To d a y : w w w. C o m p o u nd in g To d a y. c om b . I nt e r na t io na l J ou r n al o f P ha r m a ce u ti c a l Co mpo u n di ng : ww w. i j p c .c om c . P ad do c k La b or a to r i es , I n c . : ww w. p a d d oc kl a bs .c om
III. COMPOUNDING OF SOLUTIONS A. D e f i n i t i o n. U S P 3 0 de f i ne s s o lu t i on s a s l iq u id p r ep a ra t io ns th a t c on ta i n o ne o r m o r e ch em ic a l s u bs t an c e s d is s o l ve d ( i .e . , m ol ec u l a rl y d is pe r s e d ) i n a s u it a b le s o l ven t o r m i xt u r e o f m u tu a ll y m is c i bl e s ol ve n ts . A l t h ou gh t he un i fo rm i t y o f t he d o sa g e i n a s ol u ti o n c a n b e a s s um e d, th e s t ab il i ty, p H , so lu b il i t y o f th e d ru g o r c h em ic al s , t as te ( fo r o ra l s ol u ti o ns ) , a nd pa ck ag in g ne e d t o b e c on s i de r ed . B . T yp e s o f so l u t io n s 1 . S t e ri l e p a r en t e r al a nd o p h th a lm i c s o lu t i on s r e q ui r e s p e ci al c o ns id e ra t i on fo r t h e ir p re p a ra t io n ( s e e XI ) . 2 . N o ns t e r il e s o l u ti o ns i n c l ud e o r a l, t op ic al , a n d o t ic s o lu t io ns . C . P r e p a ra t i on o f s o lu t io n s . So lu t io ns a re th e ea s ie st o f t he do s a g e f o rm s t o c om p ou n d e xt e m po r a ne ou s l y , a s l on g a s a fe w g en e r al r ul es a re fo l lo we d . 1 . E ac h d r ug o r c h em ic a l i s d is so l ved in t he s o l v en t in wh i c h i t is m o s t s o lu b le . Th us t h e s ol u bi li t y c h a r ac te r is t i c s of ea c h d ru g o r c h em ic a l m u s t b e k n o wn .
2 . I f a n a lc oh o li c s o l ut i on o f a po o rl y wa t e r - s o l ubl e dr u g i s us e d, th e aq ueo u s s o lu t io n i s a dd e d t o t he a l c o h ol ic s ol u ti o n t o m ain t a in as h i gh an al co h ol c o nc en t r at i on as p os s i b le . P.101
3 . Th e s a lt fo r m o f t h e d ru g — no t th e f r e e -a c i d o r b a s e fo r m , wh i c h b ot h ha v e p oo r s o lu bi l it y— i s u s e d . 4 . Fl a v o r in g o r s we e t e nin g ag e nt s a r e p r ep a re d a h e ad of ti m e . 5 . W he n a dd i ng a s a l t t o a s y r up , d is s o l v e t h e s al t in a f e w m il li l it e rs of wa t e r f i rs t ; t h e n a dd th e s y r u p t o v olu m e. 6 . Th e pr o pe r v e hi c l e (e .g . , s y r u p , e li xi r , a r om a tic wa t e r , p u ri f ie d wa t e r ) m us t be s e le ct e d. D . E x am p l es 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Triamcinolone acetonide
100 mg
Menthol
50 mg
Ethanol
10 mL
Propylene glycol
30 mL
Glycerin
20 mL
Sorbitol 70% solution, qs
100 mL
Sodium saccharin
100 mg
Sodium metabisulfite
20 mg
Disodium EDTA
100 mg
Purified water
5 mL
b . C o mp o u nd i n g p r o ced u r e . Tr i am c i no lo n e a c et o n id e 0 . 1% m o ut h wa s h s o lu t io n i s p r e pa r e d b y di s s ol v i n g th e t ri am c i n ol on e a c e t on id e an d m en t ho l i n t h e e th a n ol . Ad d t h e p r o p y le ne gl y c ol , gl y c e r in , a n d a bo u t 1 0 m L of t h e 7 0% s o rb i to l a n d m ix we l l .
D i s so l v e t h e s o d iu m s a c c h a ri n , so d iu m m e t ab is u lf i t e , an d di s o di um E D TA i n th e p u r if i ed wa t e r . Ad d t h e aq u e ou s s o l ut i on to th e dru g m i xt u r e an d m i x we l l . A d d s u f fi ci en t 70 % s or b it o l s o l u ti on t o v o l um e a nd m ix we l l . H ow m u c h o f th e t ri a mc i n o lo n e b as e is p re s en t i n th i s p r e sc r i p ti o n ? Th e m o le cu l ar we i g ht o f t r iam c i n ol o ne i s 3 9 4. 4 a n d th a t o f t ri am c i no l on e a ce to n id e i s 4 3 4 .5 .
2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Potassium chloride
1 mEq/mL
Preserved flavored, oral vehicle, qs
100 mL
b . C a lc u la t i o ns . Th e m ol e c u la r we i g ht o f p ot as s iu m c hl o r id e i s 7 4. 5 ( K = 3 9 ; Cl = 3 5 . 5 ). O n e m i ll i eq u i v al ent ( m Eq ) we i g hs 7 4 .5 m g . 1 0 0 m L × 74 . 5 m g /m L = 7 4 5 0 m g o r 7 .4 5 g o f K Cl r eq u i re d W h a t i s th e m o l a r c o nce n t r a t io n of t h is p re s c ri p t i o n? 7 . 4 5 g p e r 1 0 0 m L o r 7 4.5 g p e r 1 0 00 m L 1 m o l e o f K C l we i gh t s 7 4. 5 g I t is a 1 m ol a r s ol u ti o n c . C om p o un d i ng p r oc ed u r e . Th e s ol ub i li t y of po t as s i um c h lo r i de is 1 g i n 2. 8 m L wa t e r . Th e r e fo r e , d is s o l ve t he 7 .4 5 g K C l i n 2 1 m L o f p u ri f ie d wa t e r. A dd s u f fi ci en t p r e se r ve d f l a v or e d o r al ve h ic le t o vo l um e a nd m i x we l l . 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Salicylic acid
2%
Lactic acid
6 mL
Flexible collodion, ad
30 mL
b . C o mp o u nd i n g p r o ced u r e . Ph a rm ac is ts m u st u s e c a u ti o n wh e n p re p a ri n g t h is p r e sc ri p ti o n b ec au s e f lexi b l e c ol lo d io n i s e xt r e m e l y f la m m ab l e. A 1 - o z . ap p li c a t o r t i p b o tt l e is c a li b r at e d, us i ng et h an o l, wh i ch is pou r e d o u t a nd an y r em a in in g al c o h ol a l lo we d t o P.102
e va p o ra t e , r es u lt in g i n a d r y b ot t le . S al ic y l ic ac i d ( 0 . 6 g ) i s a dd e d d ir e c t l y i n to th e b o t tl e , t o wh ic h i s a dd e d t h e 6 m L o f l ac t ic ac id . Th e b o t tl e is a gi ta t e d o r a g la s s s t i r ri ng r od is u s e d to dis s o l v e th e s al ic yl ic ac id . F l e xi b l e c o l lo di o n is ad de d up to t h e c al i b ra t ed 30 -m L m ar k on th e a p pl ic a to r - ti p bo t t le . 4 . E xa m pl e 4 a . M e d ic a t io n o rd e r
Iodine
2%
Sodium iodide
2.4%
Alcohol, qs
30 mL
b . C o mp o u nd i n g p r o ced u r e . I o di n e ( 0 .6 g ) a nd s o di um io di d e ( 0 .7 2 g ) ar e d i ss ol ve d i n t h e a lc oh o l, a n d t h e f in a l so l ut i on is p l ac e d in a n am b er bo t t le . A r u b b e r o r p l as t ic s pa t ul a is us ed be c a us e i o d ine i s c o r r os i ve .
IV. COMPOUNDING OF SUSPENSIONS
A. D e f i n i t i o n. S us p en s io n s a r e d e fi n ed b y U S P 3 0 as l i qu id p re p a ra t io ns t h a t c o ns is t o f s ol i d p a rt ic le s d is p e rs ed th r o ug ho u t a l i qu i d p ha s e in wh i c h t he p a r ti cl es a r e no t s ol u bl e . B . G e n e r al ch a r ac t e r is ti c s 1 . S om e s us pe ns i on s s ho u ld c o n ta i n a n a nt im ic ro b ia l a g en t a s a p re se r v a t i v e . 2 . P a rt ic l es s e tt l e i n s u s p e ns i on s e v e n wh e n a s u s pe n di ng ag e nt is ad ded ; t hu s s us p en s i o ns m us t b e we ll s h ak e n b ef o r e us e to en s u re th e d is t r ib u ti on o f p a r ti cl e s f o r a u ni f o rm d os e . 3 . Ti g ht c o n ta i ne rs a re ne c es s a r y t o e ns u re th e s t a b il i t y o f th e f i na l p r ep ar a t io n . 4 . P r in c i pl es t o k e e p i n m i nd wh e n c om po u nd i ng i nc l ud e t h e f ol l o wi n g: a . I ns ol ub l e p o wd e rs s h ou l d b e sm a ll an d u ni f o rm i n s i z e t o d ec r e as e se t tli n g . b . Th e s us p en s i o n s h o uld b e v i sc o us . c . To p ic al s us p en s i o ns s h o ul d h a v e a s m oo t h , im p a lp a bl e t e xt u r e . d . O r a l s u s p e ns io ns s h ou l d h a v e a pl e as an t o d o r a n d t as t e. C . F o r ma t i o n o f s u sp e ns i o ns . S us pe ns i on s a re e a s y to c om p ou n d; ho we v e r , p h ys ic al s t a bi li t y a ft e r c o m po u nd in g th e f i na l p r ep a r a ti on is pr o bl em a ti c . Th e f o l lo wi n g s t ep s m a y m in im i z e s t ab il i t y pr o bl em s . 1 . Th e pa r ti c l e s i z e o f a l l p o wd e r s us e d i n t he f o rm u la t io n s ho ul d be re d uc e d. 2 . A th ic k e ni n g ( s u s pe ndi n g ) a ge n t m a y b e u se d to i nc r ea se v is c o s i t y . C om m o n t h ic ke n in g a g en ts in c l u de a lg in ic ac id , be n to ni t e , V E E G U M, m e t h y l ce ll u los e , a nd t r a g ac an t h. 3 . A l e vi ga t in g a g en t m ay a i d i n t h e i ni t ia l d is p ers i on of in s o l ub le p ar t ic les . C om m o n l e vi ga t in g a g en t s i nc lu de g l y c e r i n, p ro p y le n e g l y co l , a lc o ho l , s yr up s , a nd wa t e r . 4 . Fl a v o r in g a g en ts an d p r e s e r v a ti v e s s ho u ld be s e le c t e d a nd ad d ed if t he p r e pa r a ti o n is in t en d ed fo r o ra l u s e . C om m o n p r es e r va ti v e s i nc lu d e m e t h yl p a ra b en , p r o p ylp a r ab en , be n z o ic a c id , a n d s o d iu m b en z o at e . Fl a vo ri n g a ge n ts m a y b e a n y f l a v o r ed s y r u p o r fl a v o r c o nc en t r at e ( Ta bl e 5 - 1 ). 5 . Th e s o ur c e o f t he ac t iv e i n g re di e nt s ( e .g . , b u lk p o wd e r s v e r su s t a bl e ts o r c a ps ul es ) m us t be c o ns id e r ed ; if c om m er c i a l d os a g e f o rm s a r e us e d, t he i n ac t i ve i n g re d ie n ts m us t b e c ons i de r ed an d o n l y i m m ed ia t e - re l ea s e ta b le ts o r c ap s ul es s h ou l d b e us e d a nd no t m o di f ie d r e le as e . D . P r e p a ra t i on o f s u spe n s io n s 1 . Th e i n s o lu b le po wd e rs a re t ri t u ra t ed to a f i ne p o wd e r . 2 . A s m a ll po r t io n o f l i qui d is u s e d a s a le vi ga t in g a g en t , a nd t he po wd e r s a r e t r i t u ra t ed un t il a s m oo t h p a s t e i s f o rm e d. 3 . Th e v e hi c l e c on t ai ni ng t he s u sp e nd in g a g en t is ad d ed in di v i d ed po r ti on s . A hi g h s p ee d m i xe r g r ea t l y i nc re a s e s t h e di s pe rs i on . P.103
Table 5-1. Selected Flavor Applications
Drug Category
Preferred Flavors
Antibiotics
Cherry, maple, pineapple, orange, raspberry, bananapineapple, banana-vanilla, butterscotch-maple, coconut custard, strawberry, vanilla, lemon custard, cherry custard, fruit-cinnamon
Antihistamines
Apricot, black currant, cherry, cinnamon, custard, grape, honey, lime, loganberry, peach-orange, peachrum, raspberry, root beer, wild cherry
Barbiturates
Banana-pineapple, banana-vanilla, black currant, cinnamonpeppermint, grenadine-strawberry, lime, orange, peach-orange, root beer
Decongestants and expectorants
Anise, apricot, black currant, butterscotch, cherry, coconut custard, custard mint-strawberry, grenadinepeach, strawberry, lemon, coriander, orange-peach, pineapple, raspberry, strawberry, tangerine
Electrolyte solutions
Cherry, grape, lemon-lime, raspberry, wild cherry, black currant, grenadine-strawberry, lime, Port wine, Sherry wine, root beer, wild strawberry
4 . Th e pr e pa r a ti on is br ou g h t t o t h e r eq u i re d vol um e u s i n g t he v e hi c l e . 5 . Th e fi na l m i xt u r e i s t ra n s f e r re d to a “ t ig h t ” b ott l e f o r d is p en s i n g t o t he p a t ie n t. 6 . A ll s us p en s i o ns a r e d is p en s e d wi t h a “s h ak e we l l ” l ab el . 7 . S us pe ns i on s a r e n ot fil t e re d . 8 . Th e wa t e r -s ol u bl e i ng re d ie n ts , i nc l ud in g fl a vo rin g ag e nt s, a re m i xe d i n th e ve h i cl e b e fo r e m i xi n g wi th t he in s o l ub le in g r ed ie nt s . E . E x am p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Propranolol HCI
4 mg/mL
Disp
30 mL
Sig:
1 mL p.o. t.i.d.
b . C a lc u la t i o ns . P ro p ran o lo l H C l: 4 m g / m L × 3 0 m L = 1 20 m g . P r o pr a no lo l H C l is a va i la b le as a p o wd e r o r i n i m m ed i at e - re l ea se and e xt e n d ed - r el e as e ( l on g- a c ti n g) d o sa g e f o rm s . O nl y t h e p o wd e r o r t h e im m e d ia t e- r e l ea s e ta b le ts a re us ed f o r c om p ou n di ng p re s c r ip t ion s ; t h er e fo r e , s om e co m b i na t io n o f p ro p ra n ol ol HC l t ab l et s t h a t yie ld s 1 20 m g ac ti v e d r u g ( e .g . , 3 × 4 0 m g t ab l e ts ) m a y be us ed . c . C om p o un d i ng p r oc ed u r e . Th e p r op r an o lo l t ab l e ts a r e re du c ed to a f in e po wd e r i n a m o r t a r. Th e p o wd e r o r t he c o m m i n u te d t a bl e ts a re le v i g at e d t o a s m oo t h p as t e , u s in g a 2% m e th y l c el lu l os e s ol u ti o n. To t hi s m i xt u r e , a b ou t 1 0 m L o f a s ui t a bl e f l a v o ri n g a ge n t i s a dd ed . Th e m i xt u r e i s t r an sf e r re d to a c al ib r a te d c on t ain e r an d b r o ug h t t o t h e f in a l v o l um e wi t h p u ri f ie d wa t e r o r s ui t ab l e s u s p e nd i ng v e hi c le . A “ s h ak e we l l ” l a be l i s a t tac h ed to t he p re sc ri p ti o n c o nt a in e r . 2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Zinc oxide
10
Ppt sulfur
10
Bentonite
3.6
Purified water, ad
90 mL
Sig:
Apply t.i.d.
b . C o mp o u nd i n g p r o ced u r e . Th e p o wd e rs a re re d uc e d t o a fi ne un i fo r m m i xt u r e in a m o r t a r. Th e p o wd e r s ar e m i xe d t o fo r m a sm o o th p as te us in g wa t e r a n d t r a ns f e r re d t o P.104
a ca l ib r a te d b o tt l e. Th e fi n al v o lu m e is at t ai n ed wi t h p u ri f ie d wa t e r . A “s h ak e we l l ” l a be l i s a t ta c h e d t o t h e pr e s c r ip t io n c o nt ai n e r. 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Rifampin suspension
20 mg/mL
Disp
120 mL
Sig:
u.d.
b . C a lc u la t i o ns . Ri f am pin : 20 m g /m L × 12 0 m L = 2 4 0 0 m g . Ri f am pi n i s a v a i la b le in 1 5 0 -m g a nd 30 0 -m g c aps u le s . H e nc e, 8 c ap s u les c o n ta in i ng 30 0 m g o f rif a m p i n i n e a ch c a ps ul e o r 16 c a ps u l es c o nt a in i ng 15 0 m g o f r i f am p in pe r c a ps ul e ar e n ee de d . c . C om p o un d i ng p r oc ed u r e . Th e c on t en ts of t he a pp r op r i at e n um b e r o f r i f am pi n c a ps ul es a re em pt i ed in to a m o rt a r a n d co m m in u te d wi t h a pe s tl e . Th i s p owd e r i s l e vi ga t ed wi t h a s m al l am o un t o f 1% m e th y l c e l lul o se s o lu t io n . Th e n 2 0 m L o f s im pl e s yr u p a r e a d de d a nd m i x e d . Th e m i xt u r e i s b r ou gh t t o t he fi n al v o lu m e wi th si m p l e s yr u p . “ S h ak e we l l ” an d “ r e f r ig e ra t e ” l ab e ls a r e at t a c h ed t o t he p re sc r ip t io n c o nt a in e r .
V. EMULSIONS A. D e f i n i t i o n. Em u ls io ns a r e tw o- p h as e s ys t e m s i n wh ic h o n e l iq ui d i s d is p e rs ed t h r o ug ho u t a no t he r li q uid i n t he f or m o f s m a ll d ro p le t s ( se e Ch a pt e r 3 . V I. D ) . B . G e n e r al ch a r ac t e r is ti c s . E m ul si on s c an be us e d e x te r n al l y a s l ot i ons an d c r e am s o r i n te r n a ll y t o m as k t h e t as t e o f m ed ica t i on s . 1 . Th e t wo li q ui ds in an e m ul s i o n a re im m i s c ib le a n d re qu i r e t he us e o f an e m u ls i f yi n g a g e n t . 2 . Em u ls io ns a re c l as s i fie d as e i th e r o i l - in -w a t e r ( o /w ) o r w a t e r - in - o il (w / o ) ; t h e r e c a n a ls o b e m ul ti p le em ul s io ns , s uc h a s o i l -i n -w at e r - i n - oi l ( o/w / o ) a n d w a t e r - i n o i l - i n -w at e r (w /o /w ) , a s we l l a s em u ls io n -g e ls , i n wh i c h th e e xt e r n a l p h a s e o f a n o il i n wa t e r e m u ls i on is t h ic k e ne d wi t h a ge ll i ng ag en t . 3 . Em u ls io ns a re u ns t abl e b y na t ur e , a n d t he fo l lo wi n g s t e ps s h ou ld be t ak e n t o p r e ve n t t he t wo p ha s e s o f an em ul s i o n f r om s e pa r a ti n g i nt o t wo la ye r s a ft e r p r e pa r a ti o n. a . Th e c o r re c t p r o po r t i on s o f oi l a n d wa t e r s h o uld b e us e d d u ri ng p re p a ra t i on . Th e i n t er n al ph as e s ho u ld r ep r e s e n t 4 0% - 60 % o f th e t o t al vo lu m e .
b . A n e m u ls i f y in g a g en t i s n e ed e d f o r em u ls io n fo r m at i on . c . A h a nd h om o ge n iz e r , wh i c h re d uc es th e s i z e o f gl o bu le s o f th e i n te r na l ph as e , m a y be us e d; if s m al l q ua n t it i es a r e c om po u nd e d, t wo 6 0 -m L s y r i ng es at ta c he d wi t h a L eu r - Lo c k ad ap t e r c an b e u s e d a n d t h e m a t e ri al s p us h ed ba c k an d f o r th b e t we e n t h e t wo s y r i n ge s . d . P r e se r va t i ve s s h ou ld b e a d de d i f th e p r ep a r ati o n i s i nt e nd ed t o l as t l on g e r t h an a f e w d a y s . G e ne r al l y , a c om b in a ti o n o f m e t h y lp ar a b en ( 0. 2 % ) a nd p ro p y lp a r ab e n ( 0 . 0 2% ) m a y be us ed . e . A “ s ha k e w e l l” la b el s h ou l d b e p la c e d o n t h e f i n al pr e pa r a ti on . f . Th e p re p ar a ti o n s ho uld b e p r o t ec t ed f ro m l ig ht a nd e xt r e m e t em pe r a tur e . B ot h f r e e zi ng an d h ea t m a y ha v e a n e f fe c t on s t a bi li t y . C . E m u ls i f yi n g a g e n t s 1 . G u ms , s uc h a s a c a c i a o r t ra g ac an t h, a re us ed t o f or m o / w e m u ls i on s . Th e s e e m ul si f y i ng ag e nt s a r e fo r g en e ra l u s e , e s pe ci al ly f o r em ul si o ns i n te n de d f o r i n t er n al ad m i n is t ra t io n (Ta b l e 5- 2 ) . a . U se 1 g o f ac ac ia po wd e r fo r e v e r y 4 m L of fi x e d oi l o r 1 g t o 2 m L fo r a vo l at i le oil. b . I f u s i ng t ra g ac an t h i n p l ac e o f a ca c i a , 0 . 1 g o f t r a g ac an t h is us ed f or e ve r y 1 g o f a c ac ia . 2 . M e t h yl c e l l u l o se a nd c a r b ox ym e t h yl c e l l u l o se a r e us e d f o r o / w e m u ls i o ns . Th e c o nc en t r at i on s o f t h es e a g e nt s v a r y , d ep en d in g o n th e g r a de th a t i s us ed . Me t h yl c e l lu lo s e is a v ai l ab l e i n s e v e ra l v isc os i t y g r a d es , ra n gi ng f ro m 1 5 to 4 00 0 a n d d e si g na t ed b y a c e n ti po is e n um b e r, wh i c h is a u ni t of vi sc os it y . P.105
Table 5-2. Agents Used in Prescription Compounding Ointments Oleaginous or hydrocarbon bases
Hydrous emulsion bases (w/o)
Anhydrous
Hydrous
Nonhydrophilic
Will absorb water
Insoluble in water
Insoluble in water
Not water removable (occlusive)
Not water removable (occlusive)
Good vehicles for antibiotics Example Petrolatum Absorption bases
Examples Cold cream Hydrous lanolin Emulsion bases (o/w)
Anhydrous
Hydrous
Will absorb water
Hydrophilic
Insoluble in water
Insoluble in water
Not water removable (occlusive)
Water removable
Examples Hydrophilic petrolatum Lanolin USP (anhydrous)
Can absorb 30-50% of weight Examples Hydrophilic ointment USP Acid mantle cream Water soluble Anhydrous or hydrous Soluble in water Water removable Hydrophilic
Example Polyethylene glycol ointment Suspending Agents Acacia 10%
Methylcellulose 1%-7%
Alginic acid 1%-2%
Sodium alginate 1%-2%
Bentonite 6%
Tragacanth 1%-3%
Carboxymethylcellulose 1%-5%
VEEGUM 6%
Preservatives Methylparaben 0.02%-0.2%
Propylparaben 0.01%-0.04% Emulsifying Agents
Hydrophilic colloids
Surfactants, nonionic
Acacia
Concentrations used (1-30%)
Tragacanth
Tweens (e.g., polysorbate 80)
Pectin; favor o/w
Spans
Carboxymethylcellulose Methylcellulose Proteins
Soaps
Gelatin
Triethanolamine
Egg whites; favor o/w
Stearic acid
Inorganic gels and magmas
Others
Milk of magnesia
Sodium lauryl sulfate
Bentonite; favor o/w
Dioctyl sodium sulfosuccinate Cetyl pyridinium chloride
o/w, oil-in-water; w/o, water-in-oil P.106
3 . S oa p s c an be us ed to p r e pa r e o / w o r w/ o em uls i on s f o r e xt e r n a l p r ep a ra t i on s . 4 . N o ni o n ic em u ls i f yi n g a ge n t s c an be us ed for o / w a n d w/ o e m u ls i on s. D . F o r ma t i o n a nd p r ep ar a t i o n o f em u ls i o ns . The p r oc ed u re f or p re p ar i ng a n e m ul si o n d ep en ds on t he d es i r ed em ul si f y i ng ag en t i n th e fo r m u la t io n . 1 . A m o r t a r a n d p es t l e a r e f re qu e nt l y al l th e e qu i pm e nt th a t i s n ee de d . a . A m o r ta r wi t h a r o ug h s u r f ac e (e . g. , W ed g wo od ) sh o ul d b e u se d . Th i s ro u g h s u r fa ce al l o ws m a xi m al d i s p e rs io n o f gl ob u le s t o p r o du c e a f in e p a r ti cl e s i z e . b . A r ap i d m o t io n i s e s s e n t ia l wh e n t r it u ra t in g a n e m u ls i on us in g a m o r ta r a n d p e st l e. c . Th e m o rt a r s ho u ld be a b le t o h ol d a t l e as t t h ree t im es th e q u a nt i t y b e i n g m a de . Tr i t u r a ti o n s el do m r e qu i re s m o re t ha n 5 m i n t o c re a t e t he em ul s i o n. 2 . E le c t r ic m ix e r s a nd ha n d h om o ge ni z e r s a r e us e fu l fo r p r o du c i ng em u ls i on s a f te r t h e c oa r s e em ul s i o n is fo r m ed in th e m o rt a r . 3 . Th e o rd e r of m i xi n g of i ng r e di en t s i n a n em u lsi o n d ep e nd s o n t h e t yp e o f e m ul si o n b ei ng p re p ar e d ( i . e. , o/ w o r w/ o ) a s we l l a s t h e em u ls if y i n g a ge nt c ho s e n . Me t h o d s u s ed fo r c om p ou n di n g i nc lu d e t he f ol lo wi n g : a . D r y g u m ( c o n ti n en t al ) m e th od is us ed fo r fo r m in g em ul s i o ns u s i n g n at ur a l e m ul si f y i ng ag e nt s a nd re q ui r es a s pe c i f ic o r d er o f m i xi n g . b . W et g um ( E ng li s h ) m e t h od is u se d fo r fo r m i ng e m u ls i on s us i ng na t u ra l e m ul si f y i ng ag e nt s a nd re q ui r es a s pe c i f ic o r d er o f m i xi n g . c . B o t tl e m e t ho d i s u s ed f o r f o rm in g e m u ls i on s u s in g n a tu r al em ul si f yi ng a g en ts a n d re qu i r es a s p ec i fi c or d e r o f m i xi n g . d . B e ak e r m e t ho d i s u s e d to p re p ar e e m ul si on s u s in g s yn t he ti c e m u ls i f yin g ag e nt s a n d p r od uc e s a s at is f ac to r y p r ep a r at i on r eg a rd l es s o f t h e o r de r of m i xi n g. 4 . P r es e r va t i ve s . I f th e e m ul s i o n is k e pt f or a n ext e n d e d pe r io d o f ti m e , r e f r ig e r at i on i s u s u a ll y s u f f ic ie n t. Th e p re pa r a ti on sh o ul d n o t b e f r o zen . If a p r e se r va ti v e is us ed , i t m us t be s o lu bl e i n th e wa t e r p h as e t o b e e f fe ct i ve .
5 . F la vo r i n g a g en t s . I f th e ad di t io n o f a f la v o r is n e ed e d t o m a sk th e ta s te o f t h e o il p h as e , t he f la v o r s h ou ld b e ad d ed to th e e xt e r n a l p h as e b ef o r e em u ls if ic at i o n ( Ta b le 5-3). E . E x am p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Mineral oil
18 mL
Acacia
qs
Distilled water, qs ad
90.0 mL
Sig:
1 tablespoon q.d.
b . C o mp o u nd i n g p r o ced u r e . W ith t he dr y g um m e th o d, an in i ti a l em u ls io n ( pr im a r y e m ul si o n) is fo r m e d , us in g 4 p a rt s ( 1 8 m L ) of oi l , 2 pa r ts ( 9 m L) o f wa t e r , a n d 1 pa r t ( 4 . 5 g ) of po wd e r e d a c a c i a . Th e m i n e ra l o il is t ri tu r a t ed wi t h t h e a ca c i a i n a W edg wo o d m o r t a r. Th e 9 m L o f wa t e r is ad d ed al l a t on c e an d , wi t h r ap i d tr i t u ra t io n , f o r m t he p ri m a r y em u ls ion , wh i c h is t ri t u ra t ed fo r a b o ut 5 m i n . Th e r em ai n in g wa t e r i s i nc o r po r at e d i n s m al l a m ou n ts wi t h t r i tu r a ti on . Th e e m u ls i on is tr a ns fe r re d to a 9 0 - m L pr e s c ri p ti o n b ot t le, a nd a “ s h a ke we l l ” l ab el is at t ac h ed to th e c o nt ai n e r.
Table 5-3. Flavor Selection Guide Taste
Masking Flavor
Salt
Butterscotch, maple
Bitter
Wild cherry, walnut, chocolate mint, licorice
Sweet
Fruit, berry, vanilla
Acid
Citrus
P.107
2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Olive oil
30 mL
Zinc oxide
8g
Calamine
8g
Lime water
30 mL
b . C o mp o u nd i n g p r o ced u r e . Th e o li v e oi l i s p lac e d i n a s ui t ab l y s i z e d be a k e r . U s i ng an el ec t r ic m i xe r , t h e z in c o xi d e , th e c al am i n e , a nd th e l im e wa t e r ar e a dd ed i n th a t o r de r . Th is y ie l ds a w/ o em u ls io n . Th i s p ro c ed u re is k n o wn as th e n a sc en t s o ap m e th o d . Th e ol i v e o i l r e ac ts wi t h th e c al ci um h y d ro xi d e s o l ut i on (l im e wa t e r ) a n d f o rm s a s o ap . F o r t hi s re ac t io n t o o c c u r , f r es h l im e wa t e r (c a lc iu m h yd r o xi d e s o lu t io n ) i s r eq u i re d . A s m a ll qu an t i t y o f ol ei c a c id ca n a ls o b e a d de d to fu r t h er s t ab i li ze th e e m u ls i on . 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Mineral oil
50 mL
Water, qs
100 mL
Sig:
2.5 mL p.o. h.s.
b . C o mp o u nd i n g p r o ced u r e . Us in g a co m b in a tio n of no n io ni c e m u ls i f y ing a ge n ts , s uc h a s Sp a n 4 0 a nd Tw e e n 4 0 , t he c o r r ec t h y d ro p hi l ic - li po p hi li c b al a nc e ( H L B ) is o b t ai ne d . Ne xt , t h e m in er a l o i l is wa r m ed in a wat e r ba t h t o a bo u t 6 0 ° C , an d th e S p a n 4 0 i s d is s o l v ed in th e he a te d m in e ra l o i l. The wa t e r is wa r m ed to abo u t 6 5 ° C , a n d t h e Twe e n 4 0 i s d is s o l v e d i n t h e h ea t ed wa t er . Th i s m i xt u r e i s a dd e d t o t he
m i ne r al oi l a n d d is s o l v ed S p a n 4 0 a nd s t i r re d u n til co o le d . A n “e xt e r n a l u s e o nl y ” l a be l i s a dd e d t o t h e c o nt a i ne r .
VI. POWDERED DOSAGE FORMS A. D e f i n i t i o n. P ow de r s a r e i n ti m a t e m i xt u r es o f d r y, f in e l y d i v i de d d r ug s a n d /o r c h em ic al s t ha t m a y be int e n de d f o r i n te r na l (o r al p o wd e r s ) o r e xt e r n a l (t op i c a l p o wd e r s ) u s e . Th e m aj o r t y p e s a r e p o wd e r p ap e rs , bu lk po wd e r s , a nd in s u f f la t io ns . B . G e n e r al ch a r ac t e r is ti c s 1 . P o wd e r d os a ge fo r m s a r e us ed wh e n d r u g s t ab i l i t y o r s o l u b i li t y i s a c o n ce r n . Th e s e d os a ge f or m s m a y a ls o b e u s e d wh e n t h e p o wd e r s a r e t o o b ul k y to m ak e i n to c a ps ul es an d wh e n t h e pa t i en t h as di f fi c ul t y s wa l lo wi n g a c ap s u l e. 2 . S om e d i sa d va n t ag e s t o po wd e r s i nc l ud e u n pl ea s an t - ta s ti ng m e di ca t io ns an d , o cc a si on a ll y , th e ra p id de t e ri o r at i on of po wd e r s . 3 . B l en d i ng of po wd e r s m a y be ac co m p l is he d b y u si n g t r it u r at i on i n a m or t a r , s t i r ri ng wi t h a s p a tu l a, an d s i f ti ng . G eo m e t r ic d i lu t i on s h ou l d b e us e d i f ne e d ed . W hen h ea v y p o wd e r s a re m i xe d wi t h l ig h te r on es , t h e h ea v i e r p o wd e r s hou l d b e p l ac e d o n t op of t he li gh te r o ne an d t h en bl en d ed. W hen m i xi n g t wo o r m or e p o wd e r s , e ac h p o wd e r s h o ul d b e pu l v e ri z e d s epa r a t el y t o a bo u t t h e sa m e p a rt ic l e s i z e b e fo r e b l en di n g t oge t h e r. a . Th e m o r ta r a n d p es t le m e th od is pr e fe r r e d wh e n p u l ve r iz a ti o n a n d a t ho r o ug h m i xi n g of in g r ed ie n ts ar e d es i r ed (g e om e tr ic di l ut i o n ) . A W edg wo o d m o rt a r i s p r e f er a bl e , b ut gl as s o r p o r c e la i n m a y a ls o b e u s e d . b . Li g ht po wd e r s ar e m i xe d be s t b y us in g t h e s i f ti n g me t h od . Th e s if t in g i s r e p ea t ed t hr e e t o f o u r t im es t o e ns u re th o ro u gh m i xi n g of t he po wd e r s . C . P r e p a ra t i on o f p ow de r d o sa g e f o r ms 1 . B u lk p ow de r s , wh i c h m a y be us e d i nt e rn a ll y or t o pi c a ll y , i nc lu d e d us tin g p o wd e r s , d ou c h e p o wd e rs , la xa t i v e s , a n ta ci ds , a nd i ns uf f la t io n p o wd e r s . 2 . A f te r a b ul k p o wd e r ha s b e en pu l v e ri z e d an d b l en d e d , i t s h ou l d b e di sp e ns e d i n a n ap p ro p r ia t e c o n ta i ne r. a . H yg r o s c o p i c o r e f f e rve s c e n t s al ts sh ou l d a l wa ys be pl a ce d i n a ti gh t , wi d e m o ut h j a r . b . D u s ti n g p o wd e rs s h ou l d b e p la c ed i n a co n ta in e r wi t h a s i f te r to p . P.108
3 . E u te c t ic mi x t u re s o f p o wd e r s c an c a us e p r ob le m s be c au s e th e y m a y l iq u e f y . O n e r em ed y i s t o a dd an i n er t po wd e r , s uc h as m a g n es iu m o xi d e , t o s e par a t e t h e e u t ec ti c m at e ri a ls . 4 . P ow de r p ap e r s a r e a ls o c al l ed di vi d ed po wd e rs . a . Th e en ti r e p o wd e r is in i t ia ll y b le n de d . E ac h d os e i s t h en in di v i d ua ll y w e i gh e d. b . Th e do s a g e sh o ul d b e we i g h e d, th e n t r an s fe r re d on t o a p o wd e r pa p er a n d f o ld e d. Th i s t ec hn iq u e r e qu i re s p r a c t ic e . H yg r o sc op ic , de l i q u es c e n t, an d e f fe r v es c e n t p o wd e r s re qu i r e t he us e o f gl as si n e p ap e r a s a n in s id e l in i ng . Pl as t ic ba gs o r e n ve l op es wi t h s na p - an d- s e al c l os ur e s o ff e r a c on v e n i en t a l te r na t i v e t o po wd e r p a p er s .
c . Th e f o ld e d p ap e rs ar e d is p en s e d i n a po wd e r b o x o r o t he r s u it a bl e c ont a i ne r ; h o we ve r , t he s e c o n ta i ner s a re no t c hi l d r es is t an t. D . E x am p l es 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Camphor
100 mg
Menthol
200 mg
Zinc oxide
800 mg
Talc
1.9 g
M foot powder Sig:
Apply to feet b.i.d.
b . C o mp o u nd i n g p r o ced u r e . Th e c am ph o r a nd m e nt h ol a re t ri t ur a te d tog e t he r in a g l as s m o r t a r, wh e r e a li qu i d e u te c t ic is fo r m e d . Th e zi nc o xi d e a nd t al c a re b le nd e d a n d m i xe d wi t h th e e u te c t i c , us i ng ge om e tr ic di l uti o n . Th i s m i xi n g r es u lt s in a d r y p o wd e r , wh i c h is pa s s ed t h r ou g h a wi r e m es h s i eve . Th e f in al p re p a ra t io n i s d i sp e ns ed in a c o n ta i ne r wi t h a s i ft e r to p . 2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Citric acid
0.3 g
Sodium bicarbonate
0.25 g
Psyllium mucilloid
2g
Powdered flavor, qs M. Ft d.t.d. charts v
Sig: Empty the contents of one chart into a glass of water and take h.s.
b . C a lc u la t i o ns . Ca lc u lat e f or on e e xt r a p o wd e r p a p er :
Citric acid 0.3 g × 6 doses
=
1.8 g
Sodium bicarbonate 0.25 g × 6 doses
=
1.5 g
Psyllium mucilloid 2 g × 6 doses
=
12 g
Total wight
=
15.3 g
15.3 g/6 doses
=
2.55 g/dose
N o t e : Al s o c o ns id e r t h e we i g h t of t he po wd e r e d fl a v o r . c . C om p o un d i ng p r oc ed u r e . Th e i ng r ed i en ts a re f i rs t p ul v e r i z e d a nd we i g he d . Th e c i t ri c ac i d a nd s o di um bic a r bo na t e a r e m i xe d to ge t h e r f i rs t; t he ps y l li um m uc i ll oi d i s t h e n a dd e d a lo ng wi t h the p o wd e r ed fl a vo r , us i ng g e om et r ic di l ut io n . Ea c h d os e ( 2 . 5 5 g ) o f t h e r es u lt a nt m i xt u r e is we i gh e d a nd pl a ce d i n to a p o wd e r p a pe r . Th is p r e pa r a ti o n is an ef f e r v es c e n t p o wd e r . W hen di s s o l v e d i n wa t e r, t he c i t ri c a c id an d s o di um bi c a r bo n at e re ac t t o f o rm c a r bo n ic a ci d , wh i c h yi el ds c a r bo n d i o xi d e , m a k i n g t h e s ol u ti o n m o r e p a la t ab l e .
VII. CAPSULES A. D e f i n i t i o n. C a ps u le s a r e s ol i d d os ag e f o rm s in wh i c h t h e d ru g i s e nc los e d wi t h i n e i t he r a h ar d o r s o f t s o l ub l e c on t ai n er o r s h e ll . Th e s h el ls a re us ua ll y m ad e f ro m a s u it a bl e g el a ti n . Ha r d g el a t in c a ps ul es m a y b e m a n u al l y fi ll e d f o r e xt e m po r a ne o us c om p ou n di ng . P.109
Table 5-4. Approximate Amount of Powder Contained in Capsules Capsule SizeRange of Powder Capacity (mg) No. 5
60-130
No. 4
95-260
No. 3
130-390
No. 2
195-520
No. 1
225-650
No. 0
325-910
No. 00
390-1300
No. 000
650-2000
B . C a p su l e s iz e s 1 . A l is t of c a ps ul e s i z es a n d t he ap p r o xi m at e a m o u n t o f p o wd e r th a t m a y b e c o nt a in e d i n t he c a ps ul e a p pe a r o n t h e si d e o f t he ca ps u le bo x ( Ta b l e 5 - 4) . 2 . C ap s ul e s i z es f o r o r a l a dm i ni st r a ti o n in hu m ans r an g e f r om n o . 5 , t h e s m a ll es t , t o n o . 0 0 0, t he la r ge s t. 3 . N o . 0 i s u s u al l y t he lar g e s t o ra l s i z e s u i ta b le fo r h um an pa t ie n ts . 4 . C ap s ul es fo r v e te r i na ri a ns a re a v ai la b le in no . 1 0 , n o . 1 1 , a nd no . 1 2 , c o n t ai ni n g a p p ro xi m a t el y 3 0 , 1 5, and 7 .5 g , r es p ec ti v e l y . C . P r e p a ra t i on o f h a r d a n d s o f t c a ps u l es 1 . A s wi t h th e b u lk p o wd e r s , a ll in g re d ie n ts a r e t ri t u ra t e d a nd bl en d ed , u sin g g e om e t ri c d il u ti on . 2 . Th e c o r re c t s i z e c a ps u l e m us t b e d e te r m i ne d b y t r y i n g d if f e re n t c ap su le s i z e s , we i g h i ng t he m , an d t h en c ho os i ng th e a p p ro p ri a te s i z e . 3 . B ef o r e f il li n g c ap s u le s wi t h t h e m e d ic at i on , t h e b o d y a n d c ap of th e c a ps u le a re s e pa r a te d . F il li n g is ac c o m pl is h ed b y u s i n g t he “p u nc h ” m et h od ( Al t e rn a tive l y, sm a ll c a ps ul e m ac hi n es a r e c om m o n l y u s e d to p re pa r e u p to 30 0 c ap s ul es at a ti m e, e xt e m p o r an e ou s l y ) . a . Th e po wd e r f or m u l at i on is c o m p r es se d wi t h a sp a t ul a o n a pi ll ti l e o r p ap e r s h ee t wi t h a un i fo r m d ep t h o f ap p r o xi m a te l y ha l f t he le ng t h o f th e c ap s u l e b od y.
b . Th e em pt y c ap s u l e b od y i s r e pe a te d l y p r es se d i n to th e po wd e r un t il fu l l. c . Th e c ap s u l e is t he n we i gh e d t o e ns u re an ac c u r a t e d os e. A n em p t y ta re c a ps u le o f t he s am e s i z e i s p la c ed o n t he pa n c o nt ai n in g th e we i g ht s . 4 . F or a l a rg e n um b er o f c a ps ul es , c a ps ul e -f i ll in g m ac h in es ca n b e u se d f or sm a ll s ca l e us e to s a v e ti m e . Mo s t c om m o n l y, c ap s u l es m a c h in e s a re us e d c a pa b le o f p r e pa r i ng 10 0 t o 3 0 0 c ap s ul es at a t im e . 5 . Th e c a ps ul e i s wi p e d c l ea n o f a n y po wd e r o r oi l an d d is pe n s e d i n a s u it a b le p r e sc ri p ti o n v i a l. D . E x am p l es 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Rifampin
100 mg
dtd #50 Sig:
1 cap p.o. q.d.
b . C a lc u la t i o ns . Co m p ou n d t h is p r es c ri p ti on us in g th e c om m e r c i al l y a v ail a bl e 3 0 0 m g c ap s ul es as t h e d r ug s ou r c e . C al c u la t e f o r a t l e as t o n e e xt r a c ap su le .
51 caps × 100 mg/cap
=
5100 mg rifampin
5100 mg rifampin ÷ 300 mg/cap
=
17 caps
P.110
c . C om p o un d i ng p r oc ed u r e . Us e 1 7 ri fa m pi n c ap s ul es , e a c h c o nt a in in g 3 0 0 m g r i f am pi n . Th e c o n te n t o f e a c h c a ps ul e i s e m p t ie d , a n d t he po wd e r is we i g he d . Th e p o wd e r e qu i v al e nt t o 1 00 m g r if am p in is p l ac ed in a c ap s ul e ( e .g . , i f th e to t a l c o nt e nt s o f o n e c a p s u le we i g h 3 60 m g ; t h en 10 0 /3 0 0 = x / 3 60 ; x = 1 20 m g o f ac t i v e d r u g p o wd e r re q ui r ed f rom t he c a ps ul e c on t en t s to p r o vid e 1 00 m g ac ti v e d r u g ) a nd s u f fi ci en t la c t os e a d de d t o fi l l t he c a ps ul e . Th e to t a l f il le d c a ps ul e c on t en t s we ig h 2 0 0 m g. Th e we i g ht of t he ac t i v e d r ug po wd e r is s u bt r ac t ed f ro m 2 00 m g t o ob t ai n t h e a m o u nt o f l ac to s e r eq u i re d p e r c ap s u l e, wh i c h i s 20 0 m g - 12 0 m g = 80 m g . Th is i s m ul t ip li e d b y 5 1 c a ps ul e s . E no u gh la ct os e (5 1 c a ps ul es × 8 0 m g/ c a p = 4 . 0 8 g ) i s a d d ed to m a k e a t ot a l o f 1 0 .2 g o f p o wd e r . Th e po wd e r s a re c om b in e d, usi n g g e om e t ri c d il u ti on , a n d 50 c a ps u le s c an be pu nc he d ou t . E a c h c a ps ul e s ho u ld we i g h 2 0 0 m g ( 1 0. 2 g / 51 c a ps ). 2 . E xa m pl e 2 a . M e d ic a t io n o rd e r . Thi s o r d er is fo r v e te r i na r y u s e o nl y.
Castor oil
8 mL
Disp
12 caps
Sig:
2 caps p.o. h.s.
b . C a lc u la t i o ns . No c a lc u l a ti on s a r e n ec es s a r y. c . C om p o un d i ng p r oc ed u r e . A n o. 11 v e t e ri na ry c a ps ul e i s u s e d . U s in g a c a li b ra t ed d ro p pe r o r a pi p e tt e , 8 m L o f th e o il is c a r ef u ll y a dd ed t o t he ins i de of e a ch c a ps ul e b o d y . Ne xt , t h e lo we r i ns i de po r t io n o f th e c ap is m oi s te n ed , u s i n g a g l as s r o d o r b r us h . Th e c a p a nd bo d y a re jo in e d t o g et h e r, us in g a t wi s ti ng m o t io n , t o f or m a ti g ht s e al . Th e c a ps ul es a re pl ac e d o n a p ie c e of f il te r pa p e r a nd c h ec k ed f o r s i gn s o f l ea k ag e . Th e c ap s u l es ar e d is p en se d i n th e a p p ro p ri a te s i z e an d t ype o f p r e sc ri p ti o n v i a l. Th e y c a n be s t o re d i n a r ef r i ge ra t o r i f d es i r ed .
VIII. MOLDED TABLETS (TABLET TRITURATES) A. D e f i n i t i o n. Ta b le t tr i tu r a t es a r e s m a ll , u s u a ll y c y l in d ri c al m ol d ed o r com p r es s e d t a b le ts . Th e y a re m a de of p o wd e rs c re a te d b y m oi s te n in g t h e p o wd e r m i xt u r e wi t h a l co h ol a n d wa t e r o r b y th e p ro c e ss o f s i nt e ri n g. Th e y c a n b e u s e d f o r c om p ou n di ng p o t en t d r u gs i n s m a ll dos es an d fo r pr e pa r a ti on o f a r a pi dl y d is i nt e gr a ti ng / d iss o l v in g d o sa g e f o rm . B . F o r m ul a t io n a n d p r ep a r a t io n o f t a bl e t t ri t u ra t e s u s in g m o i s te n ed pow de r s
1 . Ta b le t t ri tu r a te s a r e m a d e i n s pe c i a l m o l ds c ons is t in g o f a p eg bo a r d a nd a c o r re s po nd i ng pe r f or a ted p la t e. 2 . I n a dd i ti on t o t he m o ld , a d il u en t , u s u al l y a m ixt u r e o f la c to se an d s uc ro s e ( 8 0 : 20 ) , a nd a m oi s t e ni ng a ge n t, us ua l l y a m i xt u r e o f e t h y l a lc oh ol an d wa t e r ( 6 0 : 40 ) , a r e r e qu i re d . 3 . Th e di lu e nt is t ri tu r a ted wi t h t he ac ti ve in g r ed ie n ts . 4 . A p a s t e i s t he n m ad e , u s i n g t he al c o h ol an d wa t e r m i xt u r e . 5 . Th i s p as te is s p re a d in t o th e m ol d ; t he ta b le ts a r e p u nc he d o u t a nd r em a in on th e p e gs un t il d r y . C . E x am p l e 1 . M e d ic a t io n o rd e r
Atropine sulfate
0.4 mg
Disp
#500 TT
Sig:
u.d.
2 . C a lc u la t i on s . F o r 5 0 0 TT: 5 0 0 × 0 . 4 m g = 20 0 m g a t r op i ne s u lf a te 3 . C o mp o u nd i ng p r oc ed u r e . Th e m o l d p r ep a re s 7 0 -m g t a bl e ts . Th e 2 00 m g o f a t r o pi ne s u l fa t e, 6. 8 g o f s uc r os e , a nd 28 g o f l ac t o se a re we i g he d a n d m ixe d b y g e om e t ri c d il u ti on . Th e po wd e r i s we t wi t h a m i xt u r e of 40 % p u ri f ie d wa t er a n d 6 0% e t h yl a lc o ho l (9 5% ) . Th e p as t e t h at is fo r m e d i s s p r e ad on t o t h e t ab l et t ri tu r a t e m o ld ; th e t a bl e ts a r e t h en p un c h e d o ut o f t he m o ld a nd al lo we d t o d r y o n th e pe gs . Th i s p ro c e d ur e i s re pe a te d un t il th e re q ui r ed num b e r o f t ab l et t ri t u ra t es h a s b ee n p r e pa r e d. P.111
D . F o r m ul a t io n a n d p r ep a r a t io n o f t a bl e t t ri t u ra t e s u s in g si n t e ri n g 1 . Th e se ta b le t t r i tu r a te s a r e m ad e i n s pe c i a l m o ld s c on s i s ti n g o f m a t e ri a ls t ha t c an t o l er a t e h ea t t o a b ou t 1 00 ° C . 2 . I n a dd i ti on t o t he m o ld , a d il u en t , u s u al l y a m ixt u r e o f ac t i v e d r ug an d d i lu e nt , wh i c h m a k e up ap p ro xi m a t e l y 6 5 % o f t h e t ab l et we i gh t , a r e b l en de d to ge th e r . Ma n n i t o l i s g oo d t o u s e in c o m b i na t io n wi t h l ac tos e fo r p a r ti c l e s i z es of 60 - 8 0 m es h f r a ct i on . 3 . Th e m i xt u r e is t r i tu r a te d wi t h p o l yet h yl en e g l yc o l 3 35 0 wi t h a p a r ti cl e s i z e o f 80 1 0 0 m es h f r ac t io n .
4 . Th e po wd e r m i xt u r e is p l ac ed in t o a pp r op r i at e m o ld s a nd li gh t l y ta m p e d. 5 . Th e m o ld s c o n ta i ni ng t h e p o wd e r a re pl ac ed in a n o v e n a t ab o ut 90 ° C fo r 1 0- 2 0 m i n, r em o v ed an d a l lo we d t o c oo l . D e pe n di ng on t h e m ol ds us e d, th e ta ble t s c an be d i sp e ns ed in th e m ol ds or r e m o v e d f r om th e m ol ds an d p a c k ag ed an d l a bel e d . E . E x am p le 6 . M e d ic a t io n o rd e r
Homatropine hydrobromide
300 mg
Mannitol
3.5 g
Lactose
3.47 g
Flavor (dry powder type), qs Polyethylene glycol 3350
3.5 g
7 . C a lc u la t i on s . As p r es e n t ed , th is fo r m u la is fo r 1 0 0 r a pi d -d is s o l v i ng ta bl e t t r i t u ra t es . 8 . C o mp o u nd i ng p r oc ed u r e . Bl e nd th e h om a t rop i ne h yd ro b r om id e , m a nn i t ol , l a ct os e , a nd d r y fl a v o r t og e t he r un t il fi ne an d un i fo r m l y m i xe d . Se p a ra t el y , r e d uc e t h e p a r ti c l e s i z e o f t h e po l y e t h y le n e g l yc o l 3 35 0 to 1 00 - 20 0 m es h f r ac t io n . L i gh t l y b l en d i n th e p ol y e t h y l ene g l yc o l 3 35 0 i n to th e p re v i o us l y bl e nd ed po wd e r s . Pl a ce 1 0 0 m g o f t h e p o wd e r i n to t he c a vi t ie s o f a m ol d (s om e b l is te r pa c k s wo r k we l l ; o t h e r wi s e , o b ta i n a ta bl et t r it u r at e m ol d o r a s pe c i a l m ol d f o r p r ep a ri n g t he s e t a b le ts ) . Pl ac e th e m ol d c o nt a in in g th e p o wd e r i n a n o v e n a t 80 - 90 ° C f or 1 5 - 20 m i n . Th e t im e de pe n ds o n th e m ol d , f o rm ul a ti o n, o v en , e t c . R em o v e f r om th e ov e n a nd p l ac e i n a r ef r ig e r at o r f or a p pr o xi m a te l y 5 m in . Re m o v e f r om th e re f ri g e rat o r an d l e t s e t a t ro om te m p e r at u r e. P a c k ag e a n d l ab e l.
IX. OINTMENTS, CREAMS, PASTES, AND GELS A. D e f i n i t i o ns 1 . O i n tm e n ts , c r e am s , a n d pa s te s a r e s em is ol id d os ag e f o rm s i n te nd e d f o r to pi ca l a p pl ic a ti o n t o t h e s k in o r m uc ou s m em b ra ne s . O in t m e nt s ar e c ha r ac t e ri ze d as b e in g o l ea g in ou s i n n a tur e ; c re a ms a re ge ne r a ll y o / w o r w/ o e m u ls io ns , an d pa s t es a r e c h ar a c t e ri z e d b y t h eir h ig h c o nt e nt of s o li d s (a b o ut 25 % ) . 2 . G e ls (s o m e ti m es c al l ed j el li es ) a re s em is o li d sy s t e m s c on si s ti n g o f su s p e ns i on s m a de up of ei t he r s m al l in o r ga n ic p a r ti c l es o r l arg e o rg an ic m o le cu l es i n t er p en e t ra t ed b y a li q ui d . B . G e n e r al ch a r ac t e r is ti c s . Th es e d os ag e f o rm s a r e s em is ol i d p re p a ra t ion s g e n er a ll y a pp li e d e xt e r na l l y . Se m i s o li d do s a ge fo r m s m a y c o n ta i n ac t i ve d r u gs i n t en de d to :
1 . A c t s o le l y on th e s u r fa c e o f t h e s k in t o p ro d uce a l oc a l e f fe c t ( e. g . , a nti f u ng al a g e nt ; to pi c a ls ) 2 . R el e as e t h e m e d ic at i on , wh i c h , in tu r n , p en e t ra t es in t o t h e s k in ( e. g . , h yd r o co r ti s on e c r ea m ) 3 . R el e as e m ed ic a ti on f or s y s te m i c a bs o rp t io n t h ro u g h t he s k i n (e . g ., ni t r og l y c e ri n ; t r a ns d er m al s ) C . T yp e s o f o in t me n t ba s e s 1 . H yd r op h ob ic ba s e s f ee l gr e as y a nd c o nt a in m ixt u r e s o f f a ts , o i ls , a nd wa xe s . H yd r o p h ob ic ba s e s c a n no t be wa s h ed of f u s i n g w a t e r . P.112
2 . H yd r op h il ic ba s e s a r e u s ua ll y e m u ls i on ba se s . Th e o / w- t y p e em u ls io n ba s es c a n b e ea si l y wa s he d o f f wi th wa t e r , bu t t h e w/ o t y p e i s s li gh t l y m o re di f fi c ul t t o r em o v e . D . P r e p a ra t i on o f o i n tme n t s , c r ea m s, p as t es , an d g el s 1 . Mi xi n g c a n b e d on e i n a m o r ta r o r o n a n o in tm e n t s la b o r ti l e o r u s i n g a n oi n tm en t m i ll . 2 . Li q ui ds a re in c o r po r a te d b y g r a du al l y ad d in g th e m t o a n a bs o rp t io n - t y pe b as e a nd m i xi n g . 3 . I ns ol ub l e p o wd e rs a re r e d uc ed to a f in e po wd er a n d t he n a d de d t o th e b a s e , u s in g g e om et r ic di lu t io n . 4 . W at e r -s ol u bl e s ub s t a nc es a re di s s ol ve d wi t h wa t e r a n d t he n i nc o r po r ate d in t o t he b a se . 5 . Th e fi na l p r e pa r a ti on s h ou l d b e s m oo t h ( im p alp a bl e ) a n d f r ee of an y ab r a si ve p a r ti c l e s . E . E x am p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Sulfur Salicylic acid, aa
600 mg
White petrolatum, ad
30 g
Sig:
Apply t.i.d.
b . C o mp o u nd i n g p r o ced u r e . Th e p a rt ic l e s i z e s o f t he s u lf u r a nd s a li c y lic ac id a re r e d uc ed s e p ar a te l y in a W edg wo o d m o r t a r a nd the n bl en d ed t og e th e r. U s in g a p il l t i l e, th e p o wd e r m i xt u r e is le v i g at e d wi t h t he ba s e. U s in g g e om et r ic di lu t ion , t he
b a se an d p o wd e r s a r e b le n d ed to th e fi na l we i gh t. A n o i nt m e n t j a r o r p l as ti c tu be is u s ed fo r di s p e ns in g , a nd a n “e xt e r n a l u s e on l y” la b el is pl ac e d o n t he c on t a in e r . c . Al t e r n a te me t h od . Sup p os e y ou ha v e s u l fu r 5% i n wh i t e p e t ro l at um oin t m e n t a nd a sa l ic y l ic a c i d 5 % o i nt m e n t . How c an yo u p r e p a r e t h e p r e sc r i p ti o n u s in g t he s e a n d di l u ti n g w i th w h i te p e t r o la t u m?
H o we ve r , s i nc e we a r e us i ng t wo di f f er e n t 5 % oi nt m en t s, 2 p a rt s o f e ac h , t h is l e a ves 1 p a rt f or t he wh i te p et r o la t um . A t ot al o f 5 p a r ts i s t o b e u se d to m a k e 3 0 g ( 6 g p e r p a rt ) : 2 p ar t s ( 12 g ) o f th e s ul f u r 5% , 2 pa r t s ( 1 2 g ) o f th e s al ic y l ic ac id 5% , a n d 1 pa r t (6 g ) o f t he wh i t e p et r ol a t um c ou l d b e u s ed . To c h ec k :
12 g × 0.05
=
600 mg of sulfur
12 g × 0.05
=
600 mg of salicylic acid
12 g + 12 g + 6 g
=
30 g
2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Methylparaben
0.25 g
Propylparaben
0.15 g
Sodium lauryl sulfate
10 g
Propylene glycol
120 g
Stearyl alcohol
250 g
White petrolatum
250 g
Purified water
370 g
Disp
60 g
Sig:
Apply u.d.
P.113
b . C a lc u la t i o ns . Th e q ua n t it y o f e ac h i n gr e di e nt r e q ui r e d t o p r ep a re 60 g i s o b t ai ne d as f o ll o ws . Th e m ed ic a ti o n o r de r i s f o r 1 0 0 0 g ; t he r e fo r e , t he m u l t ip li c a t io n f a c to r i s 6 0 /1 0 00 = 0 .0 6 .
0.25 g × 0.06
=
0.15 g methylparaben
0.15 g × 0.06
=
0.009 g propylparaben
10 g × 0.06
=
0.6 g sodium lauryl sulfate
120 g × 0.06
=
7.2 g propylene glycol
250 g × 0.06
=
15 g stearyl alcohol
250 g × 0.06
=
15 g white petrolatum
370 g × 0.06
=
22.2 g purified water
S i n ce th e 0 . 00 9 g o f p rop y l p a ra b en is to o sm a ll to ac c u r a te l y we i g h, a d ilu t i on c a n b e p re pa r e d as f ol lo ws , a s s u m i ng a m i n im um we ig h a bl e q ua n ti t y o f 1 20 m g . W ei gh 1 2 0 m g o f p r op y l p a ra be n a n d a dd to 40 m L of p rop yl e n e gl yc o l, r es ul t in g in a p r o p ylp a r ab en c o nc e nt r at i o n o f 3 m g /m L. Ta k e 3 m L o f th is s o lu t io n t o o b ta i n t h e p r o p ylp a r ab en an d s u bt ra c t t h e 3 m L f r om th e q ua n t it y o f p r op yl e ne gl yc ol r eq u i re d i n th e f o rm u la . c . C om p o un d i ng p r oc ed u r e . Th e s te a r y l a lc oh ol a nd th e wh i te pe t r ol a tum a re m e lt e d o n a s t ea m b at h a n d h e at e d t o a bo u t 7 5 °C . Th e o th e r i ng r e di en t s , p r e v i ou sl y d i ss ol ve d i n p u ri f ie d wa te r a t a bo u t 7 8 ° C, a re add e d . Th e m i xt u r e is s t i r re d un t il it c o ng e al s . A n o in tm e nt jar i s us e d f o r d is pe ns i ng , a n d a n “e xt e r n a l u se on ly ” l a b el i s p l ac e d o n t he ja r . 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Scopolamine hydrobromide
0.25%
Soy lecithin
12 g
Isopropyl palmitate
12 g
Pluronic F-127 20% gel, qs
100 mL
Sig:
Apply 0.1 mL t.i.d.
b . C a lc u la t i o ns . Th e q ua n t it y o f s co po l am in e h y d r o b ro m i d e r eq u i re d f o r th e p r e sc ri p ti o n wi l l be 0 . 0 02 5 × 10 0 m L = 0. 2 5 g o r 2 5 0 m g
c . C om p o un d i ng p r oc ed u r e . Mi x t h e s o y l e ci th in wi t h t he is op r op y l pa lm i t a te . D i s so l v e t h e s c op o la m i ne h y d r ob r om id e i n a b ou t 3 m L o f p ur i fi e d wa t e r and a dd to a b o ut 70 m L o f th e Pl u ron i c F - 12 7 g e l. A dd th e so y l ec i th i n -i s o p ro p yl p a lm i ta t e m i xt u r e , a n d m i x we l l . Ad d s u f fi c i en t Pl u r on ic F -1 2 7 g el t o v o l um e, an d m i x we l l u s in g a s h ea r in g te c h ni qu e . Pa c k ag e a n d l ab e l.
X. SUPPOSITORIES A. G e n e r a l ch a r ac t e r is ti c s 1 . S up p os it o ri e s a re s ol id b o di e s o f v a ri ou s we i gh t s a nd sh a pe s , ad a pt e d f o r i n t ro d uc t io n i n to th e re c ta l , v ag i na l , o r u r e th r al o ri f ic es o f t he hu m a n b o d y. Th e y a r e u s ed to de l i v e r d ru g s f o r t h ei r lo ca l o r s ys t em ic ef f e ct s. 2 . S up p os it o ri e s di f f e r i n s i z e an d s h ap e a n d i nc lu d e a . R ec t al b . V ag i na l c . U r et h ra l B . C o m mo n s u p po s i to r y b a s e s 1 . C o co a b u t t e r ( t he o b ro m a o il ) , wh ic h m el t s a t b o d y te m p e r at u r e, is a fa t - s o l ub le m i xt u r e of t ri g l yc e r id es th a t i s m os t o f te n u s e d f or r e c t a l s u p po si t o ri es . W i t e ps ol is a s yn th e ti c t r ig l y c e r id e . F a t t y ac id ba se s i nc lu d e F a t ti b as e . 2 . P o l ye t h yl e n e g l yc o l ( P E G , c a rb o wa x) d e r i v a t iv e s a re wa t e r -s o lu b le bas es s u it a bl e f o r v ag i na l a nd re c ta l s up p os it o r ie s . P ol y b a s e is a n e xa m p l e . 3 . G l yc e r i n a t e d g el a t in i s a wa t e r -m is ci b le ba se o f t en us ed in v a gi n al and r ec t al s u pp os i to r ie s . P.114
C . S u p po s i to r y m o l d s 1 . S up p os it o r y m o ld s c an b e m a d e o f r u bb e r , p las t ic , b r as s , s t a in le s s s t ee l , o r ot h e r s u it a bl e m at e r ia l. 2 . Th e fo r m u la t io n a n d v o l um e o f th e b as e d e pe nd o n t he s i z e of t he m o ld u se d , l e ss th e d is pl ac e m e n t c au s ed b y th e a c t i ve i n g red i e n t . D . M e th o ds o f p r e pa r i ng a n d d is p e ns i ng s up po s i t o r ie s 1 . M o l de d su p po s i to r i es a r e p re p a re d b y f i rs t m e l t in g t h e b as e a nd th e n i n co r po r a ti n g t he m e di c at i o ns u n if o rm l y in t o t he ba s e. Th i s m i xt u r e is t he n p o u re d i n t o t he s u pp os i to r y m old ( f us io n m et h od ) . 2 . H a nd - r o l le d s u p po s i to r i e s re qu i r e a s pe ci a l te c hn i qu e . W ith p r o pe r tec h ni q ue , i t i s p os si b le to m a k e a p re p a ra t io n e q ua l i n q u al ity t o t he m o ld e d su p po s i to r i es . 3 . C o n ta i ne r s fo r t h e su p p o si t o r ie s a r e d e te r m i n ed b y th e m e th od a nd b a se us ed i n pr e pa r a ti o n. H an d - ro l le d an d m ol d ed s u pp os i tor i e s sh o ul d b e d is pe n se d i n s p ec ia l b o xe s t ha t p r e v en t t he s u pp os i to r ie s f r om c om in g i n c on t ac t wi t h ea c h o th e r . S u p po si t o ri es m a de us ing p la s t ic st r ip m o ld s a r e e a s i l y di s p e ns ed in v a ri ou s t y pe s o f pa ck a ge s . 4 . S t o ra g e c o nd i t i on s . If a pp r o pr i at e , a “ re f r ig e ra t e ” l a be l s ho ul d a p pe a r o n th e c o nt a in e r . R e ga r dl es s o f t h e b as e o r m e di c a t io n u s ed in th e fo rm u la t io n , t h e p a ti e nt s h ou l d b e i ns t ru c t e d t o s t o r e t h e su p po s i t o ri es in a co o l, d r y p l ac e .
E . E x am p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Naproxen suppository
500 mg
Disp
#12
Sig:
Insert u.d. into rectum
b . C a lc u la t i o ns . Ea c h s ta n d ar d a d ul t s up p os it o r y s ho u ld we i g h 2 g , bu t i t d e p en ds o n th e m ol d u s e d a n d s ho u ld be c a li b r at e d b ef o re c o m p o un d in g . A ls o , t he d i sp la c em en t m us t b e d et e r m i n ed fo r th e a d de d po wd e r . 2 g (t o ta l we i gh t ) - 0 .5 4 0 g ( we i g ht of b as e d is pl ac e d b y t he 50 0 -m g t a bl e t) p e r s u pp os i to r y
=
1.46 g cocoa butter per suppository × 13 suppositories
=
18.98 g cocoa butter
c . C om p o un d i ng p r oc ed u r e . Th e 1 3 n ap r o xe n 50 0 - m g ta b le ts a re t ri t u ra te d to a f i n e p o wd e r , us i ng a W ed g wo o d o r p or ce l ai n m o rt a r . Th e 1 8 .9 8 g c oc o a bu t t e r b as e i s m el t ed in a b ea k e r , u s i n g a wa t e r b a th . Th e t em p e ra t ur e o f th e wa t e r ba t h s ho u ld n o t e xc e e d 36 ° C . Th e p owd e r i s th en ad d ed an d s t i r re d u n ti l m i xe d . Th e m i xt u r e is p o u re d i n to an ap p r op r iat e r ec ta l s up p os i to r y m o ld ( a bo u t 2 g pe r s u pp os it o r y) a nd p l ac e d in t o a r ef r ig e r at o r u n ti l t h e s up po si t o ri es c o n g ea l. A n y e xc e s s i s s c r a p ed f r o m t he t op of t he m o ld , a n d a s up p os it o r y bo x i s us ed f o r di s pe ns in g . A “ r e f r ig e ra t e ” l ab e l is pl ac e d on th e b o x. 2 . E xa m pl e 2
a . M e d ic a t io n o rd e r
Progesterone
50 mg
Disp
#14
Sig:
1 per vagina once daily on days 14-28 of cycle
b . C a lc u la t i o ns . To ta l we i gh t of ea c h v a gi n al s up p os i to r y is 1. 9 g. As s um i ng 50 m g p r o ge s te r on e d is p la c e s 5 0 m g P E G b as e : 5 0 m g p r o ge s t e r on e /s upp o s i t o r y × 15 = 7 5 0 m g pr o g es t er o ne 1 . 9 g ( to t al we i g ht ) - 0 . 05 0 g p r og es t e ro ne = 1 .8 5 g P E G × 1 5 s up po s it o ri e s = 2 7. 7 5 g P E G to t al P.115
c . C om p o un d i ng p r oc ed u r e . Th e P E G is m e lt e d t o 55 - 57 ° C , a n d 7 50 m g p r o ge s te r on e i s a dd e d. Th i s m i xt u r e is po u re d i nt o a v ag in a l su p po s i t o r y m o ld , a l lo we d t o c oo l , c l e an e d, a n d d is pe ns e d.
XI. PARENTERAL PREPARATIONS A. G e n e r a l r e qu i r em e n ts . Th e e xt e m p o r an eo us c om p ou n di ng o f s te r il e pr e p a ra t io ns o cc u rs in m a n y ph a rm ac y e n v i r o nm en ts , in cl ud i ng co m m un i t y, h om e h e al th c a re , h o sp i ta l , a nd nu c l e ar . Mi n i m u m r e qu i re m e n ts i n c lu d e 1 . P r op e r e qu i pm en t a n d s up p li es 2 . P r op e r f ac il i ti es , in c l ud i ng a l am in a r - fl o w c le an b en c h an d a cl ea n ro om o r i s ol a ti on ba r r ie r t ec hn ol og y e q ui pm e nt 3 . P r op e r d oc um e nt a ti on o f al l p r ep a ra t io ns m a de 4 . Q u al i t y c on t r ol , i nc l udi n g b a tc h s te r il i t y te s t i ng 5 . P r op e r s to r ag e bo t h at t h e f ac il i t y a n d i n t r an sp o r t t o th e p a ti en t ' s h om e 6 . P r op e r l ab e li ng o f t he p r e s c ri p ti o n p r ep a ra t io n 7 . K no wl e d g e o f p r od uc t 's / p re p ar a ti o n 's s t a bi li t y a n d i nc om p at i bi li t ie s 8 . K no wl e d g e o f a ll an c i ll a r y e qu ip m e n t i n v ol ve d in c o m p o un d in g o r de li v er y o f t he m e di ca t io ns B . C o m po u n di n g o f pa r e n t e r al p r ep a r a ti o ns
1 . C om p ou nd i ng of s t e ri le p r ep a ra t io ns , i nc l ud i ng i n t ra v e n ou s a dm i xt u r es , r e q ui r es s p ec ia l s k i ll s a nd t ra i ni ng . C om p ou nd i ng pa r en t er a l p r e pa r a ti on s o r p r o v id i ng t hi s s e r vic e wi t ho u t p r op e r t ra i ni n g sh o ul d n o t b e a t tem p te d . 2 . Th e se pr e pa r a ti on s m u s t b e c om po u nd ed in a c l ea n e n vi ro nm e nt , us ing as e pt ic t e ch n iq u e ( i .e . , wo r k i ng u n d er c o n t ro ll e d co n di t ion s to m i ni m i ze c o nt am i na t i on ) . 3 . D r y p o wd e rs of pa r e nte r a l d r ug s f o r r ec o ns ti t u ti o n a r e u se d f o r d r ug p rod u ct s o r p r e pa r a ti o ns t h at a re uns t ab l e as so lu t io ns . I t is i m po r t an t t o k no w t h e cor r e c t d i lu e nt s t h at c a n b e u s ed t o y ie ld a s ol u ti on . 4 . S ol u ti o ns o f d r u gs fo r p a r en t e ra l a dm i ni st r a ti on m a y al so be fu r t he r di lut e d b e fo r e a d m i ni s t ra ti o n . I f f u r th e r d i lu t io n i s r e qu i re d , t h en t h e p ha r m a c i s t m u st k no w t h e s t ab i li t y an d c om pa t ib i li ty o f t he d ru g i n t h e d il uen t . C . R e c on s t i tu t i on o f a d r y p o w de r f r o m a vi al 1 . W or k t ak es pl ac e i n a c l ea n -a i r e n v i ro nm e nt , ob s e r v in g a se p ti c t ec hn i qu e . 2 . Th e m a nu f ac tu r e r 's ins t r uc ti o ns s h ou ld be ch ec ke d to de t e rm in e t h e r eq u i re d vo l u m e of di l ue n t. 3 . Th e ap p ro p ri a te ne e dle s i z e an d s yr i ng e a r e c h o s e n , k ee pi n g i n m i n d th a t th e c a pa ci t y o f t he s y ri n ge s h o ul d b e s li g ht l y la r g e r th a n t h e v o l um e r e qu i re d f o r r e c on s t i tu t io n . 4 . U si ng t he c o r re c t d il ue n t , t h e s u r f ac e o f t h e c o n t ai ne r is c l ea ne d , u si ng a n a l co h ol p r e p p ad , a f t er wh i c h th e a lc o ho l i s p e rm it t e d t o e v a p o ra t e. 5 . Th e s y r i ng e i s f i ll ed wi t h t h e d il u en t t o th e p r op e r vo lu m e . 6 . Th e s u r fa c e of t he v i al c o n ta i ni ng t he s t e ri le po wd e r i s cl e an e d, us in g a n al co h ol p r e p p ad , af t e r wh i c h i t is pe r m i t te d to d r y . Th e di l ue n t i s i nj ec t ed in t o t he v i a l c o nt a in in g th e d r y p o wde r . 7 . Th e v i al i s g e nt l y s h ak e n o r ro ll e d, an d th e p owd e r i s a l lo we d t o d is s o lve . 8 . A f te r th e p o wd e r ha s d i s s ol v e d , t he vi al is in v e r t e d a nd th e d es i r ed v ol u m e is wi t h d r a wn . 9 . Th e v e hi c l e i s p re p a red b y s wa b bi ng t he m e di c a t i on po r t o f th e b ag o r bo t t le wi t h a n al co h ol pr e p p ad . P.116
1 0 . Th e s ol u ti on in t he s y r i n g e i s i nj ec t ed in t o t he v e h ic le . If a p la s t ic c on t a in e r i s u s ed , c a re m u s t be t ak en n ot t o p un ct u r e t he s i de wa l l s o f t h e co n ta i ne r wi t h t h e t i p o f t he ne ed l e. 1 1 . Th e c on t ai ne r s h ou l d b e s ha k en or k n ea d ed or r o t at e d t o e ns u re th o r ou g h m i xi n g of t he c o nt e nt s . 1 2 . Th e c on t en ts o f t he c o n t ai ne r s h ou l d b e c h e ck e d f o r p a rt ic u la t e m a t t er . 1 3 . A s te r il e s ea l o r c a p i s a p pl ie d o ve r t he po r t o f t he c o nt a in e r. 1 4 . Al l n e ed le s a nd s y r ing e s s h o ul d b e p r o pe r l y di s c a r de d . 1 5 . Th e b ag is la be l ed . D . R e m o vi n g t h e f l ui d co n t e n ts f r om an am p u le 1 . Th e am pu le is he ld upr i g ht t o o pe n i t , a nd t he to p is ta pp e d t o r e m o v e an y s o lu t io n t r a pp ed in t hi s ar e a . 2 . Th e ne c k o f th e a m p u le is s wa b be d wi t h a n a lco h ol s wa b .
3 . Th e am pu le is gr as p ed o n e ac h s i d e o f t h e n ec k wi t h t he t hu m b an d i nd e x f i n g e r o f ea ch ha n d a nd qu ic k l y s na p pe d o p en . 4 . A 5 - µ m f i lt e r n e ed le is a t t ac he d t o a s y ri n ge of t h e a pp r o pr i at e s i ze . 5 . Th e am pu le is ti l te d , an d th e n e ed l e is in s e r t ed. 6 . Th e ne ed l e is po s i t io ne d ne a r t h e n ec k o f t he a m pu l e, an d t h e s o l ut i on i s wi t h d r a wn f r om t he am pu l e . 7 . I f t he s o lu t io n i s f o r an i nt r a v e no us pu s h ( bo lus in j ec ti o n ), th e fi lt e r n ee d le is r e m o ved f ro m t he s y r in ge a nd r ep la c e d wi t h a c ap . 8 . I f t he s o lu t io n i s f o r an i nt r a v e no us in f us io n , th e n t h e f il t e r n ee dl e i s re m o ved an d r e p la ce d wi t h a ne w n e ed l e o f t h e a pp r o pr i at e s iz e . Th e d ru g i s i nj ec t ed in t o th e a p p ro p r ia t e v e h ic le . 9 . A ll m a te r i al s s h o ul d be d is c a r de d p r op e r l y , a nd t h e fi n al p ro d uc t o r p r ep a r a ti on s h ou l d b e l ab el e d. E . R e m o vi ng d r ug s ol u ti o n f r om a vi a l 1 . Th e ta b a r ou n d t he r ub b e r c lo s u r e o n t h e v i a l is r em o v ed , an d t h is s u rfa c e is s wa b b e d wi t h an al c oh ol p r e p p ad . 2 . A n e qu i v a le n t am o un t o f s t e ri l e a i r is in je c te d in t o th e v ia l t o p r e v e nt a n e g at i ve va c u um f ro m b ei ng c r e a te d an d t o a l lo w t h e d r u g t o be r em o ved . 3 . U si ng t he ap p ro p r ia t e n e e dl e si ze a nd s y r i n ge , t h e n ee d le is i ns e r te d i nt o t he r u b be r c l os u re . 4 . Th e pl un g e r is pu s h e d d o wn , a nd ai r i s r e le as ed i n t o t h e via l; wh e n th e p l un g e r is p u ll e d b ac k , th e s ol u ti o n i s wi t hd r a wn . 5 . Th e s o lu ti o n i s t he n i nj e c t e d i nt o th e a pp r o pr i at e v e hi cl e . F . E xa m p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Progesterone
5g
Benzyl alcohol
10 mL
Sesame oil, qs
100 mL
b . C o mp o u nd i n g p r o ced u r e . Di ss ol v e t he p ro ges t e ro n e i n t he be n zy l al c o h ol . A dd s u f fi ci en t s es am e o i l t o m ak e 1 0 0 m L. S te r il i z e by f i l t ra t io n t h r ou g h a s te ri l e 0 . 2- µ m f i l te r or b y d r y h e at ( 17 0° C f o r 1 . 5 h r ) . P ac k ag e in s te r il e via ls an d l a be l. 2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Fentanyl (as the citrate)
2 mg
Bupivacaine hydrochloride
125 mg
0.9% sodium chloride injection, qs
100 mL
P.117
b . C a lc u la t i o ns . Si nc e 15 7 µ g f e nt a n y l ci t r at e i s e q ui v a l en t to 10 0 µg f en ta n yl , th e q u a nt i t y o f fe n ta n y l c it r at e r eq u ir e d is ( 15 7 /1 0 0 ) × 2 m g = 3 .1 4 m g f en t any l c i tr a te . Th i s is th e q u an t it y o f f en t a n y l ci t r at e th a t wo u l d b e r eq ui r e d i f c o m p o un d in g as a h i gh - r is k p r ep a ra t io n f r om bu lk po wd e r s . I t wo u ld a ls o re q ui r e 1 25 m g b u pi va c ai n e, a n d t h e r em a in de r is th e 0 . 9% s o di um c h lo r i de inj e c t i on . Ho we v e r , c om m e r c ia l p r o du c ts a r e a v a i la bl e s o we c a n c a lc u la t e h o w m uc h o f ea ch m i gh t b e re q ui r e d u s in g f e nt a n y l 5 0 µ g /m L i n je c ti on an d b u pi va c a i ne h y d r oc hl o ri d e 0 .5 % i n je c ti o n.
B u p i vac ai n e h y d r oc hl o rid e 0. 5 % i nj ec t io n c on t ain s 5 0 0 m g / 1 00 m L ; t he r ef o r e ,
I f 4 0 m L of f en t an y l in je c t i o n is us ed , an d 2 5 m L o f bu p i vac ai n e h yd r oc hl or i d e i n je c ti on is us ed , th en 40 + 2 5 = 6 5 m L ; th e q u an t i t y of 0. 9 % s o d iu m c hlo r i de i n je c ti on r eq u ir e d is 1 00 m L - 6 5 m L = 3 5 m L . N o te : I f t h e o r d e r i s to b e fi l l e d i n a 2 0 - m L pu m p w it h de l i ver y f o r 3 0 d a ys , w h a t i s t h e de l i ve r y r a t e i n µ L/h r ?
c . C om p o un d i ng p r oc ed u r e . Us in g c om m e r ci al ly a va i l ab le in j ec ti o ns , a c c u r at e l y m e as u re th e v ol um e o f ea c h a nd fi l l i nt o a s t e ri l e a m b u la t o r y p um p re s e r vo i r . An ai r b u b bl e c an be in je c te d an d us ed to t ho r ou g hl y m ix t h e s o lu t io n . R em o v e th e ai r f ro m t h e re se r v o i r , a nd ti g ht l y s ea l /c lo s e t he ou t le t . L ab e l . 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Morphine sulfate
5g
Citric acid
100 mg
Sodium chloride, qs to isotonic Methylparaben
150 mg
Sterile water for injection, qs
100 mL
b . C a lc u la t i o ns . Us in g a s od i um c hl o r id e e qu i va le n t o f 0. 0 9 f o r a 5 % m o rp h in e s u lf a te s o lu t io n , 0 . 18 fo r c i tr ic ac id , 1 f o r s o d iu m c h lo r id e , a nd ig n o ri ng t he m e th y l p a ra be n , t h e c a lc u l a ti on s c an be m a de as f o ll o ws : 5 g m o rp h in e s ul f at e i s eq u i v al e nt t o 4 50 m g s o diu m c hl o r id e ( 5 g × 0 . 09 = 4 50 m g ) . 1 0 0 m g ci t r ic a c i d i s e q ui v a l en t to 18 m g s o di um c h lo r id e (1 0 0 m g × 0 . 18 = 1 8 ) 4 5 0 m g + 18 m g = 46 8 m g To b e is o to ni c , t he s o lu t io n ne e ds t h e e qu i v a le n t o f 90 0 m g o f s od i um c hlo r i de in t h e 1 0 0 m L : 90 0 m g - 468 m g = 4 3 2 m g s o di um c h l o ri d e n ee ds to be ad d ed . c . C om p o un d i ng p r oc ed u r e . Di ss ol v e t he m e thy l p a r ab e n i n a bo u t 9 0 m L o f s te r i l e wa t e r f o r i n je c t i on . A s m a l l a m o un t of he a t m a y be r e qu i re d . C o ol th e s o lut i o n t o r o o m t em pe r a tu r e ; t he n a d d t h e m o r p hi ne s u l fa t e, c it r ic ac id , a n d s o d iu m c h lo r id e . A d d s u f fi c i en t s t e ri le wa t e r f o r i nj ec t io n t o v ol um e a n d m i x we l l . S te r il i ze by f i l t ra t io n t h ro u gh a s te r ile 0 .2 - µ m f i lt e r i n to a s t er i l e vi a l o r re s e r v o i r. P ac k a ge an d l a be l . 4 . E xa m pl e 4 a . M e d ic a t io n o rd e r
Mefoxitin Diluent to final concentration of 125 mg/mL
P.118
1g
b . C a lc u la t i o ns . A 1 - g v i a l o f Me f o xi n ( c e f o xi t i n fo r in j ec ti o n ) is r ec on s ti tut e d wi t h 1 0 m L o f di lu e nt t o p ro v id e fo r ap p ro xi m a t e wi t hdr a wa l o f 1 0 .5 m L an d a n a p p ro xi m a t e a v e r ag e c on c en t r at i on of 95 m g /m L . W h a t q u an t i t y o f d i l u en t s ho u l d b e ad d e d t o p r o vi d e a n a p p r ox i ma t e a ve r a g e co n c en t r a t io n o f 1 25 m g /m L ?
c . C om p o un d i ng p r oc ed u r e . As ep t ic al l y , wi t h dra w 7 . 5 m L of di l ue n t a nd i n je c t in t o t h e via l t o be re c o n s t i tu te d , u s i n g a n a pp r op r i at e v e n t ed ne e dl e . G e n tl y s wi r l u n ti l d i ss ol ve d . P.119
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 3 : E ac h q ue s ti on o r in c om pl e te s t a te m e n t i n th i s s ec t io n c a n b e c o r r ec t l y a n s we r e d o r c om pl e te d b y o n e o f th e s ug g es te d a n s we r s o r p h r as es . Ch o os e t h e b es t a ns we r . Th e fo ll o wi n g m ed ic a ti o n o r de r i s g i v en t o t h e p h a rm ac is t b y t h e p h ys ic i a n .
Olive oil
60.0 mL
Vitamin A
60,000 units
Water
120.0 mL
Sig:
15 mL t.i.d.
1 . T he f in a l d o sa g e f o rm o f th i s p r e sc r i p t io n w i l l b e ( A ) a s o lu ti o n. ( B ) a n e li xi r . ( C ) a n e m u ls i on . ( D ) a s us p en s i o n. ( E ) a l o ti o n. V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . W h en pr e p a r i ng t h is p re s c r ip t io n , t h e ph a r ma c is t ne e ds to a d d ( A ) Twe e n 8 0 . ( B ) a ca c i a . ( C ) g l yc e r in .
( D ) a lc o ho l. ( E ) p r op y l e ne gl y c ol . V i e w A n s we r 2 . T h e a n sw e r i s B [ se e] . 3 . W h ic h o f t h e f o l low i n g c a ut i on l a b e ls sh o ul d t he ph a rm a c is t af f i x t o th e co n ta i n e r w he n d i s pe n si n g t h i s p r e p a r at i o n? ( A ) D o no t re f ri g e ra t e. ( B ) S h ak e we ll . ( C ) F o r e xt e r n a l u s e on l y. ( D ) N o p re s e r v a t i v es a dd e d . V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . F o r 1 - 3 : Di r e c t i on s fo r q ue s t io n s 4 - 9 : E a c h q ue s t i on o r s ta t em e n t i n t h is s ec t io n c an be c o r r ec t l y a ns we r e d o r c om p le t ed b y o n e o r m o re of t he s u g g es te d a ns we r s o r p h ra s es . Ch o os e t he co r r ec t a ns we r , A-E: 4 . W hi c h s t a te me n t s a bo u t t he f o ll ow i ng p r es cr i p t i o n a r e c o r r ec t ?
Morphine
1 mg/mL
Flavored vehicle, qs ad
120 mL
Sig:
5-20 mg p.o. q 3-4 hours prn pain
I . T he am o u nt o f m o r p hi n e ne e de d i s 24 0 m g . I I . P ow de r e d m o r ph i n e a l k al o i d s ho u l d b e u s ed w h e n c o mp o u nd i ng th i s p r e s c r ip t i on . I I I . Th e fi n al d os a ge f o rm o f th i s p r e sc r i p t io n is a s o l u ti o n . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 . T h e a n sw e r i s B [ se e] . 5 . W h en pr e p a r i ng t he f o ll ow i n g p r e s c r ip t i on , t he ph a r ma c i s t s ho u l d
Podophyllum
5%
Salicylic acid
10%
Acetone
20%
Flexible collodion, ad
30 mL
Sig:
Apply q h.s.
I . t r i t u ra t e 1 . 5 g of p odo p h yl l u m w i t h th e 8 m L o f ac e t on e . I I . ad d 3 g o f sa l ic yl i c a c i d t o t h e c ol l o di o n w i th t r i t u r a ti o n. I I I . a f f i x a n “ ex t e r na l us e on l y” l a b e l t o th e c on t a i ne r . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 5 . T h e a n sw e r i s B [ se e] . P . 12 0
6 . W hi c h s t a te me n t s a bo u t t he f o ll ow i ng p r es cr i p t i o n a r e c o r r ec t ?
Sulfur
6g
Purified water Camphor water, aa qs ad
60
I . P r e ci p i ta t e d s ul f u r can b e u s ed t o p r e pa r e thi s p r es c r ip t i o n. I I . Th e su l f u r c an b e t r it u r a t e d w i t h gl yc e r i n be f o r e m i x in g w i th o th e r i n g r e di e n ts . I I I . A “ sh a ke w e ll ” l a be l s h o ul d be af f i xe d t o t he b o t tl e . A i f I o n l y i s c o r re c t
B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 6 . T h e a n sw e r i s E [s e ea n d] . 7 . W h ic h s ta t em e n ts ab o u t t he f o l l ow i ng p r es c r ip t i o n a r e co r r e c t ?
Starch
10%
Menthol
1%
Camphor
2%
Calamine, qs ad
120
I . T he p ow de r s s h o ul d b e b le n de d to g e th e r in a m o r ta r , us i n g g eo m e tr i c d i l u t io n . I I . Th e p re s c ri p t i on sh ou l d be p r ep a r ed b y d i s s o l vi n g th e c a mp h o r i n a s u f f i ci e n t a mo u n t o f 9 0% a l c o h o l . I I I . A e u t ec t ic m ix t u r e sh o u l d b e a vo i d ed . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 7 . T h e a n sw e r i s A [ se e] . 8 . W h en pr e p a r i ng t he f o ll ow i n g p r e s c r ip t i on , t he ph a r ma c i s t s ho u l d
Salicylic acid
3g
Sulfur ppt
7g
Lanolin
10 g
White petrolatum
10 g
I . r e du c e t h e p a r t ic l e s iz e of t he p ow de r s , u s ing a m o r t a r a n d p e st l e or u s i ng t h e p il l ti l e w it h a s pa tu l a . I I . p la ce o n a n o i n tm e nt t i l e a n d l e vi g at e th e ing r e d i en t s , u si n g g e om et r i c d i l u t io n . I I I . pa ck a ge t he o in t m en t i n a n o i n tm e n t j a r o r t u b e . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 8 . T h e a n sw e r i s E [s e ea n d] . 9 . An e q u al vo l u me o f a i r i s i n j e ct e d w he n re m o vi ng d r u g s o lu t i o ns f r om I . vi a l s. I I . am p ul e s . I I I . s yr i n g e s . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 9 . T h e a n sw e r i s A [ se e] . P . 12 1
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C [ s ee V . B . 1 .] . 2 . T he an sw e r is B [ s ee V . B . 2 ; V . C .1 ] . 3 . T he an sw e r is B [ s ee V . B . 3 ]. F o r 1 -3 : B e c au s e ol i v e oi l an d wa t e r a re t wo im m i sc i bl e l iq u id s, t he i r i nc or p o r at i on r e q ui r es a t wo - p h as e s ys t em in wh i c h on e l iq u id i s d is p e rs ed th r o ug ho u t a n o th e r l i qu i d i n t he f or m o f s m a ll d ro p le t s . To ac c o m p li s h t hi s , a n em u ls if yi n g a ge n t i s
n e ce ss a r y . Ac ac ia is th e m os t s ui t ab l e em u ls if yi ng a ge n t wh e n f or m i n g a n o i l- i n wa t e r e m u ls i on th a t i s i nt e n de d f o r i n te r na l u se . E m u ls io ns a re ph y s ic al l y u ns t ab l e, an d th e y m us t b e p r o te c t e d a ga i ns t t he e f fe ct s o f m ic r o bi al c o n ta m i na t io n a n d p h ys i ca l s ep a r at i on . S h ak i ng be f o re us e r e dis t r ib u te s t h e t wo la y e r s o f e m u ls ion . B ec au se li g ht , ai r , a nd m i c ro o rg a ni sm s a ls o af f e c t th e s t ab i li t y o f a n em u ls io n , p r e s e r va ti ve s c an be add e d . 4 . T he an sw e r is B (I I I ) [ s ee I II . A . C .3 ] . Th e c on c e n t ra t io n o f m or p h in e n e ed e d f o r t he p re s c r i pt i on de s c r ib ed in th e qu es t io n i s 1 m g /m L , a nd be c a us e 1 2 0 m L is th e f i na l v ol um e , 1 20 m g of m o r ph i ne i s n e ed e d t o co m p ou n d t hi s p r es c rip t i on . Mo r p h in e a lk al o id h a s p oo r s o lu bi l it y; t he r ef o r e , o ne o f t he s a lt fo r m s s h ou ld b e us ed . Be ca u s e m o rp hi n e i s d iss o l v ed in th e v eh i cl e , r e s ul ti n g i n a l i qu i d p re pa r a ti o n , t he fi n al do s a g e f o rm is a s o l ut i on . 5 . T he an sw e r is B (I I I ) [ s ee I II . C . 1. ; II I . C .5 ; II I .D . 3 ] . C a l cu l at i ng fo r th e a m o un t o f e ac h i ng r ed i en t o f th e p re sc ri p ti o n i n t he que s ti o n r e q ui r es 1. 5 g o f p od o phy l l u m , 3 g of s a li c yli c ac i d , an d 6 m L of ac e to ne . Th e c o r re c t p r oc ed u re wo u l d b e to t ri t u ra t e t he po d oph y l l um wi t h th e a ce t on e , t h e n a dd t h e tr i tu r a te d s al ic y l ic ac i d to a c al ib r a te d b o tt l e c o nt a in in g th e p o do ph y l lu m a n d a c et o ne . Fl e xi b l e c o l lo dio n is th en ad d ed up t o th e 30 - m L c a li b ra t io n . A n “ e xt e r n a l u s e o nl y ” l ab el s h ou l d be a f fi xe d t o t h e c on t ai ner . 6 . T he an sw e r is E ( I , II, a nd I II ) [s e e I V . B. 2 ; I V .C . 5 ; I V. D . 1 a n d 2 ]. W hile pr ec i pi t at e d s u l fu r c an be us e d t o p r ep a re t h e p r es c ri p ti on de sc r ib ed i n t he q u es t io n , i t i s di f f ic ul t t o t r i tu r a te ; th e re f o re , i t m u s t f i rs t b e l e v i ga t ed wi th a s ui t ab l e l e vi ga t in g a g en t (e . g ., gly c e r i n) . A ll s us p en si on s , o wi n g to t he i r i ns ta b il i t y, r e qu i re s h ak in g b e fo r e u s e to r ed i s t r ib u t e t he in s o l ub le in g r ed i en ts . 7 . T he an sw e r is A ( I ) [s e e V I. C . 3 ; V I . D .1 ] . Th e p r o pe r p r oc e du r e f or c om po u nd in g th e p r es cr i p ti o n d es c r i be d i n t h e qu e st i on is t o fi r s t f o rm a li q ui d e u tec t ic . Th is i s d on e b y t r i tur a t in g th e m en t ho l a n d c a m ph o r t o g et h e r i n a m o rt a r . Th is eu t ec t ic i s t h en bl en d ed wi t h t he po wd e r e d s ta rc h a n d c a la m i n e, us in g g e om et ri c d i lu t io n . 8 . T he an sw e r is E ( I , II, a nd I II ) [s e e I X. D . 1 an d 3 ; I X. E . 1] . Th e p r o pe r p r oc e du r e f or p r ep a r in g t h e p re s c r ip t io n gi v e n i n t h e q ue s t i on i s to r e d uc e t h e p a rt ic le s i z e o f ea c h po wd e r a nd m i x t h em t og e th e r, us i ng ge om e t ri c d i lu t io n . Thi s e ns u re s t he p r op e r b le n di ng o f t he p o wd e r s . N e xt , t h is po wd e r ed m i xt u r e is i nc o r po r a te d , g e om e t ri ca ll y , wi t h th e pe t r ol a t um . Th e n , t h e l ano l in is a d d ed ge om e tr ic a ll y . 9 . T he an sw e r is A ( I ) [s e e XI . E . 2 ]. A n e qu al v o lu m e o f a ir m u s t b e i nj ec t ed wh e n rem o vi ng a d r ug s o lu t io n f ro m a v i al . Th i s is do ne t o p re v e n t th e fo r m a t io n o f a va c u um wi t h in t he v i al . Th is p ro b le m d o es n o t o cc u r wi t h am p ul es an d s y r i n ge s c o n ta i ni n g dr u g s o lu t io ns ; t h e re f o re , i t is u n n ec es s a r y t o in j ec t a ny a i r wh e n re m o vi n g t hem .
6 Basic Pharmacokinetics R i c c a r do L . B o n i L e o n Sh a r ge l
I. PHARMACOKINETICS A. I N T R O D U C T I O N 1 . P ha r m ac o k in e t ic s i s t h e q u an t it a ti ve m e as u rem e nt o f d ru g a b so r pt i on , d i st r ib u ti o n, a nd el im in a ti o n ( i .e . , e xc r e t i on an d m e ta b ol is m ) a nd in c l ud es t h e ra t e p r oc es s e s f o r d ru g m o v em e n t in t o t h e b od y , wi t h i n t h e b od y , an d o u t o f th e b o d y . 2 . C om m o nl y u s e d u n it s i n ph a rm ac ok in e ti cs a re t a b ul a te d i n Ta bl e 6 - 1. 3 . R a te s a n d o r d e r s o f r e a c t io n s . Th e r a te of a c he m i ca l re ac t io n o r p h a rm ac ok i ne ti c p r oc es s i s t h e v e l oc it y wi t h wh i c h i t o c c ur s . T h e o r de r o f a r e a ct i on is t h e wa y i n wh i c h t he co nc e nt r a ti on o f a d r ug or r ea c ta n t i n a c h em ic al r ea c t i on af f ec ts t h e r a te . a . Z e ro - o r de r r e ac t i on . Th e d r u g co nc e nt r a ti o n c h a n ge s wi t h r es pe c t t o t i m e a t a c on s ta n t r a te , a c c o r di ng t o t he f ol lo wi n g e qu a ti o n:
Table 6-1. Common Units in Pharmacokinetics Pharmacokinetic Parameter
Abbreviation
Fundamental Units
Units Example
Area under the curve
AUC
Concentration X time
µg X hr/mL
Total body clearance
ClT
Volume/time
Liters/hr
Renal clearance
ClR
Volume/time
Liters/hr
Hepatic clearance
ClH
Volume/time
Liters/hr
Apparent volume of distribution
VD
Volume
Liters
Volume of distribution at
Vss
Volume
Liters
steady state Peak plasma drug concentration
Cmax
Concentration
mg/L
Plasma drug concentration
Cp
Concentration
mg/L
Steady-state drug concentration
Css or Cav
Concentration
mg/L
Time for peak drug concentration
Tmax
Time
hr
Dose
Do
Mass
mg
Loading dose
DL
Mass
mg
Maintenance dose
DM
Mass
mg
Amount of drug in the body
DB
Mass
mg
Rate of drug infusion
R
Mass/time
mg/hr
First order rate constant for drug absorption
ka
1/time
1/hr or hr-1
Zero order rate constant for drug absorption
ko
Mass/time
mg/hr
First order rate constant for drug absorption
K (sometimes referred to as kel)
1/time
1/hr or hr-1
Elimination halflife
t½
Time
hr
Fraction of drug absorbed
F
(no units)
Ranges from 0 to 1 (0 to 100%)
P.123
wh e r e C is t he d ru g c on c e n t r at i on an d k 0 is t he z e r o - o r d e r r a t e c o ns t an t e xp r e s s ed in un i ts o f c on c en t r at i on pe r ti m e ( e. g. , m i ll i g ra m s p e r m il li l it e r p e r ho u r ). In t e gr a ti o n o f t h is eq u at i on y i el ds th e li n ea r (s t r ai g ht - li n e ) e q u at io n : C = -k0t + C0 wh e r e k 0 i s t he s l op e o f th e li ne ( s e e F ig u r e 3 - 5) a n d C 0 is th e y in t er ce p t , o r d ru g c o nc en t ra t io n , wh e n t im e (t ) eq u al s z e r o . Th e n eg a ti v e si gn i n di ca t es th a t t h e s l o pe is de c re as i ng . b . F i rs t - o r de r r e ac t i on . Th e c ha n ge in d ru g c on c e n t r at i on wi t h re s p ec t to t i m e eq u al s t he p ro d uc t o f t he ra t e c on s t a nt an d t h e c on c en t ra t io n o f dr ug r e m ai ni n g, ac c o r di n g t o th e fo l lo wi n g eq ua t io n :
wh e r e k i s t h e f i rs t -o r de r r a t e c o n st a nt , e xp r e s s ed i n u ni ts o f r ec ip r oc a l t i m e , or ti m e
-1
-1
( e .g . , 1 / h r o r h r ) .
( 1 ) I nt e gr a ti o n o f t h is e qu a t io n yie ld s t h e f ol l o wi ng m a t he m a t ic al l y e q ui va l en t eq ua t io ns :
( 2 ) A gr a ph of t he eq ua t io n in Fi g ur e 6 - 1 s ho ws th e li ne a r re la t io n o f th e lo g o f t he c o nc en t r at i on v e rs u s ti m e . I n Fi gu r e 6 - 1 , t he s l o pe of t he li ne is e q u al to -k / 2. 3 , a n d t he y in t e rc ep t i s C 0 . Th e v alu e s f o r C a re pl o t te d o n l o ga r i th m i c c oo r di n at es , a n d t h e v a l ue s f o r t a re s h o wn on li n ea r c o o rd in a te s .
( 3 ) Th e ha l f - li f e (t ½ ) o f a r e ac ti o n o r p r oc es s is th e ti m e r eq u ir e d f o r t he c o nc en t r at i on of a d r ug to d ec r ea s e b y o n e h al f . F o r a f i rs t -o r de r r ea ct i on o r p ro ce s s , th e h al f - li f e is a c on st a nt an d i s r e la te d to t he fi r st - o rd e r ra t e c o ns ta n t , ac c o r d in g t o the f ol l o wi ng e qu a ti on :
2 . M o d el s a n d c o mp a r tm e n t s a . A m o d el is a m a t he m a t ic de s c r ip t io n o f a bi o lo g ic s y s t em a n d is us e d t o e xp r e s s q u an t it a ti v e r el at i o ns hi ps . b . A co m pa r t m en t i s a gr o u p o f t is s u e s wi t h s i m i la r bl o od fl o w a n d d r ug a f f in i t y . A c o m p a r tm en t is no t a r ea l p h ys io lo g ic o r a na t om ic re gi o n. 3 . D r u g d i s t ri b u t io n a . D r ug s d is t ri b ut e ra p id ly t o t is s u es wi t h h i gh bl oo d fl o w a n d m or e s lo wl y t o ti ss u es wi t h l o w b lo o d f l o w. b . D r ug s ra pi d l y c r os s c a p il l a r y m em b ra n es i n to t i ss ue s b ec a us e o f p a ssi ve d i f f u si o n a n d h yd r o s t a t i c p r es s u re . D r u g p e rme a b i li t y a c r o ss c ap i ll a r y m em b r an es v a r ie s . ( 1 ) D r ug s e as il y c r os s t he c a p il la r i es o f th e g lo m e r u l u s o f t h e k i d ne y a nd t h e s in us o id s o f t h e l i v e r. ( 2 ) Th e c a pi ll a ri e s o f t he b r ai n ar e s u r ro u nd ed b y g l i a l c el ls th a t c re a te a b l o o d -b r a i n b a r r ie r , wh ic h a c ts a s a th ic k l ip i d m e m b ra ne . P ol a r a nd io nic h yd r o ph i li c d r ug s c ro s s th i s b a rr i e r sl o wl y . ( 3 ) I n d is ea s e s t a te s , m em b r an es m a y be c om e m o r e pe rm e ab l e t o d r ug s . F o r e xa m pl e , i n m e n in g iti s , t h e bl o od b ra i n b ar r i er b ec om es m o r e p e r m e ab l e t o t h e p en e t ra t i on of d ru gs in t o b r ai n . c . D r u gs ma y a c c u m ul at e i n t i ss u es as a r es u lt o f th ei r ph y s ic oc h em ic al c h a ra ct e ri s ti c s o r s p ec ial a ff i ni t y o f t he ti ss u e f o r t h e d r ug . ( 1 ) Li p id - s o lu b le d ru gs m a y a c c um u la t e i n a di po s e ( f at ) ti ss u e b ec au se of p a r ti t io n in g o f th e d r ug . ( 2 ) Te t r ac y c li n e m a y a c c u m ul a te in bo n e b ec au s e c om pl e xe s a re f or m e d wi t h c al c i um . P.124
d . P l as ma p r o te i n b i n din g o f d r ug s a ff e c t s d r ug d i st r ib u ti o n. ( 1 ) A dr u g b ou n d t o a p ro t e in fo r m s a c o m p l e x t ha t is to o l a rg e to c r os s c e l l m em b r an es . ( 2 ) Al b u m i n is th e m aj o r p l as m a p r o te i n i n v ol v e d i n d r u g p ro t e i n b i nd in g . α 1 - G l yc o p r o t e i n , a ls o fou n d i n p la s m a , is im po r ta n t fo r th e b in d in g o f s uc h b a si c d r ug s as p ro p r an olo l . ( 3 ) P o te n t d ru gs , s uc h as ph e n yt oi n, t ha t a r e h i gh l y b ou n d ( > 9 0 %) t o p l as m a p ro t ei ns m a y be d i s p la c ed b y o t he r hi gh l y b o un d d r ug s . Th e d i sp la c em en t o f th e b o un d d ru g r e su lt s i n m o re fr e e (n o nb o un d ) d r ug , wh i c h
r a p id l y r ea c h es t he dr u g r e c ep t or s a n d ca us es a m o r e i nt e ns e p h a rm ac ol o gi c r es p on s e . ( 4 ) A fe w h o r m o n al dr u gs bi n d t o s pe ci f ic p l as m a p r o te i ns . F o r e xa m p le , p r e dn is o ne bi n di ng t o t ra n s c o rt i n ( a nd al bu m i n ) r e s ul ts in do se - d ep en d en t p h a rm ac ok i ne ti c s of p red n is o ne . Th is n o nl in e a r p h a rm ac ok i ne ti c s is d u e t o s a tu r a bl e p r ot e in bi n di ng. Tr a n sc o r ti n h as hi gh a ff i n it y a nd lo w c a pa c i t y wh i l e al b um in ha s l o w a ff i n it y a nd a h ig h c ap ac i ty . B . O n e - co m pa r t m en t mo d e l 1 . I n t ra ve n o us b ol u s i nj e c t io n . Th e e nt i r e d ru g d o s e en t e rs th e b od y r a p id l y , an d t h e r a te of ab s o rp t io n i s n eg le c te d i n c al c u l at i on s ( F ig u re 6 -1) . Th e e n ti r e b o d y a c ts a s a s i n gl e c om pa r tm e nt , an d th e d r u g r ap i dl y e q ui l ib r a te s wi t h al l o f the t is s u es in th e b o d y. a . D r u g e l im i na t i o n is a f i rs t - o rd e r k i n e ti c p ro c es s , ac c o r d in g t o t h e e q u at io n s i n I . A. 1 . b. ( 1 ) Th e fi r s t - o rd e r e li m i na t i on r at e c on s ta n t ( k o r k e l ) i s t h e su m o f t h e r a te c o ns ta n ts fo r r em o v al of d r u g f r om th e b o d y , i nc lud i ng t he r at e c on s ta n ts f o r r en al e xc r e ti o n a nd m e ta b ol is m ( b i ot r a n sf o rm a t i on ) as d es c ri b ed b y t h e fo ll o wi n g e q ua t io n : k = ke + km wh e r e k e i s t he r at e c on s t a n t f o r r e na l e xc r e t i on an d k m i s t h e r a te c o ns ta nt f o r m e ta b ol is m . Th i s e qua t i on ass um e s t ha t a l l r at e s a r e f i rs t -o r d er p r o ce s s es .
Figure 6-1. Generalized pharmacokinetic model for a drug administered by rapid intravenous bolus injection. , extrapolated drug concentration; VD, apparent volume of distribution; DB, amount of drug in the body; k, elimination rate constant; t1/2, elimination half-life. [Adapted with permission from Gibaldi M, Perrier D. Pharmacokinetics, 2nd ed. New York, Marcel Dekker, Inc., 1982. Copyright © 1982 Routledge/Taylor & Francis Group, LLC.]
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( 2 ) Th e el i mi n a ti o n h a l f- l i f e (t 1 / 2 ) is gi v e n b y t h e f o ll o wi n g e q ua ti o n :
b . Ap p a r e n t vo lu m e o f d i s t r i bu t i on ( V D ) i s t h e h y p o t he t ic al vo lu m e of b o d y fl u id in wh i c h th e dr u g i s d is s o l v e d. Th is v a l u e is n o t a t ru e a n at om ic o r p h ys ic a l v o l um e. ( 1 ) V D i s n e ed ed t o es t im a te t he am ou n t o f d r ug i n t h e b od y r e la t i v e t o th e c o nc en t r at i on of d ru g i n t h e p l asm a , a s s h o wn i n t h e fo ll o wi n g : VD × Cp = DB wh e r e V D ( li t e rs ) i s t h e ap p a re n t v ol um e o f d is t r ibu t i on , C p ( m g / li t er ) is th e p l as m a d ru g c on c e n t ra t io n , a n d D B ( m g ) is th e am o un t o f dr u g i n t he bo dy . ( 2 ) To c a lc u la t e t he V D af t e r a n i n t ra v e n ou s b ol us i n je c t i on , t h e e qu a ti o n is r e a r r an ge d to gi v e :
wh e r e i s t he do s e ( D B ) of d r ug gi v e n b y i nt r a v e nou s b o lu s a nd is th e e xt r a p o l a te d d r ug c o nc en t r a ti o n a t z e r o tim e o n th e y a xi s , a f t er t he dr u g e q ui l ib r a te s ( F ig u re 6 -1 ) . ( 3 ) A cc or d in g t o th e e q ua t i on , V D is in c re as e d a nd is de c re as e d wh e n t he d r u g i s d is t ri bu t ed m o r e e xt r a v a s c ul a r l y i n to th e ti s s u es . W hen m o r e d ru g i s c o nt a in e d i n t he v a s c ul ar s pa c e o r p la sm a, is in cr e a se d a nd V D is d e c re as e d. 2 . S i ng l e o r a l d o se . I f th e d ru g i s g i ven in an ora l do sa g e f o rm (e . g. , t a b le t , c ap s u le ) , th e d r ug is ge n e ra ll y a bs o rb e d b y f i rs t - o rd e r k in e ti cs . E l i m i na t io n o f th e d r ug al s o f ol l o ws th e p r in c i p le s o f fi r s t - o rd e r k in e ti cs ( F i gu r e 6 - 2 ) . a . Th e fo ll o wi n g e q ua t ion d es c r i be s t he ph a rm ac o k in e ti cs o f f i rs t - o r de r a b s o r pt i o n a n d e li m i nat i o n :
wh e r e k A is th e f i rs t - or d er a bs o rp t io n ra t e c on s t an t an d F is th e fr a ct io n of d r u g b io a v a il ab l e. C h an ge s i n F, D 0 , V D , k A , an d k a f f ec t t he pl a sm a d ru g c o nc en t r at i on . b . Th e ti m e f or m a xi m u m , o r pe ak , d r ug ab s o r pt io n is gi v e n b y t he f o l lo wi n g e q ua t io ns :
wh e r e t m a x d e p e nd s o nl y o n th e ra t e c on st a nt s k A a n d k , n o t o n F , D 0 , or V D .
Figure 6-2. Generalized plot for a onecompartment model showing first-order drug absorption and first-order drug elimination. [Adapted with permission from Shargel L, WuPong S, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005.]
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c . A ft e r t m a x i s ob t ai n ed , t h e p e ak d r u g co nc e n tr a ti o n ( C m a x ) i s ca lc ul a te d , u s in g t h e e qu a ti o n i n I . B. 2 . a a nd s u bs t it u ti n g t m a x f o r t. d . Th e a re a u nd e r t h e c ur v e ( A U C ) m a y b e d e te rm i ne d b y i nt e g ra t io n o f C P d t u s i ng t he t ra pe z o i da l ru l e o r b y t h e f ol l o wi ng e qu a ti o n:
c h an g es i n F , D 0 , k , an d V D a f f ec t t he A U C . Mi n o r c ha n ge s i n k A do no t a f f ec t t h e A U C . e . To o bt ai n , o bt a in th e [ A U C ] f r om 0 t o t b y t h e t r a p e z oi da l ru l e a nd ad d o n th e e xt r a p o l at e d s e c tio n of A U C , wh i c h i s t h e la s t m ea s u r ab l e d r ug c o nc en t r at i on at ti m e t d iv i d e d b y t he s l op e of th e t e rm i na l e li m i n at i on c u r ve , a s s h o wn i n t he fo l lo wi n g eq u at i on :
f . L a g t i me oc c u rs at t he b e gi nn i ng of s ys t em ic dr u g ab so r p ti on . Fo r s om e i n di vi d ua ls , s y s te m i c d r ug a bs o rp t io n i s d el a y ed a f t e r o r al dr u g a d m i ni s t ra ti o n b ec au s e o f de l a y ed s t om ac h e m p ty i n g o r o th e r f ac t o rs . 3 . I n t ra ve n o us i nf u s io n a . I nt r a v en o us in f us io n is an e xa m pl e of z e r o- o r de r a bs or p ti o n a nd fi r s to r d e r e li m i na t io n (F i gu r e 6 - 3 ) . b . A fe w o r a l c on t r ol le d - re l ea s e d ru g p r o du ct s r e le a s e th e d r u g b y z e r o o r d e r ki n et ic s a n d h a v e z e r o - o rd e r s ys t e m i c abs o r p t i on . c . Th e p l as m a d r u g c o nc e n t r at i on at an y t im e a f te r t he s t a r t o f a n i n t ra ve n ou s i n fu s i on is gi v e n b y th e f o ll o wi n g e qua t i on :
wh e r e R is t he z e r o- o r der r a t e o f i nf us i on gi v e n in u ni ts as m i ll ig r am s p e r h o u r o r m il l ig r am s p er m in u t e. d . I f t h e i nt r a v en o us i n f us i on is d is co n ti n ue d , t he p l asm a d r u g c o nc en t r at i on de c l in e s by a f i rs t -o r d e r p ro c es s . Th e el im in a ti o n h al f -l i fe , or e l im in a ti o n r a te c o ns t an t, k , m a y b e o b ta i ne d f r om t he de cl in i ng pl as m a d r u g c on c e n t ra t io n v er s us t im e cu r ve . e . A s t he d ru g i s i nf us e d, t h e pl a sm a d ru g c o nc en t r a ti o n in c re as e s t o a p l a te au , o r s te a d y- s t a t e c o nc e n t ra t i o n ( C S S ) .
Figure 6-3. Generalized semilogarithmic plot for a drug showing zero-order absorption and firstorder elimination. Css, steady-state concentration; k, elimination rate constant. [Adapted with permission from Gibaldi M, Perrier D. Pharmacokinetics, 2nd ed. New York, Marcel Dekker, Inc., 1982. Copyright © 1982 Routledge/Taylor & Francis Group, LLC.]
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( 1 ) U n de r s t ea d y- s t a te c o n di t io ns , th e fr ac t io n o f d r u g a bs o rb ed eq u al s t he f r a ct i on of d ru g e l im in a te d f ro m t he bo d y. ( 2 ) Th e pl as m a c o nc en t ra t i on at s t e ad y s ta t e ( C s s ) i s g i v en b y th e f o ll o win g e q u at io n :
W her e, C l T i s t o ta l b o d y c l ea r an c e ( se e Se c t i on I.E . ) ( 3 ) Th e ra t e o f d r u g in f us i on ( R ) m a y b e c a lc ul a te d f ro m a re a r ra n ge m e n t o f t h e e q ua t io n i f th e d es i re d C s s , t he V D , a n d t he k a r e k no wn . Th e s e v a l ues c a n o f te n b e o b ta in e d f ro m th e d r ug li t e ra t ur e . To c a lc u la t e t he r at e of i n f us io n , t he f ol lo wi n g eq u a ti on is us ed : R = Css VDk = Css ClT wh e r e C s s is th e d e s i r ed ( t a r ge t ) p l as m a dr u g c o nc e nt r a ti o n a nd C l T i s t o ta l b o d y c l ea r an c e. f . A l oa d in g do s e ( D L ) is gi v e n a s a n i ni t ia l i n t rav e n o us bo l us d os e to p r o du c e t he C s s a s r a pi dly a s po s s ib l e. Th e i n t ra ve n o us i n fu si o n i s s t a r te d a t t he s am e tim e as t h e D L .
( 1 ) Th e ti m e to r ea c h C s s d e pe n ds o n t h e e li m i n ati o n h al f - li f e o f t h e d ru g . R e a ch i ng 90 % , 9 5% , o r 9 9 % o f th e C s s wi t h o ut a D L t ak es 3 .3 2 , 4 .3 2 , o r 6 . 6 5 h al f -l i v e s , r es pe c t i ve l y . Th u s, fo r a d r ug wi th a n e li m i na t io n t 1 / 2 o f 8 h r , i t wi l l t ak e 3. 3 2 × 8 h r, or 2 6 .5 6 h r , t o re ac h 9 0 % o f C s s i f no lo ad i ng do s e i s g i v e n. ( 2 ) Th e D L is t he am ou n t o f dr u g t ha t , wh e n d is sol v e d in th e a p pa r en t V D , p r o du c e s t h e d es i re d C s s . Th u s D L is c a lc ul a te d by t h e fo ll o wi n g e q ua t io n :
g . A n i n tr a v e no us in f us ion p r o v id es a r el a ti v e l y co n s t a nt pl as m a d ru g c o nc en t r at i on an d i s p a rti c ul a rl y u se f ul fo r dr u gs t h a t h a v e a na r r o w t h e r ap eu t ic ra n ge . Th e IV i n fu s i o n ke e ps th e p las m a d ru g c on ce n t ra t io n b e t we e n th e m in im um toxi c c o nc e nt r a ti on ( MTC ) a n d t h e m i n im um e f f ec tive c o nc en t r at i on ( ME C ) . 4 . I n te r m i tt e n t i n t r a ve no u s in f u si o ns a . I nt e rm i tt e nt in t r a v en ou s i n fu si o ns a r e i n fu s i o ns in wh i c h t he d ru g i s i n f us ed fo r s h o rt pe r i od s t o pr e ve nt ac c u m u l at i on a n d t o xi c i t y . b . I nt e rm i tt e nt in t r a v en ou s i n fu si o ns a r e u s e d fo r a f e w d r ug s, s u c h as the a m in o gl y c os id es . F o r e x a m pl e , g en t am ic in m a y be g i v en as a 1 -h r in f us ion e ve r y 1 2 h r . In th is c a s e , s t ea d y- s t a te d ru g c on cen t r a ti o ns a r e n o t a c hi e v e d. c . Th e p e ak d r u g c o nc e nt r a t io n i n t h e p la s m a f o r a d r ug gi v e n b y i n t er m i t t en t i n t ra v e n ou s in f us i on m a y b e c a lc u la t ed b y t he fo l lo wi n g e q u at io n :
wh e r e C p , n i s t h e p ea k d ru g c o nc en t r at i on , R i s t he r a te of d ru g i n fu s i o n, C l i s to t al b o d y c l ea r an c e , k is th e d os a ge in t e r val , n is t he nu m b e r o f i n f us io ns , t is th e ti m e for t h e i nf us i on , a n d τ i s t he d os ag e i n te r va l . 5 . M u l t ip l e d o se s . Ma n y d r u gs a r e g i ve n in t e rm i tt e n tl y i n a m ul t ip l e -d os e r e g im en f or c o n ti nu o us or p r ol o ng e d t he r ap e ut ic a c ti vi t y . Th is r eg im e n is o f t en us ed t o t r ea t c h ro ni c d is e as e. a . I f d r ug do s e s a r e g i v en f r eq u en t l y b e fo r e t h e pr e v i o us do s e is c om pl e tel y e l im in a te d , t h en pl as m a d r u g c on ce n t ra t io ns ac cu m ul a te an d i nc r ea s e t o a s t ea d y - s ta t e l e v el . b . A t s t ea d y s t a t e , p l as m a d r u g c o nc e nt r a ti o n f lu c tu a te s b e t we e n a m a xi m um ( ) a n d a m in im u m ( ) v a l ue ( Fi gu r e 6 - 4 ) . c . W he n a m ul t ip le - d os e r e g im en is c a lc ul a te d , t he s up e r p os i t io n p r in c ipl e a ss u m e s t ha t p r e v i ou s dr u g do s e s h a v e n o e f fe ct o n s ub s eq ue n t d os es . Th u s t he pr e di c t e d p la s m a d r u g c o nc e nt r a ti o n is t h e t o ta l p la sm a d r ug c o nc en t r at i on ob t ai ne d by a d d in g t h e r es i du al d rug c o nc e n tr a ti o ns fo un d a f t e r e ac h p r e v io us do s e. d . W hen a m u lt i pl e -d os e r e gi m en i s d es i gn ed , onl y t h e d o si n g ra t e ( D 0 / τ ) c a n b e a dj us t ed ea s i l y .
( 1 ) Th e do s i ng r at e i s b as e d o n t he s iz e o f th e do s e ( D 0 ) an d th e i n t e r val ( τ ) b e tw e en d os e s, o r th e f r eq u en c y o f d o s in g. P.128
Figure 6-4. Generalized plot showing plasma drug concentration levels after administration of multiple doses and levels of accumulation when equal doses are given at equal time intervals. τ, time interval between doses (t), or the frequency of dosing. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGraw-Hill, 2005]
( 2 ) Th e do s i ng r at e i s g iv e n b y t he fo l lo wi n g eq ua t i on :
( 3 ) A s l on g a s t he do s i ng r a te is th e s am e, t he exp e c t e d a ve r ag e d r u g c o n ce n t r a ti o n a t st e ady s t a t e ( ) is t he s am e (Fi g u re 6 -4 ) . ( a ) F or e xa m pl e , i f a 60 0- m g d os e i s g i v en e v e r y 1 2 h r, th e d o s i ng r at e i s 6 0 0 m g/ 1 2 h r , o r 5 0 m g /h r . ( b ) A do s e of 30 0 m g e v e r y 6 h r o r 2 0 0 m g e v e r y 4 h r a ls o g i v es th e s am e d o si n g r a te (5 0 m g /h r ) , wi t h t h e s am e e xp e c t ed . H o we v e r , t h e a nd v a lu es wi l l b e d i ff e re n t . ( c ) F or a l a rg e r d os e g i ve n o v e r a l o ng e r i nt e r va l ( e . g. , 60 0 m g e v e r y 12 h r ) , th e i s h ig h er an d th e l o we r co m p a r ed wi t h a s m a ll e r d os e g i ven m o r e f r e q ue n tl y ( e .g . , 2 00 m g e v e r y 4 h r ). e . C e r ta in an t ib i ot ic s a r e g i v e n b y m ul t i pl e r ap i d i n t r a ve n ou s b o l us i n j e ct i o ns . ( 1 ) Th e pe ak , o r ma x im um , se r u m d r u g c o nc e n tr a t i o n a t s t ea d y s t a te m a y b e es ti m a t ed b y th e fo ll owi n g e q ua t io n :
( 2 ) Th e mi n im u m s e r um d r u g c o n ce n t r at i o n ( ) a t s t e ad y s ta t e is th e dr ug c o nc en t r at i on af t e r t he dr u g de cl in es on e d o s a ge i n te r v a l . Th u s i s d e t e rm in ed b y th e fo ll o wi n g e qu a ti o n:
( 3 ) Th e a ve r ag e d r u g co n c en t r a t io n ( ) a t s te a dy s t a te is es ti m a t ed wi t h t h e e q ua t io n u s e d f o r m ul t i pl e o r al do s e s :
F o r in t r a v en ou s b ol u s in je c ti o ns , F = 1 . P.129
f . O r a ll y a dm in is t e re d d ru g s g i v en in im m ed i a te -r e l e as e do s ag e fo r m s ( e . g ., so lu t io ns , c o n v en t io n al t ab le t s , c a ps ul e s) by m u l ti pl e o r al do s es a r e u s ua ll y r a pi d l y a bs o r be d a n d s l o wl y e l im in a te d k A ≥ k ) . a nd fo r th e s e dr u gs a r e ap p ro xi m a t ed b y th e e q u at io n s s h o wn i n I . B .5. e . ( 1 ) a nd (2 ) . ( 1 ) F or m o r e e xa c t c a lc ul a t io ns of an d a f t er m u l tip l e o r al do s e s , t he f o l lo wi n g e q ua t io ns a re u s ed :
( 2 ) Th e c a lc ul a ti on o f is t h e s am e a s f o r m u l ti p le i n t ra v e n ou s b ol u s i n je c ti on s , us i ng th e e q ua t i on s h o wn in I . B. 5 .e . ( 3) . ( 3 ) Th e te r m 1 / (1 - e
-kτ
) is k n o wn as t he ac c um u la t i o n ra t e .
( 4 ) Th e f ra c t i on of d ru g re m ai ni n g i n t he bo d y ( f ) a f t e r a d os a ge in t e r v al is g i ve n b y t he f ol lo wi n g equ a t io n : f = e
-kτ
g . L oa d i ng d os e . A n i ni ti a l l oa d in g d os e ( D L ) i s gi v e n to ob t ai n a t h e r ap eu t ic s t ea d y - s ta t e d r u g l e v el qu ic kl y. ( 1 ) F or m u l ti pl e o r al do s e s , D L is c a lc ul a te d b y :
wh e r e D M i s th e m ai n te na n c e do s e . ( 2 ) I f D M i s g i v e n a t a d os a ge in t e r v al eq ua l to the e li m i na t io n h a lf - li f e o f t h e d r u g, th e n D L eq u al s t wi c e th e m ai n te n an c e do s e. C . M ul t i co m pa r t m en t mo d e ls 1 . D r ug s t h at e xh i b it m u lt i c o m p a r tm en t ph a rm ac ok i ne t i cs di s tr i bu t e i nt o d i f fe r e nt ti s s ue g ro u ps at d if f e re n t r a te s . Ti s s u es wi t h h ig h b l oo d f l o w e q ui l ib r a te wi t h a d ru g m o r e ra p id l y th a n t is su es wi t h l o w b l oo d f l o w. D r ug c o nc en t r at i on in v a ri o us t i s s ue s d e pe nd s o n t h e p h y s ic al an d c he m i c a l
c h a ra ct e ri s ti c s o f th e d r ug a nd th e n a tu r e o f th e t is s u e . F o r e xa m p l e, hi g hly l i pi d -s o lu bl e d r u gs a c c um u la t e sl o wl y i n fa t (l ip id ) t iss u e. 2 . Tw o -c o mp a r t me n t mo d e l (i n t r a ve no u s b o lus i n je c t io n ) a . A f te r an i n t ra v e n ou s bo l us in je c ti on , th e d r u g di s t ri bu t es an d e q ui li b r at es r a p id l y in t o h ig h l y p e r fu s e d ti s s ue s (c e nt r a l c o mp a r t m en t ) an d m or e s lowl y i n t o p e ri ph e r al ti s s ue s ( ti s s ue c om pa r t m en t ) .
b . Th e in i ti al r ap id de c l in e in pl as m a d ru g c on c en t r a ti o n is k n o wn as th e d i s t r i bu t i on p ha s e. Th e s lo we r r a t e o f d ec li n e i n d r u g c o nc e nt r a ti o n a ft e r c om p le t e e qu il i b ra t io n i s a c h i e v ed is k n o wn as the e l im i na t i on p ha se ( F i gu r e 6 - 5 ) . P.130
Figure 6-5. Generalized plot showing drug distribution and equilibration for a twocompartment model (intravenous bolus injection). The distribution phase is the initial rapid decline in plasma drug concentration. The elimination phase is the slower rate of decline after complete equilibration of the drug is achieved. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005.]
c . Th e p l as m a d r u g c o nc e n t r a ti o n a t a n y ti m e is t h e s um o f t wo fi r s t- o r de r p r o ce s s es , a s g i v en in the f ol l o wi ng e qu a ti on : Cp = Ae
-at
+ Be
-bt
wh e r e a an d b a re h y b ri d f i rs t - o rd e r r a te c o ns t an ts an d A a nd B ar e y i n t er c ep ts . ( 1 ) Th e h yb r i d f i r s t - o r de r r a t e c o ns t a nt b i s o bt a i ne d f r om th e s lo p e o f t h e e l im in a ti on ph as e o f t h e c u r v e ( F ig u r e 6 -5 ) and r e pr es e n ts t h e f i rs t o r d e r e li m i na t io n o f dr u g f r om t he bo d y af t e r t he d r u g e qu i li b ra t es wi t h a l l t i ss ue s . ( 2 ) Th e h yb r i d f i r s t - o r de r r a t e c o ns t a nt a i s o bta i ne d f ro m t he s l op e o f th e r e s id ua l l i ne of th e d is t r ib u t io n p h as e a ft e r th e e li m in a ti on ph as e i s s u bt r ac t ed . d . Th e ap p a re n t vo l um e o f d is t r i bu t i o n d ep e nds on t he t ype o f p h a rm ac ok i ne ti c c al c u l ati o n . V o lu m e s o f d is t ri b ut io n in c l ud e th e vol um e o f t h e c en t r al c o m p a rt m e n t ( V p ) , th e v ol um e o f di s t r ib u t io n a t s t ea d y s t a te ( V s s ) , an d t h e v ol um e o f t h e ti s s ue c om p a rt m e n t (V t ) . P.131
3 . Tw o -c o mp a r t me n t mo d e l (o r a l d r u g a d mi n ist r a t i o n ) a . A d r u g wi t h a r a pi d d is t r ib u ti o n p ha s e m a y no t s ho w t wo - c o m pa r tm e nt c h a ra ct e ri s ti c s a f t e r o ra l a dm i ni s t r a ti o n. As t he dr u g i s a bs o r be d , i t e q ui l ib r a te s wi t h t he ti s s u e s s o t ha t th e e li m i n at i o n ha l f -l if e o f th e e l im in a ti o n p o rt i on of th e c u r v e e qu a ls 0 . 69 3 /b . b . Two - c o m pa r tm e nt c h ar a c te r is t ic s a re s e en if th e d ru g i s a bs o rb ed r ap id l y a n d t h e d is t ri b ut i on ph as e is s l o we r . 4 . M o d el s w i th a dd i t io na l c om pa r t m en t s a . Th e ad di t io n o f ea c h n e w c o m p a rt m e n t t o th e m o de l re qu i r es a n a d di t io n al fi r s t - o r de r p l ot. b . Th e ad di t io n o f a t hi r d c om pa r t m e n t s u g ge st s th a t th e d r ug s l o wl y e q ui l ib r a te s i nt o a de e p ti s s u e sp a ce . I f th e d r u g is gi ve n a t f re q ue n t i n t er va l s , th e d r u g b eg ins t o ac cu m u l at e i n to t he t h i rd c o m p a r tm en t . c . Th e t e rm i na l l in e ar p ha s e g en e ra l l y re p r es en ts t h e e li m i n at i on of th e d r u g f r om th e b o d y a f t er e q ui l ib r a ti on oc c u r s . Th e r a t e c o n s t a nt f ro m t h e e l im in a ti o n p ha s e is u s ed t o c al cu la t e d os a ge reg i m e ns . d . A de q ua t e p ha r m a c o k in e t ic d es c ri p ti o n o f m ul tic om p a rt m e n t m od el s i s o f t en di f fi c ul t a n d d ep end s o n p r o pe r pl as m a s am p li ng an d d e t er m i n at i on o f d r u g c on c e n t ra t io ns . 5 . E l im i na t i on r a te c ons t a n ts a . Th e el im in a ti o n r a te c o n s t a nt , k , re p r es en ts d ru g el im in a ti o n f r om th e c e nt r a l c o m p a r tm en t . b . Th e te r m i n al e l im in a tio n r at e c on s ta n t ( λ o r b in t he t wo - c om pa r tm e nt m o de l ) r e p re s e n ts d r u g e l im in a ti o n a f te r d r u g d is t r i bu t io n i s m os tl y c om p le t ed . D . N o n l in e a r p h a rm a cok i n e ti c s a r e a ls o k n o wn a s c ap a c i t y- li m i t ed , d o s ed e p en de n t , o r s at u r at i on p h a rm ac ok in e ti cs . No n lin e a r p ha r m a c o ki n et ic s do n o t fo ll o w f i rs t - o rd e r k ine t ic s a s t he do s e in c re as e s (F i gu r e 6 - 6 ). N on l in ea r
p h a rm ac ok i ne ti c s m a y r es u lt f ro m t h e sa t u ra t io n o f an en z ym e o r c a rr i e rm e di a te d s y s te m . 1 . C h a ra c te r i s t ic s o f n on l i n ea r p ha r m ac o ki n e tic s in c l ud e a . Th e A U C i s n o t p ro p o rt i o na l t o t h e d os e . b . Th e am ou n t o f d r ug exc r e t e d in th e ur i ne is n ot p r op o r ti on a l t o t h e d os e . c . Th e e li m i n at i on ha l f -l ife m a y i nc r ea s e a t h ig h do s es . d . Th e r at io o f m e t ab o li te s fo rm e d c ha ng e s wi t h in c r ea se d d os e . 2 . M i c ha e li s -M e n te n k i ne t i c s d es c r i be th e v el oc it y o f en zy m e re a ct i on s . Mi c h a e li s - Me n t en k i ne t ic s a re us ed t o d es c r i be no n l i n ea r ph a rm ac ok in e tic s .
Figure 6-6. Generalized plot showing plasma drug concentration versus time for a drug with Michaelis-Menten (nonlinear) elimination kinetics. For this one-compartment model (intravenous injection), the doses are 1 mg, 10 mg, and 100 mg; and the apparent in vivo rate constant (kM) is 10 mg. The maximum velocity of the reaction (Vmax) is 0.2 mg/min. [Adapted with permission from Gibaldi M, Perrier D. Pharmacokinetics, 2nd ed. New York, Marcel Dekker, Inc., 1982. Copyright © 1982 Routledge/Taylor & Francis Group, LLC.]
P.132
a . Th e M i ch a el i s -M en t en e q ua t i on de s c r ib es the r a te of c h a ng e ( v e l oc ity ) o f pl as m a d ru g c on c e n t ra t i on af t e r a n i nt r a v e no us bo l us i n je c t i on , a s f o l lo ws :
wh e r e V m a x i s t he m a xi m u m v el oc i t y of t he re ac t io n , C p is th e s u bs t ra t e or p l as m a d ru g c on c e n t ra t io n , a n d k M is th e Mi c ha el i s co ns t an t eq ua l to th e C p a t 0 .5 V m a x . b . A t l o w C p v a l ue s , wh er e C p << k M , t h is e q ua t ion r e du ce s t o a fi r s t - o rd e r r a t e e q ua t io n b ec au s e bo t h k M a nd V m a x a r e c o nst a n ts .
c . A t h ig h C p v a lu e s , wh e r e C p > > k M , t he Mi c h ael i s - Me n t e n eq ua t io n i s a ze r o - o r de r ra t e e qu a ti o n, a s f o ll o ws :
3 . D r ug s t h at fo l lo w n o n li n ea r ph a rm ac ok i ne t ic s m a y s h o w ze r o - o rd e r e l im in a ti o n r a te s a t h ig h d r u g c on c e n t ra t io ns , f r ac t i o na l -o r de r el im i na t io n r a t es at in t e rm ed i at e d r ug c o nc e n tr a ti o ns , a nd f irs t - o rd e r e li m i n at i on ra t es a t lo w d r u g c on c e n t ra t ion s (F i gu r e 6 - 6 ). E . C l e a ra n ce is a m e as ur e m en t o f d r u g e li m i na t ion f r om th e b od y . U n it s f or c l ea r an c e a re v o lu m e per t im e (e . g. , li t er s p e r h ou r ) . 1 . T o ta l b o d y c l e a r a n c e ( C l T ) i s t he d ru g e li m i n at i o n r a te di vi d ed b y t h e p l as m a d ru g c on c e n t ra t io n . Ac c o r di n g t o t he c o nc e pt o f c l e ar a nc e , t he bod y c o nt a in s a n a pp a r en t v olu m e o f d is t ri b ut i on in wh i c h t he d ru g i s d is s o l v ed. A c on s ta n t p or t io n o f th is v o lu m e is c l ea r ed , or re m o v ed , f ro m t he bo d y pe r u n i t t im e. a . Th e fo ll o wi n g e q ua t ion s e xp r e s s t h e m e as u r em e nt o f t ot a l b od y c l ea r an c e :
b . F o r d ru gs t ha t fo ll o w f i r s t -o r de r (l i ne a r ) p ha r m a c ok in e ti c s , t o ta l b o d y c l ea r an c e is th e s um of a l l t h e cl e ar a nc es in th e b o d y, a s s ho wn i n th e f o l lo wi n g e q ua t io n : CLT = CLR + ClNR wh e r e C L R is re n al c l ea ra n c e an d Cl N R is no n re na l c l ea r an c e . N on r en a l c l ea r an c e , C l N R , is of t en e q u at e d wi t h he p at ic c l ea r a nc e , C l H . c . Th e re la t io n b e t we e n C l T an d t 1 / 2 is ob t ai n ed by s u bs t it u ti n g 0 .6 9 3/ t 1 / 2 fo r k in t he eq ua t io n i n I. E . 1 a t o o bt a in th e f o ll o wi n g e xp r e s s i o n:
wh e r e V D a nd C l T ar e c on s id e re d i n de p en de n t v ar i a bl es , an d t 1 / 2 is c o ns id e re d a d ep en d en t v a r i a bl e . d . A s c l e a ra nc e d ec r ea s e s (e . g. , in re n al di s e as e) , t ½ i nc r ea s e s . C h an g es i n V D a ls o c au s e p ro p o rt io n al c h a ng es in t ½ . 2 . R e na l d r u g e x c re t i o n i s t h e m a j or r ou t e o f d r ug e li m i na t io n fo r p o la r d r u gs , wa t e r -s ol u bl e d r ug s , d r ug s wi t h l o w m o l ec u l a r we i g h t ( < 50 0 ), an d d r u gs th a t a r e b io t r an s f or m e d s l o wl y. Th e r el a ti on b et we e n t he dr u g e xc r e t i o n r a te an d t h e p la s m a d r u g c o nc e n tr a ti o n i s s ho wn P.133
i n Fi g ur e 6 - 7 . D r u gs ar e e xc r e t e d th r ou g h t he ki dn e y i nt o th e u r in e b y g l om e ru l a r f il t ra t io n , t u bu l a r r e ab s o r p ti on , an d ac t i v e t u bu la r s e cr e ti o n.
Figure 6-7. Generalized plot showing the excretion rate versus plasma drug concentration for a drug with active tubular secretion and for a drug secreted by glomerular filtration only. [Adapted with permission from Shargel L, WuPong S, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005.]
a . G l o me r u la r f i l t ra t i on i s a pa s s i ve p r oc es s b y wh i c h s m al l m o l ec ul es an d d r u gs ar e fi l te r ed th r o ugh t he gl om e r ul us of th e ne p h ro n . ( 1 ) D r ug s b ou n d t o p la s m a p r o te i ns a r e t o o l a rge t o b e f il t e re d a t th e g l om e ru l us . ( 2 ) D r ug s s uc h a s c r ea t in i n e a n d i n ul i n a r e n o t a c ti ve l y se c re t ed or r e a bs o rb e d. Th e y a re us e d to m e as u re t he gl o me r u l a r fi l t r a ti o n ra t e (GFR). b . T ub u l a r r e a bs o r p ti on is a p as s i v e p ro ce s s tha t f ol lo ws F ic k 's la w o f d i f fu si o n. ( 1 ) Li p id - s o lu b le d ru gs ar e r ea bs o r be d f r om th e lu m en of t he ne ph r o n b ac k i n t o t he s ys t em ic c i rc ul a ti o n . ( 2 ) F or we a k e l ec t ro l y t e d r u gs , u r in e p H a ff e c t s th e r at i o o f n on i on i z ed and i o ni ze d d r u g. ( a ) I f t he d ru g e xi s t s p r im a r il y in t he no ni o ni z e d o r li p id - s o lu b le fo r m , t hen i t is re a bs o rb ed m o r e e as i l y fr om t he lu m e n o f t he n ep h ro n . ( b ) I f t h e d ru g e xi s t s p r im a r il y in t he io ni z e d o r wa t e r - s o lu bl e fo rm , th e n i t i s e xc r e t e d m or e e a s i l y in t he u ri n e. ( c ) D e pe nd i ng on th e p K a o f t h e d r ug , a l te r a ti on o f u ri n e p H a l te r s t he r ati o o f io n i zed to no n io ni z e d d r u g a nd a ff ec t s t he r at e o f dr u g e xc r e t io n . F o r e xa m p l e , a lk al in i z a ti o n of t h e u ri n e b y t he ad m i nis t r at i on of s o di um b i ca r bo n at e i nc r e as es the e xc r e t io n o f s a li c y la t es ( we a k ac id s ) i nt o th e u r i ne . ( 3 ) A n i nc r ea s e in u ri ne fl o w c a us ed b y s im u lt a neo u s a dm in is t r at i on of a d i u re t ic de c r e as es th e t im e fo r d r u g r e ab s o r pt i on. C o ns e qu en t l y , m o re d ru g i s e xc r e t e d i f g i v e n wi t h a d iu r e ti c . c . Ac t i ve t u bu l a r s e c re ti o n is a ca r r ie r -m e di a te d a c ti v e t ra ns p or t s y s t em t h a t r e qu i re s e ne r g y . ( 1 ) Two a c t i v e t u bu la r s ec r e ti o n p at h wa y s e xi s t i n t h e k id ne y : o ne s y s t em f o r we a k a c i ds an d o n e s y s t e m f o r we a k ba se s . ( 2 ) Th e ac ti v e t ub ul a r s ec r e ti o n s y st em s h o ws c om p et i ti o n e ff e c t s . F or e xa m p l e , p r o be n ec i d (a we a k a ci d ) c o m pe t es f o r t h e s am e s y st em as
p e ni ci l li n , d ec r ea s i ng t he r a te of pe n ic il li n e xc r e t i o n , r es u lt in g i n a lo n ge r p e ni ci l li n t 1 / 2 . ( 3 ) Th e re n al c l ea r an c e o f d ru gs th a t a r e a c t i v e l y s ec r e te d , su c h as p a m i no h i pp u r a te ( P AH ) , i s u s e d to m e as u re ef f e ct i ve r e n a l b l oo d fl ow (ERBF). 3 . R e na l c l ea r a nc e i s t he v o l um e o f d r ug c o n ta ine d in th e p l as m a th a t is r e m o ved b y th e k id ne y pe r u ni t t im e . Un i t s f o r r en a l cl e a ra n ce a re e xp r e s s ed in v o lu m e pe r t im e (e . g ., m i ll il i te r s p e r m in u te o r l it e rs pe r ho u r) . a . R en a l c l e a ra nc e m a y b e m e as u re d b y d i v id i ng t h e r a te o f d r ug e xc r e ti on b y t h e p la s m a d r ug c o nc e n t r at i on , a s s ho wn i n t he f ol l o wi ng e qu a ti on :
P.134
b . Me a s u re m en t o f re n al c le a r an c e m a y al s o be e xp r e s s ed b y th e f o ll o win g e q u at io n : ClR = keVD wh e r e k e i s t he fi r s t - o r der r e na l e xc r e t i on r at e c on s ta n t a nd
wh e r e i s t he t ot a l am o unt o f p a re n t ( u nc ha n ge d ) d r u g e xc r e t e d i n t he u ri ne . c . R en al c l e ar a nc e is m ea s u re d wi t ho u t r e ga r d t o t h e p h ys i ol o gi c m ec h an is m o f re na l d r u g e xc r e t i on . Th e p r ob a bl e m ec ha n ism f o r r en a l c l ea r an c e is ob t ai ne d wi th a c l ea r a n ce r a ti o , wh ic h re l at es d ru g c le a ra nc e t o in u li n c le a ra nc e (a m ea s u re of G F R ) . ( 1 ) I f t he c l ea r a nc e r a ti o i s < 1. 0 , t h e m e c h a ni s m f o r d r u g c l e ar a nc e m a y r e s ul t f r om fi l t ra t io n p l us r e a bs or p ti o n. ( 2 ) I f t he r a ti o is 1 .0 , th e m ec ha n is m m a y b e f il t ra t i on on l y . ( 3 ) I f t he r a ti o is > 1 . 0, th e m ec h an is m m a y b e f i lt r a t io n p lu s a c t i v e tu b ul ar s ec r e ti o n. 4 . H e pa t i c c le a r an c e is t h e v ol um e o f pl as m a c on t a in in g d r u g t ha t i s c l ea r ed b y th e l i v e r p e r u n i t t im e. a . M e as u r e me n t o f he pa t i c c l ea r a nc e . He p at ic c l ea r an ce is us ua ll y m e as u re d i nd i r ec tl y , as th e di f fe r e nc e b et we e n tot a l b o d y c le a r an c e an d r e n al cl ea r a nc e, as s h o wn i n t he f ol lo wi n g eq u at io n : ClH = ClT - ClR wh e r e C l H is th e h e pa ti c c l ea r an c e . H ep a ti c cl e a ra n ce is g e ne r al l y c o ns id e re d to be eq ui v a le n t to C l N R , o r n on r en a l d r u g c le a ra nc e . He p at ic c l ea r an c e c a n a ls o b e c al c ul a te d a s t he p r o du c t o f t h e l i ve r b lo o d f l ow ( Q ) a n d t he ex t r a c ti o n ra t i o ( E R ), as s h o wn in th e fo l lo wi n g eq ua t io n : ClH = Q(ER)
( 1 ) Th e ex t r ac t i o n r a t io i s th e f r ac t io n o f d r u g t ha t is i r r e v e rs ib l y r em o v ed b y a n o r g an o r t is s u e a s t h e p l as m a -c o nt a in in g d ru g pe r f us es th a t t is s u e . ( 2 ) Th e e xt r a c t i on r at i o is ob t ai n ed b y m e as ur i ng t h e p la sm a d r ug c o nc en t r at i on en t e ri ng th e li v e r an d t h e p la s m a d r u g c on c e n t ra t io n e xi t i ng t h e l i ve r :
wh e r e C a is th e a r t e ri al p l as m a d ru g c on c e n t ra t io n en t e ri ng t he li v e r a n d C v i s th e ven ou s p la s m a d ru g c o nc en t r at i on e xi t i ng t h e l i v e r . ( 3 ) V al u es fo r th e E R r an g e f r om 0 t o 1 . F o r e xa m p le , i f th e E R is 0 .9 , t he n 9 0 % o f th e i nc om in g d r ug is r em o v ed as th e p l as m a p e r fu s e s t h e li v e r . If t h e E R i s 0 , t he n n o dr ug is r em o ved b y th e l i v e r. b . B l o od f low , i n t ri n s ic c l e a ra n ce , an d p r o t ei n b i n d in g af f ec t h e pa t ic c l ea r an c e . ( 1 ) B l oo d f low t o t h e li v e r is ap p ro xi m a t el y 1 . 5 L/ m in an d m a y be al t er e d b y e xe r c i s e , fo o d, di s e as e , o r d r ug s. ( a ) B lo o d e nt e rs th e l i v e r t h r ou g h t he he p at ic po r ta l v e in an d h e pa t ic a r t ery a n d l ea v e s t h r ou g h t he he p a ti c ve i n. ( b ) A f te r o ra l d r ug ad m i ni s t ra t io n , t he d ru g i s a bs o r b ed f ro m t h e g a st r o in t es ti n al t ra c t in to t he m e se n te r ic v es se ls a n d p r oc ee ds to t he h e p at ic po r t al v e in , l i v e r , a n d s y st em ic ci r cu la t io n. ( 2 ) I n t ri n s ic cl e a ra n ce , C l i n t d es c r i be s t he ab i li ty o f t he li v e r to r em o v e th e d r u g i nd e pe n de n tl y o f b lo o d f l o w. ( a ) I nt r in s i c d r ug c l ea r a nc e p r im a ri l y oc c u r s b ec au s e o f t h e i nh e re n t a bi l ity o f t he bi o t r a ns f o rm a t ion e nz ym e s ( m i xe d - f u nc t io n o xi d as es ) to m e t ab ol iz e t h e d r u g as it en t e rs th e l i v e r . ( b ) N o rm al l y , ba s a l l e v e l m i xe d - f un c ti on o xi d as e e n zy m e s b io t ra ns f o rm d r u gs . L e v e ls o f th es e en z y m e s m a y be i n c r e as ed b y v a r io us d ru gs ( e. g . , p h e no ba r b it al ) an d e n v i ro n m e n ta l a g en ts ( e. g . , to b a c c o sm ok e ). Th es e e n zym e s m a y b e i nh i bi t ed b y o th e r d r ug s a nd en vi r o n m en t al ag e nt s ( e .g . , c im e ti d in e , ac u te le a d po i s o ni n g ). P.135
( 3 ) P r o te i n b i n di n g . D r ug s th a t a re b ou nd t o p ro te i n a r e n o t e as il y cl e ar ed b y t h e l i v e r o r k id n e y b ec a us e o nl y t h e f r ee , o r no n pl a sm a p ro t ei n - bo un d , d r u g c ro s s es t he c e ll m em b r an e i n to th e t is s ue . ( a ) T he f r ee d r ug is a v ail a bl e to dr u g -m et a bo li zi ng e n zy m es f o r b i o tr a ns f or m a t io n . ( b ) A s u dd e n i nc re a s e i n f r e e -d r ug pl as m a c o nc en t r a ti o n r es ul t s i n m o r e a va i la b le d ru g a t p h a rm ac o lo gi c re c e p to r s, p ro duc i n g a m o r e i n te ns e e f f ec t i n th e o r g an s ( e .g . , k id ne y , l i v e r ) i n v ol v e d i n d r ug r em o va l.
( c ) B l oo d f low ( Q ) , in t r in s i c c l ea r a nc e ( Cl i n t ) , an d f ra c t i on of f r ee dr u g in p l as m a ( f ) a r e r e la t ed to h e pa t ic c le a r an c e as s ho wn i n th e fo ll o wi n g e q u at io n :
( 1 ) Th e he pa t ic c l ea r an c e o f d r ug s t h at ha v e hi gh e xt r a c ti o n r a ti os an d h ig h C l i n t va lu es ( e. g ., p ro p r an o lo l ) i s m o s t a f fe c t e d by c h an g es in bl oo d fl o w a n d i nh i bi t o rs o f th e d r ug m e t ab o li s m e n zy m es . ( 2 ) Th e he pa t ic c l ea r an c e o f d r ug s t h at ha v e lo w e xt r a c t i on r at i os a n d l o w C l i n t va lu es ( e. g ., t he o phy l l i ne ) is m os t a f f ec te d by c h an g es in C l i n t an d i s a f f ec t ed on l y s l ig h tl y b y c h an g es i n h e pa t ic b l oo d f l o w. ( 3 ) O n l y d r u gs th a t a re hi g hl y p la s m a p r o te in bo un d (i . e ., > 9 5% ) an d h a ve a l o w i nt r i ns ic c le a ra n c e ( e . g ., ph e n y t oi n ) a r e a ff ec t ed b y a su d de n s hi f t i n p r o t ei n b in d in g . Th i s s hi ft c au s e s a n i nc r ea s e in fr e e - d ru g p la s m a c o nc en t r at i on . c . B i li a r y d r u g e x c r e t ion , a n ac t i v e t r an s p o r t p ro c es s , is a ls o i nc l ud e d in h e p at ic c l ea r an c e. S ep a ra t e a c ti v e s ec r e ti o n s y ste m s e xi s t fo r we a k ac i ds a n d we ak ba s e s . ( 1 ) D r ug s t h at a re e xc r e te d in bi le a re us ua l l y h i gh m o l ec ul a r we ig h t c om p ou n ds (i . e. , > 5 00 ) o r p ol a r d r ug s , s u ch as re s e rp in e , d ig o xi n , an d va r i o us gl uc u ro n id e c on ju g a te s . ( 2 ) D r ug s m a y b e re c y c le d b y th e e n te r o h ep a t ic c i r c ul a t io n . ( a ) S om e d r ug s a r e a bs or b e d f r om th e g as t r oi n tes t in a l t r ac t t h ro u gh t he m es e nt e r ic a n d h ep a ti c p o r t al v e in s, p ro c e e di ng t o t he l i v e r . Th e li v e r m ay s ec r e te s o m e of t he dr u g ( u nc h an ge d or as a g lu c u r o ni d e m e t ab o li t e ) in t o t h e b i le . ( b ) Th e bi le an d d r u g a re s to r ed in th e g a ll bl a dde r a n d wi l l e m p t y in t o t he g a st r o in t es ti n al t ra c t t hro u g h t he bi le d uc t a nd the n m a y be r ea bs o r be d . ( c ) I f t he d ru g i s a gl u cur o n i d e m e ta b ol i t e, ba c te r i a i n t he g as t ro in t es t ina l t r a ct m a y h y d r ol y z e t he g l uc u ro n id e m oi e t y, a ll owi n g t h e r e le as e d d ru g to b e r ea bs o rb e d. d . F i rs t - p as s e f f ec t s (pr e s ys t e m i c el i mi n a ti o n ) o c c u r wi t h d ru g s gi v e n o r a ll y. A po r ti o n o f t h e dr u g i s e li m i n at e d b ef o r e s y s t em ic a bs o r pt i on o cc u rs . ( 1 ) Fi r s t- p as s e ff e c t s g en e r al l y r es ul t fr om r ap i d d r u g b io t r an sf o rm a ti o n by l i ve r e n z y m es . O t he r m ec h an is m s i n cl ud e m e ta bo l is m o f t h e d ru g b y g a st r o in t es ti n al m uc os a l c e ll s , in t es t in al fl o r a, and b il ia r y s ec re t io n . ( 2 ) Fi r s t- p as s e ff e c t s a r e u s u a ll y o bs e r ved b y m ea s u ri ng t he ab s ol u t e b i o a va i la b i li t y ( F ) o f the d r ug (s e e C h ap t e r 7 ) . If F < 1 , t h en s om e o f th e d r u g wa s e li m i na t ed b efo r e s y s t em ic d r u g a bs orp t i on oc c u r r ed . ( 3 ) D r ug s t h at ha v e a h ig h h ep a t ic ex t r a ct i o n ra t i o , s uc h as p ro p r an ol ol a n d m o rp hi n e, s h o w f i rs t- p a s s e f f ec ts . ( 4 ) To o bt a in be t te r s y s te m ic a bs o r pt i on of a d r ug t ha t de m o ns t r at es hi g h f i r s t - p as s e ff ec t s , th e n ei t h er
( a ) Th e dr u g d os e c ou ld b e in c re as ed ( e .g . , p r op ra n ol o l, pe n ic il li n ) ( b ) Th e d ru g c ou ld be giv e n b y a n al t e rn a te r ou te o f a dm in is t r at i on ( e. g ., n i t ro g l yc e r in s u bl i ng ua l , i n s u li n s ub c ut a ne ou s , est r a di o l t r an sd e rm a l) ( c ) Th e do s a g e f o rm c oul d be m o di f ie d a s a d e laye d - r e l e as e d r u g p ro d uc t ( e . g ., en t e ri c -c oa t ed as pi r i n, m e sa la m i n e ) so t ha t t h e d r ug m a y b e a bs o rbe d m o r e d is ta ll y i n t h e G I t ra c t F . N o nc o m pa r t me n t m et h o d s. S om e p ha r m a c o k i n e ti c p a ra m e t er s f o r a b so r p ti on , di s t r ib u ti o n, a n d e li m i n at i on m a y b e e s ti m a t ed wi t h n o nc om p a rt m e n t m e t ho ds . Th es e m e th od s u su al ly r e q u i r e c om p ar is o n o f t h e a r e as u n de r th e c u r ve . 1 . M e a n r e si d e nc e t i me a . M e a n r e si d e nc e t i me ( M R T ) i s t he a v e ra g e t im e fo r th e d r ug m o le cu l es t o r es id e i n t h e b od y . M R T i s a ls o kn o wn a s t he m e a n t ra ns i t t i m e a nd m e a n s o jo u rn t i m e. b . Th e MR T d e p e n ds on t h e ro u te of ad m i n is t ra t io n an d a s s um es th a t t h e d r u g i s e lim i na t ed f ro m th e c e nt r a l co m p a r tm en t . P.136
c . Th e MR T i s t he t ot a l re s id e nc e t im e f o r a ll m o le c ul es in th e b o d y di v i ded b y t h e t o ta l n um b e r o f m o l ec ul e s in t he bo d y , a s s h o wn in t he fo ll o wi n g e q u at io n :
d . M RT a f te r I V b o l us inj e c t io n ( 1 ) Th e MR T a f t e r a b o lus in t r a v en o us i n je c t i on is c al c u l at e d b y t he f o l lo wi n g e q ua t io n :
wh e r e A U MC i s t h e a r ea u n d er t he fi r s t m o m e n t ve r s us tim e c u r v e f r om t = 0 t o t = i nf i ni t y an d A U C 0 - ∞ i s t he a re a u n de r th e p l as m a d ru g c on c e n t ra t io n ve r s us t im e c u r v e f ro m t = 0 to t = in f in i t y . A U C 0 - ∞ i s a ls o k no wn a s t h e z e ro m om e nt c u r v e . ( 2 ) Th e MR T I V i s r e la t ed t o t he el im in a ti o n r a te c on s ta n t b y t he f ol lo wi n g e xp r e s s io n : MR T I V = 1 / k ( 3 ) D u ri n g MR T I V , 6 2 . 3% o f th e i n t ra ve no u s b ol us d os e i s e li m i n at e d. ( 4 ) Th e MR T f o r a d ru g gi v e n b y a no n in s t a n ta neo u s i np u t is lo n ge r th a n th e MR T I V . 2 . M e a n a bs o r p t io n ti me ( M AT ) is th e d i ff e r en ce b e t we e n MR T a n d MR T I V a f t e r a n e xt r a v a s c u l ar r ou t e i s u se d . MA T = MR T e v = MR T I V
W hen f i rs t -o r de r ab s o r p tio n oc c u rs , MA T = 1 / k a. 3 . C l ea r a nc e i s t h e v o l um e o f pl as m a c l ea r ed o f d r u g p e r u ni t ti m e an d m a y b e c a lc ul a te d wi t ho u t c on s id e ra t io n o f th e c om par t m en t m od e l.
A f t e r a n IV do s e, F = 1. 4 . S t ea d y- s t a t e vo l um e o f d i st r i b u ti o n ( V s s ) a . Th e s t ea d y- s t a te v o lum e o f di st r ib u ti o n is t he r a t io o f t he am ou n t o f d ru g i n th e b o d y a t s t ea d y s t at e an d th e a ve r ag e s t ea dy - s t a t e d ru g c o nc en t r at i on . b . A f te r an in t ra v e n ou s bo l us in je c ti on , V s s i s c a lcu l a te d b y t he f ol lo wi n g e q u at io n :
II. Clinical Pharmacokinetics i s th e a pp l ic at i on of ph a rm ac o k i ne t ic p r i nc ip le s f o r t h e r a ti o na l d es ig n o f an i n di vi d ua li z e d do s a ge r eg i m e n . Th e t wo m a i n o bje c ti v e s a r e m a in t e na n ce o f a n o p t im u m d r u g c on c e n t ra t i on a t t h e re c ep t o r s i te to p ro du c e t he d e si r ed t he r ap e ut ic r es po n s e fo r a s pe ci f ic p e ri od a nd mi n i mi z a t i on o f an y a d ve r s e o r t o xi c e f f ec ts o f t h e d ru g .
III. Toxicokinetics i s th e a pp l ic at i on of ph a rm ac o k i ne t ic p r i nc ip le s t o t h e d es ig n , c on d uc t, and i n t er p r et a ti o n o f d r ug s a fe t y e v a lu a ti o n s tu di e s . A. T o x i c ok i n et i cs is al s o us e d t o val id a te do s e- re l a te d e xp o s u r e in a n im al s . To xi c o k in e ti c s tu d ie s a r e p e rf o rm e d i n an i m a ls du r in g p r ec li n ic al d r u g d e v el o pm en t to ai d i n pr e di c ti on o f h um an dru g to xi c i t y . To xi c o k in e ti c ( n o nc li n ic al ) s t ud i es m a y c on t in u e a f te r th e d r ug h a s b ee n t e s t e d i n h u m a ns . B . C l i n ic a l t o xi c o lo g y i s t he s t ud y o f a d ve rs e e ff e c ts o f dr u gs a n d t o xi c s u bs ta n c e s ( p oi s o ns ) i n t h e h um a n b od y . Th e pha r m ac ok in e ti cs o f a d ru g i n a n o ve rm ed ic a te d (i n to xi c a te d ) p a ti e nt m a y b e ver y d i f fe r e nt f ro m t h e p h a rm ac ok i ne ti c s of t he s am e d r u g g i v en in th e r ap e u ti c d os es . F o r e xa m p l e , a v e r y hi gh t o xi c d os e m a y s h o w n on l ine a r ph a rm ac ok in e ti c s due t o sa t ur a ti o n k i n et ic s P.137
c om p a re d t o th e d r ug gi v e n at lo we r t h e ra p eu t ic do s es i n wh i ch th e d r ug lev e l s f o l lo w l i ne a r p h a rm ac ok in e t ic s .
IV. Population Pharmacokinetics i s th e s tu d y o f s o u rc es an d c o r re l at e s o f v a r i ab il it y i n dr u g co n c e n tr a ti o ns a m o n g i n di vi d ua ls wh o a re th e ta r g e t p at i en t p o pu la t io n . P o p ul a ti on ph a rm ac ok i ne t ic s i s
m os t of t en ap p li ed t o t he c li n ic al pa t ie n t wh o is re c ei vi n g r el e v a nt do s es o f a d r ug o f in t e re s t . B ot h p h ar m ac ok i ne t ic a n d n on p ha r m ac ok i ne t ic d a ta m a y b e c on s id e re d , i n cl ud i ng ge n de r , a g e, we i gh t , c r ea t in i ne c l ea r anc e , a nd co nc om i ta n t d is ea s e. P.138
STUDY QUESTIONS D i r e c t i on s : E a c h qu es t io n , s t at em e nt o r i nc om ple t e s t at em e nt in th is s e c t i o n c a n b e c o r re c tl y a ns we r e d o r c om p le t ed b y on e o f th e s ug g es t ed an s we r s o r p h r as es . C h o os e th e b e st an s we r . 1 . C r e at i n in e c l e a ra n ce i s us e d a s a m e as u r eme n t o f ( A ) r e na l e xc r e t i on ra t e . ( B ) g lo m e r ul a r fi lt r a ti o n ra t e ( G F R ). ( C ) a ct i v e re n al s ec r e ti on . ( D ) p as s i v e r en al a bs or pt i o n. ( E ) d r ug m e ta b ol is m r a te. V i e w A n s we r 1 . T h e a n sw e r i s B [ se e] . F o r q u es ti o n s 2 - 5 : A ne w c e ph a lo s p o ri n a n ti b io ti c wa s g i ve n a t a do se o f 5 m g /k g b y a s in gl e i n t ra ve n o us b o lu s i nj ec t io n to a 5 8 - ye a r - ol d m an wh o we i g hed 7 5 kg . Th e a n ti b io t ic f ol l o ws th e p h a rm ac ok i ne ti c s of a on e - c o m p a r tm en t m od e l an d ha s a n e li m i n at io n h al f - li f e o f 2 h r . Th e a p pa r en t v o lu m e o f di s t r ib u ti o n is 0 .2 8 L /k g , a nd t he d ru g i s 3 5% b o u nd to p l as m a p ro t ei ns . 2 . W ha t is t he i ni t i al p la s m a d r u g c on c en t r a t io n ( ) in t hi s pa t ie n t ? ( A ) 0 . 24 m g /L ( B ) 1 . 80 m g /L ( C ) 1 7 .9 m g /L ( D ) 5 6 .0 m g /L ( E ) 1 33 9 m g /L V i e w A n s we r 2 . T h e a n sw e r i s C [ se e] . 3 . W h a t is t h e p r e di c t ed pl a sm a d r u g c o n ce n t r a ti o n ( C p ) a t 8 h r a f t e r t h e d o se ? ( A ) 0 . 73 m g /L ( B ) 1 . 11 m g /L ( C ) 2 . 64 m g /L ( D ) 4 . 02 m g /L ( E ) 1 5 .1 0 m g/ L V i e w A n s we r 3 . T h e a n sw e r i s B [ se e I . A . 1. b . (1 ); ] .4 . H ow m u ch d r ug r e m a in s in t he pa t i en t 's b o d y ( D B ) 8 h r a f t e r th e d os e ? ( A ) 1 5 .3 m g ( B ) 2 3 .3 m g ( C ) 8 4 .4 m g ( D ) 1 0 0. 0 m g ( E ) 1 12 . 0 m g V i e w A n s we r 4 . T h e a n sw e r i s B [ se e] . 5 . How l on g a f te r t he d os e i s e xa c t l y 7 5 % o f t h e d r ug el i m ina t e d f ro m th e p a t ie n t 's b o d y?
( A ) 2 hr ( B ) 4 hr (C) 6 hr (D) 8 hr (E) 10 hr V i e w A n s we r 5 . T h e a n sw e r i s B [ se e] . C D C V t F o r q u es t i o ns 6 -1 1 : A 35 - y e a r o l d m an wh o we i g hs 7 0 k g a n d h as no rm a l r e na l f u nc t io n n e ed s a n i nt r a ve n o us i n f us io n o f th e a n ti bi o ti c c a r be ni c i l li n . Th e de s i r ed s te ad y - s t at e p l asm a d ru g c o nc en t r at i on is 1 5 m g /dL . Th e ph y s ic ia n wa n ts th e an t ib io t ic to be in f us ed i nt o t h e p a t ie n t f o r 1 0 h r . C a r be ni c il li n h as an el im i na t io n h a l f- l if e (t 1 / 2 ) o f 1 hr an d a n a p p ar e nt v o lu m e di s t ri but i o n ( V D ) of 9 L i n th is pat i e nt . 6 . As s u m in g th a t n o loa d i n g d os e w as g i ve n, w h a t r a t e o f i n t r a ve n ous i n f us i on i s r e co mm e n de d fo r t h is p a ti e n t? ( A ) 9 3 .6 m g /h r ( B ) 1 35 . 0 m g/ h r ( C ) 4 6 8. 0 m g/ h r ( D ) 9 3 6. 0 m g/ h r ( E ) 1 35 0 .0 m g / hr V i e w A n s we r 6 . T h e a n sw e r i s D [ se e] . 7 . As s um in g t ha t n o l oa d i ng i n t r a ve n o us do s e w a s g i ve n , how l o ng a f te r th e i ni t i a ti o n o f t he in t ra ve n o u s i n f u s io n w ou l d th e p l asm a d r ug co n ce n t r a ti o n r e a c h 9 5 % o f t h e t h e o re t i c s t e a d y- s t a t e d r u g c o nce n t r a t io n ? (A) 1.0 hr (B) 3.3 hr (C) 4.3 hr (D) 6.6 hr ( E ) 1 0 .0 hr V i e w A n s we r 7 . T h e a n sw e r i s C [ se e] . P . 13 9
8 . W ha t is t he r ec o mm en d e d l o ad i n g d o se ? ( A ) 9 3 .6 m g ( B ) 1 35 . 0 m g ( C ) 4 6 8. 0 m g ( D ) 9 3 6. 0 m g ( E ) 1 35 0 .0 m g V i e w A n s we r 8 . T h e a n sw e r i s E [s e e] . 9 . T o i n f us e t he an t i b io t i c a s a s o l u t io n c o n ta i n in g 1 0 g d r u g i n 5 0 0 m L 5 % d e x t r o s e, h ow m a n y m i l l i li t e r s pe r h o u r o f t h e s o lu t i on w ou l d be i nf u se d in t o th e p a t i en t ? ( A ) 1 0 .0 m L /h r ( B ) 4 6 .8 m L /h r ( C ) 1 0 0. 0 m L/ h r ( D ) 9 3 6. 0 m L/ h r ( E ) 1 14 1 .0 m L / hr
V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . 1 0. W ha t i s t he t o ta l bo d y c l e a r a n c e r a t e f o r c a r be n ic i l li n in t h i s p a t ie n t ? ( A ) 1 00 m L / hr ( B ) 9 36 m L / hr ( C ) 4 8 62 m L /h r ( D ) 6 2 37 m L /h r ( E ) 9 00 0 m L /h r V i e w A n s we r 1 0 . T he a nsw e r i s D [ se e] . 1 1. I f t h e p a t i en t ' s r e n al cl e a ra n ce f o r c a r be n ic i l li n is 86 m L /m i n , w h a t i s th e hep a t i c c le a r a nc e f o r ca rb e n ic i l l in ? ( A ) 1 08 m L / hr ( B ) 1 07 7 m L /h r ( C ) 3 8 40 m L /h r ( D ) 5 1 60 m L /h r ( E ) 6 84 4 m L /h r V i e w A n s we r 1 1 . T he a nsw e r i s B [ se e] . C R k V C C CC D C l C l C l C l C l C l C l C l 12 . T h e e a r l ie s t e vi d e nc e th a t a d r u g i s s t o r ed i n t i s s ue is ( A ) a n i nc r ea s e in pl as m a p r ot e in bi nd i ng . ( B ) a l a r ge ap p ar e nt v o lum e o f di st r ib u ti o n ( V D ) . ( C ) a de c re as e i n t h e r a te o f f o rm a ti on o f m e t ab ol i t es b y t h e li ve r . ( D ) a n i nc r ea s e in t he num b e r o f s i d e e f fe c t s p r odu c ed b y th e d r ug . ( E ) a de c r e as e i n t h e am o u n t o f f r ee d ru g e xc r e t ed i n t he u ri n e. V i e w A n s we r 1 2 . T he a nsw e r i s B [ se e] . V 1 3. T he i n t e ns i t y o f t h e p h a r ma c o lo g ic ac t i o n of a d r ug is m os t de p end e n t o n t he ( A ) c on c e n t ra ti o n o f t h e d r u g a t t h e r ec e pt o r s it e . ( B ) e li m i n at io n ha lf - l if e (t 1 / 2 ) o f th e d r ug . ( C ) o ns e t t im e o f t h e d r ug a f te r o r a l a dm in is t ra t ion . ( D ) m in im um to xi c c on c en t r a ti o n ( MTC ) o f t h e dr ug i n p la sm a. ( E ) m i n im um e f f ec ti v e c on c en t r at i on ( ME C ) o f th e d r u g i n t he bo d y. V i e w A n s we r 1 3 . T he a nsw e r i s A [ se e] . 1 4. D r u gs t h a t s h ow no n li n ea r p h a r ma c ok i n et i cs h a ve w h ic h p r o p e r t y? ( A ) A co ns t an t ra t io of d ru g m e ta b ol i te s is f or m e d a s t h e a dm in is t er e d d os e i n c re as es . ( B ) Th e el im i na t io n h al f - li f e (t 1 / 2 ) i nc re as e s as th e a dm i ni st e r ed do se in c rea s es . ( C ) Th e a r ea un de r th e pl a s m a d r ug c o nc en t r at i on v e r su s t im e c u r v e ( A UC ) i n c re as es in di r ec t p r op or t i on t o a n i nc r ea se in the a dm in is t e re d d os e . ( D ) B o t h l o w a nd hi g h d os es f ol lo w f i r s t -o r de r el im i na t io n k in e ti cs . ( E ) Th e s t e ad y - s ta t e d r ug c o nc e n tr a ti o n i nc r ea s es in di r ec t p r o po r ti o n t o th e do s i n g rate. V i e w A n s we r 1 4 . T he a nsw e r i s B [ se e] . 1 5. T he l oa d i n g d os e ( D L ) o f a d r u g i s u su a ll y b a s e d on t he ( A ) t o ta l b od y c le a ra n c e ( C l T ) o f th e d r ug . ( B ) p e rc en t ag e o f dr u g bo u n d t o p la sm a p r ot e in s . ( C ) f r ac t io n o f d r u g e xc r e t e d u nc ha n ge d i n t h e u ri n e . ( D ) a p pa r en t v ol um e of di s t ri bu t io n ( V D ) a nd de si re d d ru g c on c e n t ra t io n i n p l asm a . ( E ) a r ea un d er t he pl as m a d r ug c o nc en t r at i on ve rs us t im e c u r ve ( A U C ) .
V i e w A n s we r 1 5 . T he a nsw e r i s D [ se e] . D D V 1 6 . Th e r e na l c l ea r a nc e o f i n u l in i s u se d a s a m eas u r e me n t o f ( A ) e f fe c t i v e re n al bl oo d f l o w. ( B ) r a te o f r en a l d r ug e xc r e ti o n. ( C ) i n tr i ns ic en z y m e a c tiv i t y . ( D ) a ct i v e re n al s ec r e ti on . ( E ) g lo m e r ul a r fi lt r a ti o n ra t e ( G F R ). V i e w A n s we r 1 6 . T he a nsw e r i s E [s e e] . P . 14 0
1 7 . Al l o f t h e f o l low i n g s t a t em e n ts ab o u t p l asm a p r ot e i n b i nd i n g o f a d r u g a r e t r u e ex c ep t w h ic h on e ? ( A ) D i sp la c e m e n t o f a d ru g f ro m p la sm a p r ot e in bi n di n g si t es r es ul ts in a tr a n s i en t i n c re as ed v o lu m e o f d is tr i b ut i on ( V D ) . ( B ) D i sp la c e m e n t o f a d ru g f ro m p la sm a p r ot e in bi n di n g si t es m ak e s m o r e f r e e d r ug a va i la b le fo r gl om e r ul a r f i l t ra t io n . ( C ) D i sp l ac em en t o f a p ot e n t d r ug th a t i s n o rm al ly > 9 5 % b ou nd m a y c a us e t o xi c i t y . ( D ) A l bu m i n i s t h e m a j or p r o t ei n i n v ol ve d i n p r o te i n b in di n g o f d r ug s . ( E ) D r u gs th a t a r e h ig hl y b o un d t o p l as m a p r o te i ns ge n e ra ll y h a v e a g re a te r V D c om p a re d wi t h d r ug s t hat a r e h ig hl y b o un d t o t is su e p ro t ei ns . V i e w A n s we r 1 7 . T he a nsw e r i s E [s e e] . V 18 . Th e o n s e t t i me f o r a d ru g g i ve n o r al l y i s t h e ti m e f o r t h e d r u g t o ( A ) r e ac h t he pe a k p la s m a d r u g co nc e nt r a ti o n. ( B ) r e ac h t he m i ni m u m ef f e c t i v e c on c e n t ra t io n ( ME C ) . ( C ) r e ac h t h e m i n im um to xi c c on c en t ra t io n ( MTC ) . ( D ) b e gi n t o b e e li m i n at ed f r om th e b od y . ( E ) b eg i n t o b e a bs o rb e d f r om t he s m a l l i nt es t in e . V i e w A n s we r 1 8 . T he a nsw e r i s B [ se e] . 1 9. T he i ni t i a l d i s t ri b u t io n of a d r u g i nt o t is s ue is de t er m i n e d c hi e f l y b y t h e ( A ) r a te o f b lo od f lo w t o t i s s ue . ( B ) g lo m e r ul a r fi lt r a ti o n ra t e ( G F R ). ( C ) s to m a c h em p t y in g t im e . ( D ) a f fi n it y o f t h e d r ug for t is s u e . ( E ) p la s m a p r ot e in bi n din g of t he dr u g. V i e w A n s we r 1 9 . T he a nsw e r i s A [ se e] . 2 0. W hi c h t i s su e ha s t h e g r e a te st c a p ac i t y t o b i o t r a n s f o rm d r u gs ? ( A ) b r ai n ( B ) ki d ne y ( C ) l i ve r ( D ) l un g ( E ) sk i n V i e w A n s we r 2 0 . T he a nsw e r i s C [ se e] . 2 1. T he pr i n c i pl e of s up e r p os i t ion i n d es i gn i n g m u lt i p le - do s e re g i me n s a ss u me s t h a t ( A ) e ac h d os e a f fe c ts the n e xt s ub s e q ue n t d os e, c au s i n g n on l in ea r el im ina t i on . ( B ) e ac h d os e o f d r u g is e l im in a te d b y z e r o - o rd e r e l im in a ti on .
( C ) s te a d y -s t a te pl as m a d r u g c on c e n t ra t io ns ar e r e a ch ed a t a pp r o xi m a te ly 1 0 ha l f l i ve s. ( D ) e a rl y d os es of d ru g do n ot a ff ec t s u bs eq ue n t d o s e s. ( E ) t h e f r ac ti o n o f d r ug ab s o rb ed is eq u al to th e fr a c ti o n o f d r ug el im in a ted . V i e w A n s we r 2 1 . T he a nsw e r i s D [ se e] . C l F o r q u es t i o ns 22 - 2 4 : A ne w c a r di ac gl y c os id e i s d e ve l op e d f o r o r al an d i n t rav e n o us ad m i n is t ra t io n . Th e d ru g h a s a n e li m i na t io n h a lf - l if e ( t 1 / 2 ) o f 2 4 hr an d a n a p p ar e nt vo lu m e o f d is t rib u t io n (V D ) o f 3 L /k g . Th e e ff ec t i v e d r u g c on c e n t ra t io n i s 1 .5 n g /m L . To xi c e f f ec ts of th e d ru g a r e ob se r v e d a t d r ug c on c en t r at i on s > 4 ng / m L . Th e d r u g is bo u nd to pl as m a p r o t ei ns at ap p ro xi m a t ely 2 5 % . Th e d ru g i s 7 5% b i oa v a i la b le af t e r a n o r al d os e . 2 2 . W h a t i s th e o r a l m ai n t e na n ce d os e , i f gi ve n o n ce a d a y, f o r a 6 8 - ye a r - o ld m a n w ho w e i gh s 6 5 k g a n d ha s c o ng e s ti ve h ear t f a i l u re ( C H F ) a n d n o rm a l re n a l f u n c t io n ? ( A ) 0 . 12 5 m g ( B ) 0 . 18 0 m g ( C ) 0 . 20 3 m g ( D ) 0 . 27 0 m g ( E ) 0 . 33 3 m g V i e w A n s we r 2 2 . T he a nsw e r i s D [ se e] . 2 3. W ha t i s t he l oa d i ng do s e ( D L ) f o r t h i s p a ti e n t? ( A ) 0 . 27 0 m g ( B ) 0 . 29 3 m g ( C ) 0 . 45 0 m g ( D ) 0 . 49 8 m g ( E ) 0 . 54 0 m g V i e w A n s we r 2 3 . T he a nsw e r i s E [s e e] 2 4 . I f th e d r u g is a va i la b le i n t a bl e t s o f 0 .1 2 5 m g a nd 0. 2 50 m g , w ha t is t he pa t i en t 's p l as ma d r ug c on c en t ra t i o n i f he h a s a d os a ge r eg i me n o f 0 .1 2 5 m g e ve r y 1 2 h r? ( A ) 1 . 39 ng /m L ( B ) 1 . 85 ng /m L ( C ) 2 . 78 ng /m L ( D ) 3 . 18 ng /m L ( E ) 6 . 94 ng /m L V i e w A n s we r 2 4 . T he a nsw e r i s A [ se e] . D F V k Fk VD F D k V C C D P . 1 41
D i r e c t i on s fo r q ue s t io n 2 5 : Th e q ue s t i on in th is s ec t io n c an be c o r r ec tl y a ns we r e d b y o n e o r m o re of t he s u g g es te d a ns we r s . C ho os e th e c o rr ec t an s we r , A- E . 2 5 . W h i ch eq u a ti o n i s tr u e f o r a z e r o - o rd e r r eac t i o n ra t e o f a d r u g?
A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 5 . T he a nsw e r i s A [ se e ] . A t k Ak t A tP . 1 4 2
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee I . E . 2. a ]. A s ub s ta nc e t h at is us ed t o m e as u re th e G F R m us t be fi l te r ed bu t no t re ab s o rb ed o r a c ti ve l y s e c re t ed . Al t ho ug h in ul i n c l e a ra nc e g i v es a n a c c u ra t e m ea su r em en t o f G F R , c r e at i ni ne c l ea r a nc e is ge n e ra l l y u se d b e c a us e no e xo g e n ou s d r ug m us t b e gi v e n . H o we ve r , c r ea t in i ne fo rm a ti o n d ep e nd s o n m u sc l e m as s a nd m u s c le m e ta b ol is m , wh i c h m a y c h a ng e wi t h ag e an d va ri ou s d is e as e c o n di t io ns . 2 . T he an sw e r is C [ s ee I . B . 1. b . (2 ) ] . 3 . T he an sw e r is B [ s ee I . A . 1. b . (1 ) ; I . B . 1] . 4 . T he an sw e r is B [ s ee I . B . 1. a . (2 ) ] . 5 . T he an sw e r is B [ s ee I . B . 1. a . (2 ) ] . S u b st i tu t in g t h e d a ta fo r t h is pa t ie n t i n t h e e qu a tio n fo r th e i n it i al pl as m a d r u g c o nc en t r at i on ( ) g i v es
To o b t ai n t h e p a ti en t ' s p la s m a d r u g c o nc e n tr a ti o n ( C p ) 8 h r a f t er t he do s e , t h e f o l lo wi n g c al c ul a ti on is pe r f o rm ed :
Th e a m o u nt o f d ru g i n the p at i en t ' s b od y a t 8 h r is c a lc ul a te d a s f o ll o ws : D B = C p V D = ( 1 . 11 ) ( 0. 2 8)( 7 5 ) = 2 3. 3 m g F o r an y f i rs t -o r d er el im i na t i on p ro c e s s , 5 0% o f t he i ni t ia l a m o un t of d ru g is e l im in a te d a t th e e n d o f t h e fi rs t ha l f- l if e , a nd 50% o f t h e r em ai n in g d r ug ( i . e ., 75 %
o f t he or i gi n al a m o u n t) is el im i na t ed at t he en d of t h e s e c o n d h al f -l i fe . B ec a us e t h e d r u g i n t h e c u r r en t c as e h a s a n e li m i na t io n h a lf - l i f e ( t ½ ) of 2 h r , 7 5 % o f t he d os e is e l im in a te d i n t wo ha l f- l i ve s , o r 4 h r . 6 . T he an sw e r is D [ s ee I . B . 3. e . (3 ) ] . 7 . T he an sw e r is C [ s ee I . B . 3. c ]. 8 . T he an sw e r is E [ s e e I . B . 3. f . (2 ) ] . 9 . T he an sw e r is B [ s ee I . B . 3. e . (3 ) ] . 1 0 . Th e a n sw e r i s D [ s ee I . B .3 . e. ( 3 ) ; I . E .1 . a] . 1 1 . Th e a n sw e r i s B [ s ee I . E .4 . a] . Th e e q ua t io n f o r t h e p las m a c o nc e nt r a ti on a t s tea d y s ta t e ( C s s ) p r o vi de s t h e fo rm u la f o r c a lc ul a ti n g t he r at e of a n i nt r a v e no us in f us io n ( R ) . Th e eq ua t io n i s
wh e r e k i s t h e f i rs t -o r de r e l im in a ti on r at e c on s ta nt a nd V D i s t h e a pp a re n t v o l u m e of d i st r ib u ti o n. R e ar r a ng in g t h e e qu a ti o n a nd s u bs t itu t i ng th e d a ta f or t hi s p at i e nt gi ve t h e fo ll o wi n g c al c u l at i ons :
P.143
Th e t im e i t ta k e s f o r a n in f us e d d r ug to r ea ch th e C s s d ep e nd s o n t he el im i n a ti on h a l f- l if e o f th e d r u g. Th e t im e re q ui r ed t o r ea c h 95 % of t he C s s i s e qu al t o 4 . 3 t im es t h e h a lf - li f e , wh e r e as th e t im e re q ui r ed t o r ea c h 99 % of t he C s s i s e qu al t o 6 . 6 t im es t h e h a lf - li f e . B ec a us e t he h al f -l i fe in t he c u r re n t c as e i s 1 h r, th e ti m e to r e a ch 95 % o f t he C s s i s 4 .3 × 1 h r, o r 4 .3 h r. Th e l o ad in g d o s e ( D L ) is c a lc ul a te d a s f ol l o ws :
Th e a ns we r t o qu es t io n 6 s h o ws t ha t th e i n fu s i on r a t e s h o ul d b e 9 3 6 m g / hr . Th e r e f o re , if a d r ug s o lu ti o n c on t ai ni n g 1 0 g i n 5 00 m L is us ed , th e r e qu i red i nf us i on rate is
Th e p a ti e nt ' s to t al bo d y c l ea r an c e ( C l T ) i s c al c u la t e d as f ol lo ws :
Th e h e pa t ic c le a r an c e (C l H ) is th e di f fe r en c e be twe e n t o t al c le a r an c e ( C l T ) an d re n al c l ea r an c e ( C l R ): ClH = ClT - ClR C l H = 62 37 - (8 6 m L /m in × 6 0 m i n /h r ) = 1 07 7 m L /h r 1 2 . Th e a n sw e r i s B [ s ee I . B .1 . b. ( 1 ) ]. A l a rg e a p pa r e nt v o lu m e o f di s t r ib u ti o n ( V D ) i s a n e a rl y s ig n t h at a d r ug is n o t c o nc en t r at e d i n t he pl as m a , b u t is di st r i bu t ed wi d e l y in ti ss ue . A n in c re as e i n
p l as m a p ro t ei n b in d in g s u g g es ts th a t t he d ru g i s lo c at e d i n t he pl as m a r a th e r th a n i n t i ss ue . A d ec r ea s e i n h ep a t ic m e ta bo l is m , an in cr e a s e in s i de ef f ec ts , o r a d ec r ea s e i n ur i na r y e xc r e t io n o f f re e d ru g i s c a us e d b y a de c r ea s e in d ru g e li m i n at io n . 1 3 . Th e a n sw e r i s A [ s ee I . A .3 . d. ( 3 ) ]. A s m o r e d r ug is c on c e n tr a t e d a t t he r ec ep t o r s i t e, m or e re c e p to r s i nt e r ac t wi t h t h e d r u g t o p r od u c e a p ha rm a c ol o gi c e ff ec t . Th e i nt en s it y o f t h e r es p on s e in cr e a s e s u n t il it r ea c h es a m a xi m u m . W hen al l o f t h e a va ila b le r ec ep t o rs ar e o cc u pi e d b y d r u g m ol ec ul es , ad di t io na l dr u g d oe s n o t p r od uc e a m o r e i nt e ns e r es p on s e . 1 4 . Th e a n sw e r i s B [ s ee I . D ]. N o n l in ea r ph a rm ac ok i ne ti c s is a t e rm u s e d to in dic a te t ha t f i rs t - o rd e r e li m in a t io n o f a d r ug do es no t o c c u r a t a l l d ru g c o nc en t ra t io n s . W ith s o m e d ru gs , s uc h as p h e n yto i n, as th e p la s m a d r ug c o nc en t r at i on in c re a s e s , t he el im in a ti o n pa t h wa y f o r m e ta b ol is m o f t h e d ru g be c om es s a tu r a te d a n d t he h al f -l i fe in c re as es . Th e a r e a u n d er t he pl as m a d ru g c o n c e n t ra t io n ve rs us tim e c u r ve ( A U C ) o f t he d ru g i s n o t p r o po r t io n al to th e d os e ; n e it h e r is th e ra t e o f m et a b ol i te fo r m a t io n . Th e m e ta b ol ic r a t e i s r e la t ed to th e e f f ec t s o f t h e d ru g . 1 5 . Th e a n sw e r i s D [ s ee I . B .1 . b. ( 2 ) ; I . B .5 . g. ( 1 )]. A l o ad in g d os e ( D L ) o f a d r u g i s g i v en to ob t ai n a t h e r ap eu t ic pl as m a d ru g l e ve l a s r a p id l y as po s s ib le . Th e D L i s c a lc u la t ed on th e ba s is o f th e a p pa r en t vo lum e o f d i st r ib u ti o n ( V D ) an d t h e d e s i r ed pl as m a le v e l o f th e d ru g . 1 6 . Th e a n sw e r i s E [s ee I . E .3 .c ] . I n u li n i s n ei t he r re a bs o rb e d n o r a c t i v e l y s ec r e ted . Th e r ef o r e, it is e xc r e te d b y g l om e ru l a r f il t ra t io n o n l y. Th e in u li n c le a ra nc e ra t e is us ed as a s t a nd a rd m e as u re o f t he G F R , a te s t t ha t i s u s e f ul bo t h i n a c l in ic al s i tu a ti o n a nd in th e d e v el o pm e nt o f ne w d r u gs . 1 7 . Th e a n sw e r i s E [s ee I . A .3 . d] . D r u g s t ha t ar e h i gh l y bou n d t o p l asm a p r o te i ns di f f us e p oo r l y in t o t is s u e a n d h a ve a l o w a p p ar e nt v o l um e o f d i s t r ib u ti o n ( V D ) . 1 8 . Th e a n sw e r i s B [ s ee I . B .3 . g] . Th e o ns e t t im e i s t he t im e f r om th e a dm in is t r a ti on o f th e d r ug t o t he ti m e wh e n a b so r be d d r u g r e ac he s P.144
t h e ME C . Th e ME C i s t he d r ug c o nc en t r at i on in th e pl as m a th a t i s p r op o rti o na l , b u t n o t n ec e s s ar i l y e q ua l , t o t h e m in im um dr u g c o n c e n t r at i on at th e re ce p to r s i te t ha t e l ic i ts a ph a rm ac o lo gi c re s po ns e . 1 9 . Th e a n sw e r i s A [ s ee I . A .3 . a] . Th e i n it i al d is t r ib u ti o n o f a d ru g i s c h i ef l y de t e rm in e d b y b lo o d f lo w, wh e r e a s th e a f f in i t y o f th e d r u g f o r t is s u e d et e rm i ne s wh e t h e r t h e d r u g c o nc e nt r a te s a t t h a t s i t e. Th e G F R a f fe c ts t h e r e na l c l ea r an ce o f a d r u g, no t it s i ni t ia l d is t r ib u ti on . Th e g as t r ic e m pt y i n g t im e a nd de g r ee o f p la sm a p r ot e in bi n din g af f ec t d r u g di s t ri bu t ion b ut a re l e ss i m p o r ta n t t ha n th e ra t e o f bl oo d fl o w t o t is s ue . 2 0 . Th e a n sw e r i s C [ s ee I . E .4 . b. ( 2 ) ].
Th e k id n e y , l un g , s k i n, an d in t es ti n e a ll ha v e s om e ca p ac it y t o b i ot r a ns fo rm , or m e ta b ol i z e , d r ug s ; bu t the b r ai n h as li t tl e c ap ac i ty f o r d ru g m e ta bo l is m . Th e li ve r h a s t he hi g he s t c a p ac it y f o r d ru g m et a bo li s m . 2 1 . Th e a n sw e r i s D [ s ee I . B .5 .c ] . Th e s up e r po s i t io n p r in c ip l e , wh i c h u nd e rl i es th e d e s i g n o f m u l ti p le - do s e re g im e ns , a ss u m e s t ha t e a r li e r d r ug d os es do no t a f fe c t s ub s eq u en t d os es . If t he eli m in a ti on r a t e c on s ta n t o r t o ta l b od y c le a r an ce of t he dr u g c h an g es d u ri n g m ul ti p le d o si n g, t h e n t he s u pe r p os it i on pr i n c i pl e i s n o l on g er v a lid . C ha n ge s i n t h e t ot a l bo d y c l ea r an c e ( C l T ) m a y be c a u s e d b y e n zy m e i nd uc t io n , e n z y m e i n hi bi t io n , o r s a tu r a ti o n o f a n e li m i n at io n pa t h wa y . A n y of t he se c h a ng es wo u l d c au se n o nl i ne a r p h a rm ac ok i ne ti c s . 2 2 . Th e a n sw e r i s D [ s ee I . B .5 . e. ( 3 ) ]. 2 3 . Th e a n sw e r i s E [s ee I . B .5 . g. ( 1 ) ] 2 4 . Th e a n sw e r i s A [ s ee I . B .5 . d. ( 2 ) ; I . B .5 . e. ( 3 )]. Th e o r al m a in t e na nc e d os e ( D o ) sh ou l d m a i nt a in th e pa t ie n t 's a v e ra g e d rug c o nc en t r at i on at t he ef f ec t i v e d r ug c o nc en t r a ti on . Th e b io a v a il ab i li t y o f t he d r ug ( F) , t h e a p pa r en t v o lu m e of di s t ri bu t io n ( V D ), t he do sag e in t e r v al (τ ) , a n d t he exc r e t i o n r a t e c on s ta n t ( k ) m u s t be c o ns i de r ed in ca lc ul a tin g th e d os e . Th e e qu a ti on us e d is
F o r th is d ru g , F = 0 .7 5 , k = 0 . 69 3 /2 4 h r , V D = 3 L/ k g × 65 k g , τ = 2 4 h r , an d = 1 . 5 n g /m L , o r 1 . 5 µg / L . Th e re f o r e, b y s u bs ti t ut i on , D o = 27 0 µ g, o r 0 .2 7 0 m g. W hen t he m a in t en a nc e d os e is gi v e n at a d os ag e f re qu e ncy e q u al to t he ha l f- l if e , th e n t h e l o ad i ng do s e is eq ua l to t wi c e t he m a in t en a nc e do s e , in t hi s ca s e 54 0 µ g, o r 0. 5 40 m g . To d e te r m i ne t he pla s m a d r u g c o nc e n tr a ti o n f o r a do sa g e r e gi m e n o f 0 . 12 5 m g e ve r y 1 2 h r , th e f o rm ul a i s u s e d . Th is t im e , F = 0. 7 5 , D o = 0 . 12 5 m g, k = 0 . 6 93 / 24 h r , V D = 3 L /k g × 6 5 k g , a n d τ = 1 2 h r . Th e r e fo r e , = 1 .3 9 n g /m L. F or ca r dia c g l yc os id es , th e p e ak ( C m a x ) a n d t ro ug h ( C m i n ) c o nc e nt r a ti o ns a r e c al cu l at ed , an d p l as m a d ru g c on c e n t ra t io n s a r e m o n it o r ed af t e r d o s i n g. Th e l o ad in g d o s e ( D L ) m a y b e gi ve n i n s m a ll in c re m e n ts o v e r a s p ec if i ed pe ri o d , ac co r d in g t o t h e d os a g e r e g im en s u gg e s t e d b y the m a n uf ac t u re r . 2 5 . Th e a n sw e r i s A ( I ) [ s ee I . A. 1 .a ] . Th e f i rs t eq ua t io n i n th e q u es t io n d es c ri b es a z e ro - o r de r re a ct i on (d A / d t) in wh i c h t h e re ac t io n ra t e i nc r ea s e s o r de c re as es a t a c ons t an t ra t e (k ) . A ze r o -o r de r r e a ct i on pr o du c e s a gr a ph o f a s t r ai gh t li ne wi t h th e eq u at i on of A = - k t + A o wh e n A i s p lo t te d a g ai ns t ti m e ( t ) . Th e o t he r eq u at i on s in t he qu es t io n re p r es en t f i rs t o r d e r r e ac ti o ns .
7 Bioavailability and Bioequivalence L e o n Sh a r ge l
I. BACKGROUND A. B i o a va i l a b il i t y a n d b i o e q ui va l e nc e s t u di e s a r e i m po r ta n t f o r t h e d e ve l op m en t o f bo t h n e w d r ug p ro d uc ts ( ne w d r u g a p pl ic a ti on [N D A ] ) a nd ge n e ri c d r ug p r o du c ts ( a b b re vi a te d n e w d r u g ap p li c a t io n [ A N D A] ) B . B i o a va i la b il i t y s t u d i e s a re us ed fo r es ta b li s hi n g d os a ge re g im en s o f n e w d r u g p r o du c ts C . B i o e qu i va l en c e s t udi e s c an be us e fu l d u ri n g t h e i n v es t ig a ti o na l n e w dr u g ( I N D ) d e ve l op m e n t o r N D A d e ve l op m en t p e ri o d t o e s t a bl i s h li nk s b et we e n 1 . E a rl y a nd la t e c l i ni c a l t r i al f or m ul at i on s 2 . F or m u l at i on s us e d i n c l in ic al t ri a l a nd s t ab i li t y s t ud ie s , i f d if f e re n t 3 . C li n ic al t ri al f or m u l at io n s a nd to - b e -m ar k et e d d r u g p r od uc t D . B i o e qu i va l en c e s t udi e s a r e a c r i ti ca l c om po ne n t o f A N D A s ub m i s s io ns 1 . Th e pu r po s e o f t he s e s t ud i es i s t o d em o ns t ra te b io eq u i val e nc e b et we e n a p h a rm ac e ut ic al l y eq u i v ale n t g e ne r ic dr u g p r od uc t a n d t he co r r es po n di ng re f e r en c e l i st e d d r ug (u s u a ll y t he br a n d d r ug p ro d uc t ). 2 . To g e th e r wi t h t he de te r m in a ti on o f p ha rm a c e ut i ca l e q ui va le n c e , e s t a bl is h in g b i oe q ui v a l en c e al lo ws a r e g ul a to r y c on c l us io n o f t h e r ap eu t ic eq ui va l en c e . E . S c al e - up a nd po s t - ap p r o v al ch a n ge s ( S U P A C ) — A f t e r m a rk et ap p r o va l , a d ru g p r o du c t m a y m ak e a m anu f ac t u ri n g c h a ng e . A bi oe q ui v a l en c e st u d y m a y be n ee d ed t o sh o w t h at t he ne w f o rm u la t io n o r ne w m e th o d o f m a nu f ac t u re ( te st p rod u ct ) an d t h e p r i or f or m u l at i on o r m e th o d o f m an u fa ct u r e (r e f e re nc e pr o du ct ) a re eq u i v al e nt . 1
II. DEFINITIONS
A. B i o a va i l a b il i t y i s a m e a s u r em e nt of t he ra t e an d e xt e n t ( a m o un t ) to wh i c h t he a c ti ve in g r ed ie n t o r a c ti v e m o i et y b ec om es a vai l ab l e a t t h e s it e o f a c ti on . B i o a vai l ab il i t y is a ls o c on s id e re d a m e as u re o f t he r a te an d e xt e n t o f t he ra p e ut ic al l y a c ti ve d ru g t h a t is s y s t em ic a ll y a bs o rb ed . Fo r d ru g p ro du c ts th a t a re no t i n t en de d to b e ab so r be d i n to t he bl oo d s t r e am , b io a v a il ab i li t y m a y be as s e s s ed b y m e as u re m e n ts i n te n de d t o r ef l ec t t h e r a te an d e x t e n t t o wh ic h th e a c t i v e in g r ed i en t o r ac t i ve m oi et y b ec om es a v ai l ab le a t t he s i t e o f a c ti o n. B . B i o e qu i va l en t d r ug p r o d u c ts . A g en e ri c d r ug p r od uc t i s c on s i de r e d b i oe q ui v a l en t t o th e re f er e n c e l i s te d d r u g ( R D L) p r o d uc t if bo t h p r od uc ts a re p h a rm ac e ut ic al eq u i v al en t s a nd t he ge n er ic d ru g p r o du c t ' s ra t e a nd e xt e nt o f s ys t em ic d r u g a bs o rp t ion ( bi o a v ai l ab il i t y ) d o n o t s h o w a s t at is t ic al l y si gn if i c a n t d i f fe r e nc e wh e n ad m i n is te r e d i n t h e s a m e m o la r do s e o f t h e ac t i v e i ng r e die n t , i n t h e s am e c h em i c al fo r m , in a s i m i l ar do s ag e f o rm , by t h e s am e ro u te of ad m in i s t r a ti o n, a n d u n de r th e s am e e xp e r i m e n ta l c on di t io ns . The R D L is g e ne r al l y th e b ra n d p r o du c t. P.146
C . G e n e r ic d r ug p r od u ct 1 . Th e ge ne r ic d ru g p r odu c t r e qu i re s a n a b b re vi a t e d new d r u g a p pl i ca t i on ( A N D A ) f o r ap p ro v a l b y t h e U . S . F o o d a nd D r ug A dm in is t ra t i on ( F D A ) a nd m a y be m a rk e te d a f t e r p at e nt e xp i r a ti o n o f t h e r e fe r e nc e d r ug pr o du c t ( s ee C ha p te r 1) . 2 . Th e ge ne r ic d ru g p r odu c t m us t b e a t he r a pe u ti c e qu i va l en t to t he re f er e n ce dr u g p r o du c t b ut m a y d if f e r i n c e rt a in c h a ra c t e r is ti c s , in c lu di n g s ha pe , s c o r i ng c o nf i gu r a ti on , pa c k ag in g, a nd e xc i pi e nt s (s uc h as c ol o rs , fl a v o rs , p r es e r vat i v e s , e xp i r a t i on da t e , a nd m i no r as p ec ts of la b el in g ) . 3 . F D A b e li e v es th a t p r od u c t s c la s s if i ed as th e rap e u ti ca ll y e q ui v a le n t c an b e s u bs ti t u te d wi t h t he f ul l e xp e c t a ti o n t ha t th e s ubs t i tu t ed pr o du c t wi l l p r o du c e t he s am e c li n ic al ef f ec t a n d s a fe t y p r of il e a s t h e p r es c r i be d p r od uc t . D . P h a r ma c eu t i ca l e q u iva l e n t s a r e d r ug p ro d uc ts t ha t c on t ai n th e s am e t h e r ap eu t ic al l y ac t i v e d ru g in g re d ie n t (s ) ; c o n ta i n t h e s am e sa l t , es t e r, o r c h em ic al f o r m ; a re of t he s am e d os a ge fo r m ; a nd ar e i d en ti c al in s t r en g th , c on c en t ra t i on , a n d r o u t e o f a dm in is t r at i on . P h a r m a ce u ti ca l e qu i va len t s m a y d i ff e r i n c ha r ac te r i st ic s s uc h a s s ha p e, s c or i ng c o n f ig u ra t io n , r e le as e m ec h an is m s , p ac k a g in g , a nd e xc i p i e nt s ( i nc lu di n g c o lo r s , f la v o r i ng , a n d p r es er v a t i v e s ). E . T h e r e f e re n ce l is t ed d r u g p r od u c t is us ua l l y t h e c u r re n tl y m a r ke t ed , b r a nd n a m e p ro du c t wi t h a f u ll n ew d r u g a p pl i ca t i on (N D A) a p p r o v e d b y t h e FD A . Th e R L D i s t he r ef e r en c e dr ug p r od uc t i d en t if i ed b y FD A ( s ee “ E le c t r o ni c O r an g e Bo ok ” a t ww w. f d a . g o v / c d e r /o b /d e f au l t. h tm ) . F . T he r a pe u t ic e qu i va l en t d r u g p r o du c t s a r e p ha r m ac eu t ic al eq ui v a l en t s t h a t c a n b e e xp e c te d t o h a v e t h e s am e c li n ic al ef f ec t a n d s a fe t y p r of il e wh e n a dm in i st e r ed to p a t ie n ts u n de r th e s am e c o nd i ti on s s pe c i f ie d i n t he l ab el i ng . Th e ra p eu t ic eq u i val e nt d r u g p r od uc t s h a v e t he fo l lo wi n g c r i te r ia : 1 . Th e pr o du c t s a r e s af e a n d e f fe ct i ve . 2 . Th e pr o du c t s a r e p ha rm ac e ut ic a l e qu i va le n ts th a t c on t ai n th e s am e ac ti v e d r ug i n g re d ie n t i n t he s a m e do s ag e f o rm , gi v e n b y t he s am e r o u te of ad m i ni s t ra t i on ; m ee t c om p en d ia l o r o t he r ap p li c ab le st a nd a rd s o f s t re ng t h , q ua l it y , p ur i t y, a n d id e n ti t y; a n d m ee t a n a c c e pt a bl e i n v i t ro s t an d a rd . 3 . Th e dr u g p r od uc ts a re b i oe qu i v a le n t i n t ha t th ey d o no t pr e s e n t a k no wn p ot e nt i al p r o bl em an d a r e s ho wn t o m e e t a n a pp r o p ri at e bio e q u i va le nc e s t an d ar d . 4 . Th e dr u g p r od uc ts a re a d eq u at e l y l a be le d . 5 . Th e dr u g p r od uc ts a re m an u fa c tu r ed in co m p lia n ce wi t h c u r re n t g oo d m a nu f ac tu r i ng p ra c t ic e re g ul a ti o ns . G . P h a r ma c eu t i ca l a l t e rn a t i ve s a r e d r ug p ro d uc ts t ha t c on t ai n th e s am e t h e r ap eu t ic m o ie t y bu t are d if f e re n t s a l ts , e s te rs , o r c o m p l e xe s (e . g. , te t r ac y c li n e h yd r o ch lo r i de v e rs us t et ra c y c l i ne ph os p ha t e ) o r ar e di f f e re n t d os ag e f o rm s ( e. g . , t a b le t ve rs us c a ps ul e ; im m e di a te - r el e as e d os ag e f o r m v e r su s c on t r ol le d - re l ea s e d o sa g e f o rm ) o r s t r en g ths .
III. BIOAVAILABILITY AND BIOEQUIVALENCE. Th e s e m a y be de t e rm in ed d ir e c t l y us in g p h ar m ac o k in e ti c s tu di es ( e .g . , p la s m a d r u g c o nc en t r at i on v e rs us t im e p r of il e s, u ri na r y d r ug exc r e t i o n s t ud ie s ), m e as ur e m en ts o f a n ac ut e p h a rm ac od y n am ic e ff ec t , c om pa r a ti v e c l in ic al s t u di es , o r in v i t ro s tu di es .
Th e c ho ic e o f s t ud y u s ed is ba s e d o n th e s it e o f a c ti o n o f t h e d ru g an d t he a bi li t y o f t h e s t ud y d es ig n t o c om p a r e d r ug de l i v er e d t o t ha t s i t e b y th e t wo p ro d uc t s . A. Ac u t e p ha r m ac o d yn a m i c e f fe c t s, s u ch as c h a n ge s i n h ea r t r a t e, bl oo d p r e ss u re , e l ec t ro c a r di o gr a m ( E C G ) , c l o tt i ng ti m e , o r fo r c e d e xp i r a t o r y v o lu m e i n 1 s ec ( F E V 1 ) c a n b e u s e d to m e as u r e b io a v ai l ab il i t y wh e n n o a s s a y fo r p l as m a d r u g c o nc en t r at i on is a v a i la ble o r wh e n t he pl as m a d ru g c o nc en t r at i on do es no t r el a te to t h e p h a rm ac ol og ic a l r es p o ns e (e . g. , a b ro nc h od il a t o r P.147
s uc h a s a l bu t er o l g i v en b y i n ha la t io n ) . Qu a nt i ta t io n of t he ph a rm ac ol o gi c a l ef f ec t ve r s us t im e p ro f il e c an be us e d a s a m ea s u r e o f b i oa v a i la b il it y a n d/ o r b i oe q ui v a l en c e ( Fi gu r e 7- 1 ) .
Figure 7-1. Generalized plasma drug concentration versus time curve after oral drug administration. MEC, minimum effective concentration; MTC, minimum toxic concentration. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGraw-Hill, 2005, p. 6.]
1 . O n se t t im e . A s t h e d ru g is s y s te m i c a l l y a bs o rb e d , t he d ru g c on c e n t ra ti o n a t t h e r e c ep t or r is es to a m i nim u m e f f ec t i ve co n ce n t ra t i o n ( ME C ) a n d a p ha rm ac o lo g ic al r e s po ns e i s i ni t ia t ed . The t im e f r om dr u g a dm in ist r a t io n t o th e ME C i s k nown a s t he o n se t ti m e . 2 . I n te n si t y. Th e i n t en s it y o f th e p h a rm ac ol o gi cal e ff e ct is p r o po r ti o na l t o t h e n u m b e r o f re c e p to r s oc c u p ie d b y t h e d r ug up to a m a x i m u m p ha r m a co l ogi c al ef f ec t . Th e m a xi m um ph a rm ac olo g ic al e ff ec t m a y oc cu r b e f o re , a f te r , or a t p ea k d r u g a b so r p ti on . 3 . D u r a ti o n o f ac t i on . As lo n g as t he d ru g c on c en t r a ti o n r em ai ns ab o v e th e ME C , p h a rm ac ol o gi c a l a c t i v i t y i s o bs e r ve d. Th e du r at i on o f a c t i on is t h e t im e f or wh i c h th e d r u g c on c e n t ra t io n r em a in s a b o v e t h e ME C . 4 . T he r a pe u t ic w i n dow . A s th e d r ug c o nc e nt r a tio n in c re as es , o t he r r ec ep t o rs m a y c om b in e wi t h t h e d ru g to e xe r t a t o xi c o r ad v e r s e r e s p o ns e. Th i s d ru g c o nc e nt r a ti o n i s th e m i ni m um t ox i c c on c e n t ra t i on ( MTC ) . Th e d r u g c on ce n t ra t io n r a nge b et we e n t h e ME C a n d t h e M TC i s t h e t h er a pe u ti c wi n d o w. B . P l a sm a d r u g c o nc e nt r a t i o n . Th e pl as m a d rug c o nc e n tr a ti o n v e r su s t im e c u r ve i s m os t of t en us ed t o m e as u r e th e s y s te m i c b io a v a ila b il i t y of a d r ug f ro m a dr u g p r o du c t ( F ig u re 7 -2 ) .
1 . T im e fo r pe a k p l as ma d r u g c o nc e nt r a t i on ( T m a x ) r e l a t es t o t he r at e c o n s t a nt s f o r s ys t em ic d r u g a bs o rpt i o n a nd el im in a ti o n. I f two o r a l dr u g p r od uc t s con t a in th e s am e a m o u n t o f ac t i v e dr u g bu t d i ff e r en t e xc i p i en t s , t he do s a g e f o rm th at yi e ld s t h e f a s te r ra t e o f d r ug ab s orp t i on ha s t he s h o r te r T m a x . 2 . P ea k p l as m a d r u g c on c e n t ra t i on ( C m a x ) . Th e p l as m a d ru g c on c e n t ra t io n at T m a x r e l at e s t o t he in t en s i t y of t h e p ha rm a c o lo g ic al res p on s e . Id e al l y , C m a x s h o u ld be wi t h i n th e th e ra p eu t ic win d o w. 3 . Ar e a u n de r t he p la sm a d r ug co n ce n t r a ti o n ve r s u s t im e c u r ve ( A U C) r e la t es to t h e a m o u nt o r e xt e n t of d r u g a bs o rp t io n . Th e am o u n t o f s y s te m i c d r ug abs o r pt i on is d i r ec tl y r e la t ed t o t he AU C . Th e A U C is us ua l l y c a lc ul a te d b y t he t r a pe zo i d a l r u l e a n d i s e xp r e s s e d i n u ni ts o f c o nc en t r at i on m u lt ip l i e d b y ti m e (e . g ., ) . C . U r i n a r y d r u g e x c r e t io n . Me a s u re m e n t o f u r ina r y d r ug e xc r e t io n c an de t e rm i ne b i oa va i la b il it y f r om a d r ug p r od uc t . Th i s m et h od is m o st ac c u r a te i f th e a c t i v e t h e r ap eu t ic m o ie t y is e xc r e t e d u nc ha n ge d i n si g nif i c a n t q ua n ti t y i n t he u rin e ( Fi gu r e 7-3). P.148
Figure 7-2. Generalized plasma drug concentration versus time curve, showing peak time and peak concentration. AUC, area under the curve; MEC, minimum effective concentration; MTC, minimum toxic concentration. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005, p. 7.]
Figure 7-3. These corresponding plots show the relationship of the plasma drug concentration versus time curve to the cumulative amount of drug in the urine versus time curve. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005, p. 463.]
P.149
1 . T he cu m ul a t i ve a m ou n t o f a c ti ve d r u g e xc re t e d i n t he u r in e () is dir e c tl y r e l at e d t o t h e e xt e n t of s y s t e m i c d r ug ab s o r p ti on . 2 . T he r a te o f d r u g e xc re t i o n i n th e u r i n e ( d D U /d t ) is d i r ec tl y r e la t ed to th e r at e o f s ys t em ic d r u g a bs o rp t ion . ∞
3 . T he t im e fo r t he d r ug t o b e c om p le t e l y e x c r e t e d ( t ) c o r re s p o nd s t o th e to t al t i m e f or t he dr u g t o b e s y s t e m i c a ll y a bs o rb e d a nd c o m p l et e l y e xc r e t e d a ft e r a d m i ni s t ra ti o n . D . C o m pa r a t i ve c l i ni c al t r i a l s t o a d r u g ca n b e u s ed to m e as u re bi o a v ail a bi l it y q u a nt i ta t i v el y . C li n ic al s tu d ie s a r e h ig h l y va ri a bl e a n d l ess p re ci se t ha n o th e r m e th o ds b e c a us e o f i n div i d u al di f f er e nc es in dr ug p ha r m a c o d y n am ics and s u b je c t i v e m e as u re m e n ts . E . I n vi t r o m ea s u r em e nt s o f b i o eq u i va le n ce . Bio e q ui va le nc e m a y s om e ti m es b e d e m o ns t r at e d us i ng an in v i t r o b io e qu i val e nc e s ta n d ar d , e sp ec i al l y wh e n s uc h a n i n vi t r o te s t h as b e en c o r r el a t ed wi t h h um a n i n v i v o b i oa v a i la b il it y d a ta . Fo r e xa m p l e , t h e ra t e o f d r ug di s s ol u tio n in v i t ro fo r c e r ta i n d r ug p r od uc ts c o r r el a te s wi t h d r ug b i oa va i la b il it y i n v i v o. I f t h e d is s o l ut i on te s t i n v i tr o is c o ns id e r ed s t at is t ic a l l y a d e qu a te to p re di c t d r ug b i oa v a il a bi li t y , t he n , i n s om e c as es , di ss ol u ti on m a y be u s ed in pl ac e o f a n i n v iv o b i oa va il a bi l it y s tu d y .
IV. RELATIVE AND ABSOLUTE BIOAVAILABILITY A. R e l a t i ve b i oa va i l ab i li t y ( R B A ) i s t he s ys t em ic a v a i la bi l it y o f t h e d r ug fr o m a d o sa g e f o rm a s c om pa r ed t o a re f e re nc e s t an da rd g i v en b y th e s am e r o ute o f a d m i ni s t ra ti o n . R e la t i v e b i oa v a i la b il it y i s c a lc u la te d as th e r a ti o o f th e A UC f o r th e d o sa g e f o rm to th e A U C f o r th e re f e re nc e d os a ge f o rm gi ve n i n th e s am e d o se . A r e l at i ve bi oa v a i la bi l it y o f 1 ( o r 1 00 % ) im p li es th a t d r u g b io a vai l ab il i t y f ro m b o th d o sa g e f o rm s is th e s am e b ut do es no t in di ca t e th e c om p le t en es s o f s ys te m ic d r u g
a b so r p ti on . Th e d e te r m in a t io n o f re l at i ve b io a v a il a bi l it y i s im p or t an t in gen e r ic dr u g s t ud i es (e . g. , bi oe q ui v a le n c e s t u di es ) . B i oe q ui v al e nc e i s a re l at i v e b i oa va i la b il i t y s t ud y.
B . Ab s o l u t e b i oa va i l a bil i t y ( F ) i s th e f r ac t io n o f d r u g s ys te m i c a ll y a bs o rbe d f ro m t h e d os a ge fo r m . F i s c alc u la t ed as th e ra ti o of the A U C f o r t he do sa g e f o rm gi v e n o r a ll y t o t h e A U C o bt a ine d af t e r i nt r a ve no us ( I V ) d r u g a dm in is t ra t io n (a d ju s te d fo r d o se ) . A p a re n te r al d ru g s ol u ti o n g i v en b y I V a dm i ni st r a ti on is c o ns id e red t o h a v e 1 0 0 % s y s t em ic ab s o r p ti on ( i .e . , F = 1 ) . A n F v a l ue o f 0 . 80 (o r 80 % ) i nd ic at e s t h at o n l y 80 % o f th e d r ug wa s s ys t em ic al l y a vai l ab l e f r o m t he o ra l d os a ge fo rm .
V. BIOEQUIVALENCE STUDIES FOR SOLID ORAL DRUG PRODUCTS A. O b j e c t i ve o f b i o eq u iva l e n c e s t ud i es . Th e o bj e ct i v e o f a b io eq u i val e nc e s t ud y is t o m e as u re an d c om pa r e f o rm u la t io n p e r fo rm a nc e b et we e n t wo o r m o re p h a rm ac e ut ic al l y eq u i v ale n t d r u g p ro d uc ts . B . D e s ig n o f b i oe q ui va le n c e s t ud i es 1 . Th e F D A 's D i v is io n o f B i o eq u i v al e nc e, O f fi c e of G e n e ri c D r u gs p r o vi de s g u id an c e f o r th e p e r fo r m a nc e o f i n v i t r o d is so l ut i on an d i n v i v o b i oe q ui v a le nc e s t udi e s. Th e se g u id a nc es ar e a v ai la b le a t ww w. f d a . g o v / cd e r /g u id a nc es . 2 . F as t i ng s tu d y. B i o e q u i v a le n c e s t ud i es a r e u s u a ll y e va lu a t ed b y a s i ngl e - do s e , t wo - p e r i od , t wo - t r ea tm e nt , t wo - s eq u en ce , o p en - lab e l , r a nd om i z ed c ro s s o ve r d es ig n , c om p a ri ng eq u al do s e s of t h e t es t (g en e r ic ) a nd re f e r en c e ( br a nd ) pr o du c ts in f a s te d , a du l t, he a lt h y s ub j ec ts . a . B ot h m e n a nd wo m en m a y be us e d i n t he s t udy. b . B lo o d s a m pl in g i s p e rfo r m ed ju s t be f o re th e d os e ( z e ro ti m e ) an d a t a pp r o p ri a te i n t er va l s a ft e r t h e d os e to o bt a in an ad e qu a te des c ri p ti o n o f t he pl as m a dr u g c o nc en t r at i on v e rs us t im e p r of il e . P.150
3 . F oo d in t e r ve n t io n s tu d y. I f t h e b io a v a il a bi li t y o f th e a ct i ve dr u g i ng r ed i en t is k n o wn t o b e a ff e c t e d b y f o o d, t he ge ne r ic d ru g m a n u fa c t u r e r m u s t in c l u de a si ng l e d o se , ra n do m i z e d , c ro s s o v e r , fo o d e f fe c t s s tu d y c om p a ri ng eq u al do s e s of t h e t es t p r o du c t a nd r ef e re nc e pro d uc ts gi ve n i m m e di a te ly a f t e r a s t an d a rd hi gh - fa t - c o n te n t b r e ak f as t . 4 . O t h e r s t u d y d e s i g n s . C r o s s o v e r s tu d ie s m a y n o t b e p r ac t ic al in d ru gs wi t h a l o ng ha l f -l i fe in th e b o d y, a nd a p a ra l le l s tu d y de s i gn m a y be us e d i ns te ad . A l t e rn a te s t u d y m e th o ds , s uc h a s i n vi t r o s tu di es o r e qu i val e nc e s tu di e s wi t h c li n ic al o r p ha rm a c o d y na m i c e n d p o in ts , ar e u s ed fo r dr ug p r od uc ts wh e r e p l as m a
c o nc en t r at i on s a r e n ot us e fu l to de t er m i n e d el i v er y o f t he d ru g s ub st a nc e t o t he s i te o f ac t i v it y ( s u c h as in ha le r s , n as al s p r a y s, an d t op i c a l p r od uc t s a pp li e d t o t h e s k i n) . 5 . Wa i ve r o f a n in vi vo b i o e qu i va l en c e s t ud y ( B i ow a i ve r ) a . A c om p ar a ti v e in v i t ro d is s o l ut i on ( dr u g -r e le ase ) s t u d y be t we e n t h e t est a nd t he r e f e re nc e pr o du c t s m a y b e us ed in li eu o f a n i n v i v o b io eq u i v al e nc e s tu d y f o r s om e i m m e di a te - r el e as e ( c o n ve n t io na l ) o r al d ru g p r o duc t s . b . N o b i oe qu i v a le nc e s t ud y i s r e qu i re d fo r c e r ta in d r u g p ro d uc ts gi v e n a s a so l ut i on s uc h a s o r al , pa r en t e ra l , o p ht h al m i c , o r o th e r s olu t i on s b ec au se bi o eq ui va l en c e is s e lf - e vi de n t. In t hi s c a s e, t h e d ru g i s i n a pu r e a qu e o us s ol u ti o n a nd th e r e i s n o d r u g d is s o lu t io n ra t e c ons i de r a ti on . c . Im m e di a te r el ea s e ( I R) s ol id o ra l d r u g p ro d uc ts t ha t m ee t bi op h a rm ac eu t ic c l as s i fi c a t io n ( B C S ) s y s te m c la s s 1 d r ug s , i. e . , h ig h l y wa t e r s ol u bl e , r a pi dl y d i ss ol vi n g, an d ra pi d p e rm e at i on of c e ll u la r m em b r a ne s m a y o b ta i n a b i owa i v e r . d . D r ug p ro d uc ts c o nt a ini n g a lo we r d os e s t re n gth ( e .g . , 2 00 m g , 1 0 0 m g , a n d 5 0 m g I R t a bl e ts ) . Th e d ru g p r od u c t m u s t be in t he s am e d os ag e f o rm , l o we r s t re n g th , a n d i s p r o po r ti o na t el y s i m i l a r i n i ts ac t i ve a nd in ac t i ve i ng r ed i en ts . B . P h a r ma c ok i ne t i c e val u a t i on o f t h e d a ta . Ph ar m ac ok i ne t ic a n al y s is i nc l ud es c a lc ul a ti on f o r e ac h s u b je c t o f t h e A U C t o t h e la s t q ua n ti f ia b le c o nc en t r at io n ( A U C O t)
a nd to in f in i t y ( A U C 0 - ∞ ) , T m a x , a n d C m a x . I n a dd it i o n, th e el im in a ti o n r a te c on s ta n t
( k ) , t h e e li m i n at io n ha lf - li f e (t 1 \ 2 ), an d o t he r pa r am e te r s m a y b e e s tim a t ed . C . S t a t is t i ca l e va l u a ti on o f t he da t a 1 . Th e s t at is t ic al m e t ho do l og y f o r a n al yz i n g b io eq u i v al e nc e s tu d ie s is c a ll e d t h e t wo o n e -s id e d t es t p r oc e du r e. Two s i t u at i on s a r e t es te d wi t h th is s t a ti s t ic a l m e th o do l og y . a . Th e fi r s t of t he t wo one - s id ed t es ts de t er m i n es wh e t h e r a ge n e ri c p ro d uc t ( te st ) , wh e n s ub s ti t ut e d f o r a b ra n d -n am e p r o du c t ( r ef e re n c e ) is s ig n if ic a nt l y le ss b i oa va i la b le . b . Th e s ec o nd o f t he t wo o n e -s id ed t es ts de t er m in e s wh e t h e r a b r a nd - nam e p r o du c t ( r e f e re nc e ) wh e n s u b s t i tu t e d f o r a g e ne r ic p ro duc t ( te s t ) is s ig n if ic a nt l y le s s b i oa va i la b le . c . B as ed on th e o p in io ns o f F D A m e d ic al e xp e r ts , a di f fe r e nc e o f > 20 % f or e ac h o f t h e a b o v e t es ts wa s de t er m i ne d t o b e s ig n if ic a nt a n d , t he r e fo r e , u nd es i rab l e f o r a ll d r u g p r od uc t s . 2 . A n a na l y s i s o f v a ri an c e ( A N O V A ) s h ou l d b e p er f o r m e d o n t h e l og t ra ns fo r m ed A U C a n d C m a x v a l u e s o b ta i ne d f ro m e ac h su b je ct . Th e 9 0% co n fi de nc e i n te r va l s f o r b o t h p ha r m a c o k i n et ic par a m et e rs , A U C a n d C m a x , m us t b e e n ti r el y wi t h i n th e 80 % t o 1 2 5 % b ou nd a r ie s b as ed o n lo g t r a ns fo r m a t io n o f t h e d a ta . Th e ra t io of th e m ea ns o f t h e s t ud y d at a (t es t to r ef e r e nc e) sh o ul d l ie in th e c en t e r o f t h e 9 0% c o nf id e nc e i n t er va l , o r c l os e t o 1 00% ( e qu i val e nt t o a t es t to r e fe r en c e r a ti o o f 1 ) ( Ta b le 7 -1 ) . 3 . D i ff e re n t s ta t is t ic al c r it e r ia a re so m e t im es u s ed wh e n bi o eq ui v a l en ce is d e m o ns t r at e d t h ro u gh c om p a ra t i v e c l i ni c a l t r ia ls , p h a rm ac o d y na m i c s tu di es , or c om p a ra t i v e i n v i t r o m e th o d ol og y. 4 . Th e bi oe q ui v a le n c e m e t h od ol o g y an d c ri t e ri a de sc r i be d a bo v e s i m u l ta ne o us l y c o nt r o l f o r b ot h d i ff e r en c e s i n th e a v e r ag e re sp o ns e b e t we e n t es t an d r e fer e n ce p r o du c ts a s we ll as th e pr e c is io n wi t h wh i c h t he av e r a g e r e s p on s e in t he po p ul a ti o n
i s e s ti m a t ed . Th is p r ec is i o n d ep e nd s o n t h e wi t h in - s ub je c t ( n or m a l v ol u nte e r or p a t ie n t ) v a r ia b il i t y i n t h e p h a rm ac ok in e ti c p a ra m e t e rs ( A U C a n d C m a x ) o f t h e t wo p r o du c ts a n d o n t he nu m b e r of s u bj ec t s i n t he s t ud y . Th e wi d t h o f th e 9 0 % c o nf i de nc e i n te r v a l i s a re f l ec ti o n i n p a rt of t he wi t h i n- s ub je c t v a r ia b il i t y o f t h e t es t a n d re f er e nc e p r od uc t s in t he bi o eq ui va l en c e st ud y . P.151
Table 7-1. Bioavailability Comparison of a Generic (TEST) and Brand (Reference) Drug Product LN-Transformed Data 90 % Confide nce Geometric Mean Interval
PK Variabl e Units
x
ng/ mL
AU C0-t
ng hr/ mL
Cma
AU Cinf
ng hr/ mL
Test
344. 79
265 9.12
270 8.63
(Lower % Limit, Referenc Ratio Upper e T/R Limit)
96. 6
(89. 5, 112 )
0.3 586
0.8 791
17.9 0%
99. 4
(95. 1, 104 )
0.8 172
1.0 000
12.6 0%
271 8.52
99. 6
(95. 4, 103 )
0.8 865
1.0 000
12.2 0%
356. 81
267 4.92
hr
4.29
4.24
10 1
1/h r
0.09 61
0.09 80
98. 1
Tma x
keli m
Pvalues Power for of Product ANOV ANOVA Effects A % CV
t1/2
hr
8.47
8.33
10 1.7
AUC, area under the curve; Cmax, peak plasma drug concentration; Tmax, time for peak plasma drug concentration. The results were obtained from a two-way crossover, single-dose, fasting study in 36 healthy adult volunteers. Mean values are reported. No statistical differences were observed between AUC and Cmax values for the test and reference products.
P.152
VI. BIOEQUIVALENCE ISSUES A. P r o b l e m s i n d e t e rm in i n g b i o eq u i va le n ce in cl u de la ck of an ad e qu a te s t ud y d e si g n; in a bi li t y t o ac c u ra t e l y m ea su r e th e d r ug an a l y t es , i nc lu d in g m et a bo l i te s a nd e n a nt io m er s ( c hi r al d ru gs ) ; a n d l ac k o f s y st em ic d r u g a bs o rp t io n ( Ta bl e 7- 2 . ) B . B i o e qu i va l en c e s t udi e s fo r wh i ch ob je c ti v e bl o od d ru g c on c en t ra t io ns c an n ot be o b t ai ne d re q ui r e e i th e r a p h a rm ac od y n am ic st u d y, a c li n ic al t ri a l, o r a n i n v i t r o s t ud y t h at ha s b ee n c o r re l a te d wi t h h um an in v i vo b io a v ai l ab i li t y da t a. 1 . P ha r m a c o d y n am ic m ea s u re m e n ts a r e m o re di ff i c u l t t o o b ta in , an d t h e d a t a t en d t o be va r ia b le , re qu i r in g a l ar g e r n um be r of su bj ec t s c o m p a r ed to t he b i oe q ui v a l en c e s t ud i es fo r s y s t em ic a ll y a bs o rb ed d r u gs . a . A b i oe q ui v a le nc e s t udy u s in g p h a rm ac od y n am ic m e as u re m e n ts t ri es to o b t ai n a p h a rm ac o d y na m i c e ff e c t v e r s us t im e p ro f il e fo r the d r ug in ea c h s u bj ec t . b . Th e a re a u nd e r t h e e ff e c t v e r s u s t im e p r o fi le , p e ak ef f ec t , a nd t im e f o r p e ak e f f ec t a r e o b ta in e d f o r t he t es t a n d r e fe r en c e p rod u ct s a n d a re t he n s ta t ist i ca l l y a n al yze d . 2 . C om p ar a ti v e c l in ic a l tr i a ls a r e m o re di f fi cu l t t o r u n , d o n ot ha v e e as il y q u a nt i fi ab l e o bs e r v at i ons , an d a r e q ui t e c os tl y . 3 . I n vi t r o s tu di es m a y r eq u i re t he de v e lo pm e nt o f a r el ia b le s u r r og a te m a rk e r t h at m a y be c o r r el a te d wi t h hu m an in vi v o b i oa v a i la bi li t y d a ta . F o r e xa m p l e, t he p e n et r a ti on o f d ru g i n to la y e r s o f s k i n wi t h r es p ec t t o t im e ( d e r m a to p ha r m a c o k i n et ic s ) h as be en s u g ge st e d a s a m e t ho d f o r m ea su r in g th e b i oe q ui v a l en c e of t op ic al d r u g p ro d uc ts in t en d ed f o r lo c a l a c t i vi t y.
VII. DRUG PRODUCTION SELECTION A. G e n e r i c d r ug s ub s t itu t i o n 1 . G e ne r i c d r u g s u bs t i tu t i o n i s t he p ro c e s s of di s pe ns i ng a g en e ri c d r ug p r o du c t in p l ac e o f th e p r es c r i be d dr u g pr o du c t ( e .g . , g en e ric p ro d uc t f o r b r an d - na m e p r od uc t , g e n er ic p ro d uc t f o r a no th e r ge ne r ic p ro d uc t, b ran d - na m e p ro d uc t f o r g ene r i c
p r o du c t) . Th e s ub s ti t ut ed p r od uc t m us t b e a th e ra p e ut ic eq u i v al en t to th e p r es c ri be d p r o du c t. 2 . G e ne r ic dr u g p r od uc t s t h a t a re c l as s i f ie d a s t he r a pe u ti c e qu i v a le n ts b y t h e F D A a r e e xp e c t e d t o p r od uc e t h e s am e c li ni c a l e f f ec t a n d s af e t y p ro f il e a s t he p r e s c ri b ed drug.
Table 7-2. Problem Issues in the Determination of Bioequivalence Problem Issues
Example
Drugs with highly variable bioavailabilitya
Propranolol, verapamil
Drugs with active metabolites
Selegiline
Chiral drugs
Ibuprofen, albuterol
Drugs with nonlinear pharmacokinetics
Phenytoin
Orally administered drugs that are not systemically absorbed
Cholestyramine resin, sucralfate
Drugs with long elimination halflives
Probucol
Variable-dosage forms
Dyazide, conjugated estrogens
Nonoral drug delivery Topical drugs
Steroids, antifungals
Transdermal delivery systems
Estrogen patch
Drugs given by inhalation aerosols
Bronchodilators, steroids
Intranasal drugs
Intranasal steroids
Biotechnology derived drugs
Erythropoietin, interferon
Bioavailable drugs that should not reach peak drug levels
Potassium supplements, hormone replacement therapy
Target population used in the bioequivalence studies
Pediatric patients; renal disease
a
These drugs have high intrasubject variability.
P.153
3 . P r es c r i ba b i li t y r e f e r s t o th e m ea s u r em e nt of a v e r a ge bi o eq u i v al en c e in wh i c h t h e c om pa r is o n o f p op u la t i on m e an s o f t h e t es t an d r ef e re n c e pr o du ct s f al l s wi t h i n a cc e pt a bl e s t at is t ic al c r it e r ia . P re s c r ib a bi li t y is th e c u r re n t b as is fo r F D A a p p ro v a l o f t he r ap e ut ic eq u i v al en t g e ne r ic dr u g p r od uc ts . 4 . Sw i t ch a bi l i t y r e f e r s to t he m e as u re m e n t o f i nd i v i du a l b io e qu i v al e nc e, wh i c h r e q ui r es k n o wl e dg e o f i nd i v i du a l va r i ab il i t y (i n t ra s u bj ec t va ri a bi li t y) an d su b je c t -b y f o r m u l at io n ef f ec ts . S wi tc h ab il i t y en su r es th a t t he su bs t i tu t ed ge n er ic d rug p r od uc t p r o du c e s t h e s a m e r es po n s e in th e i n di vi d ua l p at i e n t . B . T h e ra p e ut i c s u bs t i t ut i o n 1 . Th e r ap e ut ic s u bs t it u tio n is th e p r oc es s o f d is pe n s i n g a t h e ra pe u ti c a l ter n a ti ve i n p l ac e o f th e p r es c r i be d dr u g pr o du c t. Fo r e xa m ple , am o xi c il l in is d is p en s e d fo r a m pi ci ll i n. 2 . Th e s u bs ti t ut e d d r ug p r o du c t is us ua l l y i n t h e s am e th e ra p eu t ic c la s s (e . g . , c a lc iu m c h a nn e l b lo c k e r) a n d is e xp e c te d t o h a v e a s i m i la r c l in ic al p ro f il e . C . F o r m ul a r y i s s u e s 1 . A fo r m u la r y i s a li s t of d r ug s . A po s i ti ve f o rm u l a r y l is t s a ll th e d r u gs th a t m a y be s u bs ti t u te d , wh e r e as a ne g a t i ve f o rm u la r y li s ts dr u g s f o r wh i c h t he p ha rm a c is t m a y n o t s ub s ti t ut e . A r e st r i c ti ve f o rm u la r y l is ts on l y th o s e d ru gs th a t m a y b e re i m b u rs ed wi t h o u t j us t i fi c a t io n b y th e p re s c ri b e r; f or d ru gs n o t l is t ed in th e re s tr ic t ive f o r m u l ar y , t he p re s c r ib e r m us t j us t if y t h e n ee d f o r t h e n on l is te d d r u g. 2 . Ma n y s t a te s h a v e l ega l re q ui r em e nt s t ha t ad dr e ss t he i ss u e o f d r ug p ro d uc t s e le ct i on . St a t es m a y pro v i d e i n fo r m a t io n a nd gui d an c e in d ru g p r o du ct s e l ec t io n t h r o ug h p os i ti v e , n e ga t i ve , o r r es t r ic ti v e f or m u l a rie s . 3 . Th e F D A a nn u al l y pu bl i s h es A pp r ov ed D r ug P ro d uc ts w i th Th e r ap eu t ic E q u iv al e nc e E v a l ua t io ns ( t h e “ O r a ng e Bo ok ” ) . Thi s p u bl ic a ti on is al so r epr o d uc ed in t h e Un i te d S ta t es Ph a r ma c op e ia ( U S P ), D I Vo l . I II , A pp r ov e d D r u g P r o du ct s an d L e g al R eq ui r e m e nt s , p ubl i s h ed an n ua l l y b y t h e US P C o n ve nt i on . Th e “ E l e c t r on ic O r a n g e B o ok ” m a y be fou n d a t h t t p: / / ww w. f d a . g ov / c d e r /o b /d e fa ul t . ht m .
a . Th e “ O r an ge B oo k ” p ro v i d es th e r ap e ut ic e v al ua t i on c o de s f o r d r ug p rod u c t s ( Ta b l e 7 - 3 ) .
Table 7-3. Therapeutic Equivalence Evaluation Codes A Drug products that are considered to be therapeutically equivalent Codes to other pharmaceutically equivalent products AA
Products in conventional dosage forms not presenting bioequivalence problems
AB
Products meeting bioequivalence requirements
AN
Solutions and powders for aerosolization
AO
Injectable oil solutions
AP
Injectable aqueous solutions
AT
Topical products
Drug products that the FDA does not at this time consider to be B therapeutically equivalent to other pharmaceutically equivalent Codes products BC
Extended-release tablets, extended-release capsules, and extendedrelease injectables
BD
Active ingredients and dosage forms with documented bioequivalence problems
BE
Delayed-release oral dosage forms
BN
Products in aerosol-nebulizer drug delivery systems
BP
Active ingredients and dosage forms with potential bioequivalence problems
BR
Suppositories or enemas for systemic use
BS
Products with drug standard deficiencies
BT
Topical products with bioequivalence issues
BX
Insufficient data
FDA, U.S. Food and Drug Administration.
P.154
( 1 ) “ A - “ ra t ed ” d ru g p r od uc t s a r e d ru g p r o du ct s t ha t c o n ta in ac t i v e i ng r ed ie n ts an d d o sa g e f o rm s t ha t a r e no t r eg a rd e d a s p re se n ti ng e it h e r ac t ua l o r po t en t ia l b i oe q ui v a l en c e p ro bl em s o r d ru g q ua l it y s ta n da r ds i s s u es . H o we v e r , a ll o ra l do sa g e f o r m s m us t m ee t an ap p ro p r ia t e i n vi t r o b io e qu i v al e nc e s ta n da r d t h at is ac c e pt a bl e t o t he F D A t o b e a pp r o ve d as th e ra p eu t ic al l y equ i v a le n t a n d m a y b e i nt er c h an ge d . ( 2 ) “ B “ - ra t ed ” d ru g p r od uc t s a r e d ru g p r o du ct s f o r wh i c h a c tu a l o r p o te n ti al b i oe q ui v a l en c e p ro bl em s h a v e n o t b ee n re s o l v e d b y a d eq u at e e vi d en ce of b i oe q ui v a l en c e . Th es e pr o d uc ts o ft e n h a ve sp ec if i c d os ag e fo r m p ro b le m s r at h e r t h a n a p r o bl em wi t h th e a c ti v e in g r ed ie n ts (e . g ., t wo d i f f er e nt ni c ot in e pa tc h es ) . “ B “ r a t ed ” d ru g p r od uc t s a re n ot c o ns id e r ed th e r ap eu t ic a ll y e qu i val e nt t o o the r p h a rm ac e ut ic al l y eq u i v ale n t p r o du ct s a nd a re no t i n te r c h a ng ea b le . ( 3 ) C e r ta in p ro d uc ts pr es e nt s p ec i al s i tu a ti on s t ha t de s e r v e a m or e c om p le t e e xp l a n a ti o n t h an c a n b e p r o v i de d b y t h e t wo - c ode s u s e d i n th e “ O ra n ge B o o k . ” Th e s e d r u gs h a v e p a r ti c u l a r p r ob le m s wi t h s t an da r d s o f i de n ti t y, an al yt i ca l m e th o do l og y , o r b io eq u iv a l e nc e t h at a re co ns id er e d i n di vi d ua ll y . F o r t he s e d r ug s , c o ns ul t th e “ O r a n ge B ook . ” b . F o r s o m e d ru g p r od uc t s , b i oe qu i v a le nc e h as no t be e n es t ab l is he d o r no g en e ri c p r o du c t is c u r r en t l y a v a i la b le . 4 . V a ri ou s h os p it al s , i ns ti t u ti o ns , i ns u ra nc e p l an s, h ea l th m a in t en a nc e o r ga n i za ti on s ( H M O s ) , a nd ot h e r t hi r d -p a r t y pl a ns m a y ha ve a fo r m ul a r y th a t p r o v id es gu i da n ce f o r d ru g p r od uc t s u bs ti t ut i o n. P.155
STUDY QUESTIONS
D i r e c t i on s fo r q ue s t io ns 1 - 3 : E ac h o f t h e q ue s tio n s , s t a te m e n ts , o r in c om p le t e s t a te m e n ts i n th is s ec t ion c a n b e c o r re c t l y a ns we r e d or co m p le t e d b y o ne o f th e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r . 1 . T he pa r a me t e r s u se d t o d es c r ib e b i o a va il a b il i t y a r e ( A ) C m a x , A U C 0 - t , an d A UC 0 - ∞ . ( B ) C m a x , A U C 0 - t , A U C 0 - ∞ , a nd T m a x . ( C ) C m a x , A U C 0 - t , A U C 0 - ∞ , a nd t 1 \ 2 . (D) Cma x a n d AUC0- t. ( E ) C m a x , A U C 0 - t , A U C 0 - ∞ , a nd T m a x , a n d t 1 \ 2 . V i e w A n s we r 1 . T h e a n sw e r i s B [ se e] . C T t 2 . T o d e t e r mi n e t h e a bs o l u te b i o a va i la b i li t y o f a d r ug g i ve n a s a n o ra l e x t en d e d - re l ea s e t a b le t , t he b i o a va i la b i li t y o f t h e d ru g m us t be co m pa r e d to t h e b i oa va i l ab i l i t y o f t h e d r ug from ( A ) a n im m ed ia t e - re le as e o r al ta bl e t c on t ai ni n g th e s am e a m ou n t o f ac t i ve i n g re d ie n t. ( B ) a n o r al s o lu t io n o f the d r ug in th e s am e d os e . ( C ) a pa r en t e ra l s ol u ti o n o f th e d r ug gi v e n b y i n t ra v e n o us (I V ) bo lu s o r I V i n f us io n . ( D ) a r ef e re n c e (b r a nd ) e xt e n d e d - re l ea se ta b le t t h a t i s a p h ar m a c eu t ic al e q ui v a l en t . ( E ) a n im m ed ia t e - re le as e h a rd ge la t in c a ps ul e co n t a i ni n g t he s a m e am ou n t o f ac ti ve d r u g a nd la c to s e . V i e w A n s we r 2 . T h e a n sw e r i s C [ se e] . F 3 . A s i ng l e - do s e , tw o -w a y c r o s so ve r , f a st i n g, c om p a r a ti ve b i oa va i l ab i l i ty s t u d y w as pe r f o r me d i n 2 4 h e a l th y, a d u l t ma l e s u bj e c t s. P la s ma d r ug co nc e n t r a ti o ns w e r e o b t ain e d fo r e a c h s ub j e ct , an d th e re s u l ts sh ow n in Ta b le 7- Q 3 w e r e ob t a in e d . T he r e l a t i ve b i o a va i la b i li t y o f t h e d ru g f r o m t h e g en e r i c t a bl e t co m pa r e d t o t he r e fe r e n ce tablet is
Table 7-Q3 Drug Product
Dose (mg)Cmax (µg/mL)Tmax (hr)AUC0-∞ (µg hr/mL)
IV bolus injection
100
Oral solution
200
21.3
1.2
3143
Generic tablet
200
17.0
2.1
2822
Reference tablet
200
16.5
1.9
2715
IV, intravenous. ( A ) 8 2 .3 % . ( B ) 6 9 .8 % . ( C ) 9 1 .7 % .
1714
( D ) 9 6 .2 % . ( E ) 1 03 . 9% V i e w A n s we r 3 . T h e a n sw e r i s E [s e e] . D i r ec t i o ns f o r qu e s ti o ns 4 -6 : Th e q u es t io ns an d i nc om p le te s ta t em en ts in t hi s s e c ti o n c an be c o r r ec tl y a ns we r e d o r c om p le t ed b y on e o r m or e o f t h e su g ge s te d a nswe r s . C h o os e t he an s we r , A- E . P.156
4 . F o r tw o d r ug p r od u ct s , ge n e r ic ( te s t ) a n d br a n d ( r ef e r e nc e ) , t o b e c o n si d e r ed b io e qu i va l en t I . t h e re sh o u ld be n o s ta t i s t ic a l d i f fe r e nc e b e tw e en t he ex t e nt o f b i oava i l a b i li t y o f t h e d r u g f r o m t h e t es t p r o du c t c o mp a r ed t o t h e r ef e r e nc e p r o d uc t . I I . t he 90 % c o n f i d e nc e in t e r va l s a b o ut t h e r a t io o f t he me a ns o f t h e C m a x a nd AU C va l u e s fo r t h e t es t p r o d uc t t o r e f e re n ce pr o d u c t m u st b e w i t h in 8 0 %- 1 2 5 % o f t h e r e f e re n ce p r od u ct . I I I . th e r e s h ou l d b e n o s t a t is t i ca l di f f e r en c es b e tw e e n t h e m ea n C m a x a n d AU C va l u e s fo r t h e t es t p r odu c t co m pa r e d t o t he r e fe r e n ce p r od u c t. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 . T h e a n sw e r i s E [s e e] . T C 5. F o r w h ic h of t h e f o ll ow i n g p r o d u c ts is me a su r i n g p l a sm a d r u g c o n ce n t r at i o n s n o t a p p r op r i a te fo r e s t i ma t i ng b io e qu i va l en c e ? I . m et e r e d- d os e in h al e r c o n ta i n in g a b r o nc h odi l a t o r I I . an t i f un g a l a ge n t fo r t h e t r ea t me n t of a va gin a l in f e ct i o n I I I . e n t e r ic - co a t ed t ab l et c o n ta i n in g a n on s te r oi d a l a n t i -i n f la m ma t o r y a g e n t A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 5 . T h e a n sw e r i s C [ se e] . 6 . Bi o e qui va l e n ce s tu d i es co m par e t h e b io a va i la b i li t y I . o f th e g e ne r i c d r u g pr o d u c t t o t he b ra n d d r ug p r o d uc t . I I . o f a r ef o r m ul a t ed b ra n d d ru g p ro d u ct t o the o r i gi n a l f o r mu l a ti o n of t h e b r a n d p r o d u c t. I I I . of a t o - be - m a rk e te d b r a n d p r o d uc t t o t h e d ru g p r o du c t u s ed i n t h e c l i n ic a l trials. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t
V i e w A n s we r 6 . T h e a n sw e r i s E [s e ea n d] . P . 15 7
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee I I I . B] . A U C r e l at es t o t he e xt e nt o f d r ug ab s or p ti o n. C m a x a n d T m a x r e l a t e to th e ra t e o f d r u g a bs o rp t io n . Th e el im i na t io n t 1 / 2 o f t h e d ru g i s u s u a ll y i nd e pe nd e nt of t h e r ou t e o f d ru g a dm i ni s t r a ti on and is no t us ed as a m e as u r e of bi o a vai la b il i t y. F or t h e F D A , o n l y th e C m a x a n d A U C pa r a m e t er s m us t m ee t 9 0% c o n fi d en c e in t e r v al s of 8 0 -1 2 5% o f t he re f e re nc e (b r an d ) p r o du c t ( Ta b le 7 .1 ) . 2 . T he an sw e r is C [ s ee I V . B ] . A f t e r a n IV bo l us i n je c t i on o r I V in f us io n , a ll th e do s e is ab s or b ed in t o t he b o d y. Th e r a t io o f t he A U C of t he dr u g gi v e n o r al l y to t he AU C o f th e d r u g g i ven b y I V i nj ec t io n i s u se d to ob t ai n t h e a bs o l u te bi oa v a i la b il it y ( F ) of t h e d ru g . 3 . T he an sw e r is E [ s e e I V . A ] . Th e r e la t i v e b io a v a il a bi lit y i s d e te r m i ne d f ro m t he r a t io of t he A U C o f th e g e n er ic ( t e st ) p ro d uc t t o t h e A UC o f th e re f e re nc e s ta n da r d . Th us th e re la t i v e b io a v a il a bi li t y c a n e xc e e d 1 00 % , wh e rea s th e a bs ol u te bi o a v ai la b il i t y c a nn o t e xc e e d 1 00 % . 4 . T he an sw e r is E [ s e e V . C ] . A l t h ou gh T m a x i s a n i n di c a t i on of r at e o f dr u g a bs o r p ti o n , i t is a d is c r e te m e as u re m e n t a nd us ua l ly t o o v a ri a bl e t o u s e f o r s t a ti s t ic a l c o m p a ri s on s in b i oe q ui v a l en c e s t ud i es . S t a t is ti ca l c om p ar is o ns u s e A U C a nd C m a x v a l u e s f ro m t es t a n d re f er e nc e d r ug p ro du c ts as th e b as is of bi o eq u i val e nc e . 5 . T he an sw e r is C [ s ee V . A ] . A l t h ou gh s o m e s y s t em ic a b s o r p ti on m a y b e d em on s t ra t ed af t e r a dm in is t e ri n g a m e te r e d d os e i nh al e r c on t a in in g a b ro nc h od il a t or o r a v a g in a l a nt i fu n ga l ag e n t, b i oe q ui v a l en c e c a n b e de t e rm i ne d o nl y b y us i ng a c l i ni c a l r e s p on s e m e as u r e m e n t. 6 . T he an sw e r is E [ s e e I . A , B, C , D a n d E ] . B i o eq u i v al e nc e s tu di es c o m pa r e t h e b io a v ai l ab il i ty o f a d r ug f r om o n e d rug p r od uc t t o an o th e r d r ug p ro d uc t c o nt a in in g th e s am e a ct iv e i n g re di e nt . D r ug pr o du c ts s uc h a s c ap s ul es th a t a r e us ed i n c l i ni c a l t r ia ls sh ou l d b e b i oe q ui va le n t t o t h e m a rk e te d d r u g p r od uc t wh i c h m a y b e a t ab l et . G en e r ic d r ug p r o du c t s a nd t he c o r re sp o n di ng b r a nd d ru g p r o du c t m u s t b e b i oe q ui v a le n t . F o r an y c ha n ge a f o rm ul a ti o n, t h e m a nu f ac tu r e r (b r an d o r ge n e ri c ) m u s t d em on s t r a te t ha t th e f o rm u la t io n c ha n g e d oe s n o t a f f ec t t h e bi o a v ai l ab il i t y c o m p a re d t o th e o r ig in a l p r od uc t .
8 Functional Group Chemistry and Biochemistry M a r c W . Ha r r o l d
I. FUNCTIONAL GROUP CHEMISTRY A. I n t r o d u c t io n . D ru g m o l ec ul e s ca n b e v ie we d a s a c o ll ec t io n o f fu nc t ion a l g r ou ps ( i . e ., g ro u ps o f at om s p re s en t wi t hi n th e d r ug t hat c on f er s p ec i fi c c h e m i c al a nd p h ys ic al p ro pe r t ie s [ F ig ur e 8 -1 ] ) . F u nc ti o na l g r oup s d e te r m i n e s u c h c h a rac t e ri st ic s a s i o ni z a t io n , s o l ub il i t y in a qu e ou s a nd li pi d e n v i r o n m e n ts (a k a po l ar i t y ) , r e a ct i vi t y, c h em ic al s t ab i li t y , an d i n v i v o m et a bo li c s ta b il i t y . A d d i ti on a ll y, t he se fu nc t io n al g r o up s a r e c a pa b le o f fo r m i n g s pe c i fi c bo n ds ( p r im a r il y n on co v a le n t ) wi t h t h ei r r e c ep t or s a n d a re t hu s ext r e m e l y im p o rt a nt in d rug ac t i v i t y a n d p ot e nc y. 1 . F un ct i on al g ro u ps t h at i m p a r t h yd r o p h i l i ci t y a r e li k e l y t o i nc r ea s e th e d r u g 's wa t e r s ol u bi li t y , wh i l e f un c ti o na l g r ou ps t ha t i m pa r t l ip o ph i l ic i t y ( h yd r o p h o bi c i t y) a r e l ik e l y to in c re as e t h e d r u g 's te n de nc y t o c r oss ce ll u la r m em b ra n es th ro u g h p a ss i ve d if f us io n . Se e Ch a p te r 12 V II I B 1 fo r a fu r t h er di s c us s i o n o f wa t e r a nd li pi d s o lu bi l it y . a . A c i di c a nd ba s i c f u nc ti o na l g r o up s a ll o w f o r d r u g i on i za t i on an d , i n m o s t c as es , i m pa r t e n ha nc ed wa t e r s o l ub i li t y t o t he m o le c u l e. O n e no t ab l e e xc e p ti o n to t hi s i s s e en in am p ho t e r ic d r ug s ( i. e ., t ho s e c o m p ou n ds po ss es s i n g b ot h a c i d ic a n d b as ic f u nc t io n al g ro up s ). A s e xe m pl i fi ed b y am pi c i ll i n i n F i gu r e 8 - 2 , am p ho t er ic c om p ou n ds c an f o rm z w it t e r i o ns , or i n te r n al sa lt s . S in c e th e z wi t t e ri o n fo r m o f a m pi ci ll i n h as a ne t o v e ra l l c ha r ge o f z e r o , i t h as d i ff ic u lt y d is s o l v i ng i n aq u e ou s e n vi r on m e n ts s uc h as t he g as t ro i nt es t in a l ( G I ) t ra c t . b . N e ut r al f un c t i on al g rou p s ( i .e . , t h os e t ha t ar e in c ap a bl e o f i o ni za t io n ) c a n e n h an c e ei t he r wa t e r o r li p id s o lu b il i t y d e pe n di ng o n th e i r a bi li t y t o f o rm hyd r o g e n b o n d s w i t h w a te r . H y d ro g e n b on di n g is t he pr im a r y m ec ha n ism f or in c rea s in g t h e wa t e r s ol u bi li t y o f n on e le c t ro l y t es (i . e ., c om p ou nd s th a t d o n ot po s s es s ac i di c , b a si c, o r q ua t e rn a r y am m o ni um fu nc t io n al g ro ups ) . 2 . F un ct i on al g ro u p r e act i vi t y a f f e c t s d r u g s h el f l i f e , s ta b i li t y, a n d s to r a g e . Th er e a r e a n um be r of fu nc t io na l gr o up s t h at wi l l d e gr ad e , p r im a ri l y t hr o ug h a i r o xi d a t i on a n d h yd r ol y s is , u n de r nor m a l e n vi r o n me n t al c ond i t i o ns . Two e xa m p l es of t hi s l a t te r c o nc e rn a re s e en wi t h a s p i r in an d n i tr o gl y c e r in . Bo t h co m p o un ds ar e s u b je c t t o r ap i d h y d ro l y s i s i f e xp o s ed to m o is t e n v i r on m en t s . 3 . F un ct i on al g ro u ps a ls o a f fe c t i n vi vo s t a bi l i t y a n d t he du r a ti o n o f d r ug a c ti on . Th e s us c e p ti bi l it y o f a giv e n d r ug to m e t ab ol ic bio t r a ns fo r m a t io n d e pe nd s i n p a r t u p o n t he fu nc t io n al g ro up s th a t a re p re s e n t ( s ee C h a p te r 17 I I, I II ) . a . D r ug s t h at c o n ta in a la r g e n um be r o r p e rc en t ag e of h yd ro p hi li c f u nc ti on a l g r ou ps a r e of t en el im in a te d f rom t he bo d y un c h a ng ed or wi t h m i n im al m e ta b ol ism . b . D r ug s t h at c o n ta in a la r g e n um be r o r p e rc en t ag e of li p op hi l ic fu nc t io nal g ro u ps o f t en r eq u ir e e xt e n s i v e m e ta b ol is m .
Figure 8-1. Ibuprofen, a nonsteroidal antiinflammatory agent, is comprised of an ionizable, hydrophilic carboxylic acid and three hydrophobic functional groups: an isobutyl alkyl chain, an ethyl alkyl group, and an aromatic ring.
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Figure 8-2. Ampicillin is an amphoteric compound. It contains an acidic carboxylic acid and a basic amine and exists in vivo as a zwitterion. The proton from the carboxylic acid binds to the basic amine, producing a molecule with an overall net charge equal to zero.
B . Ac i d i c f un c t io n al g ro u p s 1 . T yp e s . S h o wn i n F i gur e 8 -3 a re e xa m pl es o f th e s i x m o st c o m m on ac id i c f u nc t io n al g ro up s . I n g ene r a l, c a r bo xy l i c a ci ds ten d to be m o r e a c i di c t h an a n y o f t h e o t he r fi v e f un c t i on al g r o up s . Th e te t r a z ol e ri ng p r o vid es th e b es t c h a rg e d e lo c al i z at i on s i nc e r es on a nc e a ll o ws t he c h a rg e t o be eq u al l y s h a re d a m o n g a ll f i ve a to m s i n t h e r i ng . 2 . C o mm o n a t t r ib u t es a . A c i di c f un c ti o na l g r oup s i m p a r t h yd r o p h i l i c it y t o a d ru g m ol ec u le du e to t he i r p o t en t ia l f o r i on i z a ti o n. b . A ci di c f u nc ti o na l g r oup s c an f o rm i o n ic , io n - di p o l e, an d h yd r o g e n b on d s wi t h r e c ep t or s , e n z y m es , t r ans p o rt p ro t ei ns , a n d o th e r m ac r om ol ec u le s . c . Ac i di c f un c t i on a l g ro up s c an f o rm s a l ts w h en c o m bi n e d w i t h b a se s .
d . C a r b ox yl i c a c id s a r e o f t en es t e r if i e d f o r t he p u r po se s o f p r o dr u g f o rm a ti o n ( s e e C h a p te r 17 , s ec t io n VI for a d di ti o na l i n fo r m a t io n ). Th e y c a n a ls o u nd e rg o a c id - or e n zym e c a t al y z e d de c a rbo x yl a t i o n r ea c ti on s . e . M e t ab o l is m . A c i d ic fun c ti o na l g r ou ps ca n u n de r g o c o nj u ga t i o n wi t h glu c u ro ni c a c id , g l y c i n e, an d g l ut am i n e .
Figure 8-3. Examples of drugs that contain an acidic functional group as part of their chemical structure.
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C . B a s ic f un c t io n a l g r ou p s 1 . T yp e s a . Al i p h a ti c an d a l i c yc l i c a mi n es a re th e m os t co m m o n b as ic fu nc t io n al g r o up s . A s s h o wn in Fi g u re 8 -4 , t h es e a m i n es c a n b e p r i mar y, s e c o n d a r y, o r t e r t i a r y, d e p en di n g o n t he nu m b er o f s ub s ti t ue n ts a t t ac hed t o t h e n it r og e n. b . Ar o m a t i c a mi n es , s uc h a s t h at s e en in p ro c a in a m i d e ( Fi g u re 8 -4 ) , a r e m uc h l es s b a si c a nd fo r al l i n te n ts a n d p u rp os e s ca n b e c on s i d e re d n e ut r a l. c . Ar o m a t ic , he t e r oc yc l i c n i t ro g en s v a r y in th e ir b as ic i t y, b u t i n g en e ra l a r e m uc h l e ss b as ic t ha n a li p ha t ic a n d a li c yc l ic am in es ( Fi g u r e 8- 5 ) . d . A dd i ti o na l b as ic fu nc t io n al g ro u ps i nc l ud e i m i ne s , h yd r a z i n e s , a mi d i ne s , a n d g u a n id i ne s (F i gu r e 8 - 6 ). I m i n es te n d t o b e l es s ba s ic th an al i ph a ti c a nd al i c yc l ic a m in es , wh e r ea s g ua n id in e s t en d to be m uc h m o re b as ic . Th e b as ic it y o f th e ot h e r t wo f u n c t i on al g ro u ps l i es s o m e wh e r e i n b e t we e n. 2 . C o mm o n a t t r ib u t es a . B as ic fu nc t io n al gr o ups im pa r t h yd r o p h i l i c i t y t o a d r u g m o l ec ul e d ue t o t h ei r p o t en t ia l f o r i on i z a ti o n an d th e i r a bi li t y t o f o rm hyd r o g en bo n ds . b . B as ic fu nc t io n al g ro ups c a n f o rm i on i c, i on - d ip o l e , a nd h yd r o g e n b on d s wi t h r e c ep t or s , e n z y m es , t r ans p o rt p ro t ei ns , a n d o th e r m ac r om ol ec u le s . c . B as ic f u nc ti o na l g r ou ps c a n f o rm sa l t s w h e n co m b i ne d w i th ac i ds . d . M e t a bo l is m . Co m m on m e ta bo l ic p a th wa y s f o r p r i m a r y am in es a re o xi da t i ve d e a mi n a ti o n , a ce t yl a t i o n , a nd N - ox i d at i o n. C om m o n p a th wa ys f o r s ec on d a r y an d t e r t ia r y am i ne s a r e a ce tyl a t i o n ( s ec o nd a r y a m i ne s o n l y) , o x id a t i ve N -d ea l k yl a t i o n , a n d N -o x id a t io n . A ro m at i c a m i ne s c an be ac e t yl a t e d , wh i l e a r om a ti c h ete r o c yc l ic
n i t ro g en s c an un d er g o N - o x i da t i on o r N - de a lk yl a t i o n . Im i ne , h y d r a z i ne , a m id in e , a n d g u an id i ne g ro up s c an u nd e rg o s im il a r re ac t ion s a s t h os e l is te d fo r p r im a r y , s ec o nd a r y , a n d t e r ti a r y am i ne s . A dd i ti o na ll y , am in e s c a n be gl u cu r o n i dat e d , s u l f a te d , a nd me t h yl a t e d b y p ha s e I I c o n ju g a tio n r ea c ti on s . D . Ad d i t i o n al h yd r o p h i l i c f u nc t i on a l g r o up s 1 . S im il a r t o a m i n es , h yd r o x yl g r o u p s (o r a lc o ho l s ) m a y be c l as s i fi e d as p r im a r y, s e c on d a r y, o r t e r t i a r y, d e p en di n g o n t he nu m b er o f s ub s ti t ue n ts a t t ac hed t o t h ei r r e s pe c t i v e c a rb o ns . A g oo d e xa m pl e o f th is is s een wi t h t he gl uc oc o r ti c o id f l u dr o co r ti s o n e ( F ig u re 8- 7 ) . a . H yd r o xy l g r o up s c an fo r m i o n - di p o le an d h yd r o g e n b o n ds wi t h re ce p to r s , e n zym e s , t ra ns p o rt p ro t ei n s , an d o t he r m a c r om o le c ul es .
Figure 8-4. Examples of drugs that contain a primary, secondary, tertiary, or aromatic amine as part of their chemical structure. Whenever an amine is part of a nonaromatic ring (e.g., ticlopidine), it is referred to as an alicyclic amine. Whenever an amine amino is part of a side chain or is attached to a nonaromatic ring, it is referred to as an aliphatic or alkyl amine. Whenever an amine is directly attached to an aromatic ring (e.g., procainamide), it is referred to as an aromatic amine.
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Figure 8-5. Examples of drugs that contain aromatic, heterocyclic nitrogens as part of their chemical structure.
b . H yd r o xy l g r o u ps e n han c e w a te r so l u bi l i t y d u e t o t h ei r a b il i t y t o fo r m h yd r o ge n b o n ds wi t h wa t e r.
c . H yd r o xy l g r o up s a r e of t e n e s te r i f ie d in or d e r to p r od uc e p r od r u gs . S e e C h a pt e r 1 7 V I f o r a dd i ti o na l i n fo rm a ti o n o n p r od r ug s . d . M e t a bo l is m . P r im a r y h y d r o xyl g r o u ps a re i n it ia l l y ox i d iz ed t o a l de h yd e s an d t h e n t o c a r bo x yl i c a c i ds . S ec on d a r y h y d r o xyl g r o u ps a re ox i d iz ed t o k et o n e s, wh i l e t e rt i ar y h y d r o xy l g ro u ps a re no t u su a ll y o xi d i z e d . H yd r o xy l g r o u ps m a y al so u n d er g o p h as e I I gl u cu r o n i d e o r su l f at e c o n ju ga t i o n .
Figure 8-6. Examples of drugs that contain a basic imine, hydrazine, amidine, or guanidine functional group as part of their chemical structure.
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Figure 8-7. Examples of drugs that contain a hydroxyl group, phenol, catechol, or quaternary ammonium functional group as part of their chemical structure. Fludrocortisone contains a primary, secondary, and tertiary hydroxyl group. This designation is similar to that used for amines and depends on the number of substituents attached to the respective carbons. As illustrated with levodopa, a catechol is simply two phenol groups that are ortho to one another.
2 . P he n o ls , a s e xe m p l if ie d b y e s t ra di o l ( F ig u re 8- 7 ) , ar e h y d r o xy l g r o u ps t h a t a r e d i r ec tl y a t ta c h e d t o a n ar o m at ic r in g . a . D ue t o r es o na nc e s tab i li z a t io n o f th e a r om a ti c r i ng , ph e no ls c a n b e i oni z e d in b a si c e n v i ro nm e nt s ; ho w e v e r , m o s t ph e no ls ar e pr i m a r i l y u n i o n i z ed at p h ys io l og ic al p H a nd as s uc h s h ou ld be t re a te d as n eu t r a l, no n io ni za b le fu n c t i on al g r o up s .
b . S im il a r t o a lc o ho ls , ph e n ol s p ri m a r il y f o rm i on - d i p ol e a n d h yd r o g e n b o n d s. Th e y c a n a ls o e n ha n ce w a te r s ol u b il i t y a n d b e e s te r i fi e d t o f o rm p r o d rug s (s ee C h a p te r 17 V I ). c . D r ug m o le c u le s c on t ain i ng ph e no ls o r c a te c hol s (s e e l e vo d op a i n Fi gur e 8 -7 ) a r e s us c e p ti b le to a i r o xi d a t i on an d t o ox i da t i on o n co n t ac t w i t h f e r r ic io n s . d . M e t a bo l is m . P h en o ls u n d er g o s u lf a t io n , g l u cu r o n i da t i o n, a r om a ti c h yd r o x yl a t i o n , an d O - me t h yl a t i o n . 3 . Q u a te r n a r y a m m o n i um s al t s , as e xe m p li fi e d b y i p r at r op i um b r om i de (F i g ur e 8 7 ) , a re ne i th e r a c i di c n o r b as ic bu t c o nt a in a p e rm a n en t po s i ti ve c h a rg e. a . Th e se s a lt s e n ha n ce w a te r s ol u b il i t y; h o we v e r , du e t o th e p e rm an e nc e o f th e p o si t i ve c h a r ge , c om po un d s c o n t ai ni n g t hi s f un c ti o n a l g r o up of t en ha ve di f f i c ul t y p a s si n g th r o u gh l ip i d m e m b ra n es . b . S im il a r t o a m i n es , q ua t e r na r y am m o n iu m s a l ts c a n p a r ti ci pa t e i n i o nic a nd i on d i p o le b on d s. c . Q ua t e rn a r y am m o ni um s al t s a re ge n e ra ll y n o t m e ta b ol i z e d; ho we v e r , N d e a lk yl a t i o n c o u ld oc c ur i n s om e c as es . E . F u nc t i on a l g r o u ps w i t h i n te r m ed i a te po l a r i ty 1 . K e to n es a re le s s pr e v a l en t th a n a lc oh o ls a n d p h e no ls i n th e s t ru c tu r es o f dr u g m o le cu l es . O n e e xa m p l e i s s ee n i n t h e o ra l h y p og l yc em ic a g en t , a ce t oh exa m i d e , s h o wn in Fi g u re 8 -8 . a . K et o ne s a r e p r im ar i l y l i pi d s ol u bl e ; h o we ve r , th e y a r e a bl e t o f o rm h yd r o g e n b o n d s wi t h al c o h ol s a nd c e rt a in am in es . Th e y c an a ls o f o rm io n - di p o le bo n ds . P.163
Figure 8-8. Examples of drugs that contain a ketone, ester, amide, lactone, or lactam as part of their chemical structure.
b . M e t a bo l is m . K e to n es a r e v e r y s t ab l e. Th e i r p r im a r y r ou t e o f m et a bo li sm is r e d u c ti o n to an a lc o ho l. 2 . C om p ou nd s c on t ai ni ng e s te r s , a mi d es an d the i r re s p ec t i ve c y cl ic f o rm s , l a c t on e s, a nd la c t am s c a n be s e en in Fi g u re 8- 8. a . Th e se fu nc t io n al gr o up s a r e c ap a bl e o f fo rm i ng h yd r o g e n b on d s wi t h r e c ep t or s , e n zym e s , t ra ns p o rt p ro t ei n s , o th e r m a c ro m o l ec ule s , a nd wa t e r . Si m i la r to k e to ne s ,
e s te r s a nd la c to ne s c an f u nc t io n a s h yd r o g e n - bo n d ac ce p t o r s, wh i l e am i de s a nd l a ct am s c an fu nc t io n a s e i t he r h yd r o g e n - b o n d do n o r s o r a cc e pt o r s . b . M e t a bo l is m . E n z y m a ti c h yd r o l ys i s i s t h e p ri m a r y r o u te of m e t ab ol is m fo r t he se f u nc t io n al g ro up s . E s t e rs a n d l ac to n es a r e h y d r o ly z e d t o al c o h ol s a nd c a rb o xyl i c a c id s, wh i l e am i de s a nd l a c t am s a r e h yd r ol yz e d to a m i ne s a nd c a r bo xyl i c a c id s. E s t e rs a n d l ac to n es ar e m o r e s u s c ep t ib l e t o h y d ro l y s is th an a re am id es an d l a ct am s . A d di ti o na l l y , s om e l ac t am s m a y u nd e r go N - d e al k yl a t i o n p ri o r t o o r in pl a ce o f h yd ro l y t ic c le a v a ge . F . L ip o p hi l i c f u nc t i on a l g r o u ps 1 . Al k yl g r o u p s a re sa tu r a t e d h yd r o c a r b o n c ha i n s , l i nk s , a nd r i ng s tha t ca n v a r y i n s i ze fr om s i ng l e -c a rb on m e th yl a n d me t h yl e n e g r o up s t o l a rg e c ha i ns . S i m il a r t o t h e d es i gn a ti o ns p r e v io us l y gi v e n fo r a m i n es , t h e d es i gn a ti o n a li c yc l i c r e f e r s t o a l k yl g r ou ps th a t a r e p a rt o f a no n ar om a ti c ri ng , wh i l e t he de s i g na t io n a l ip h a t ic r e f e rs to t ho s e th a t a r e pa r t of a s id e c ha in o r t h at f u nc ti o n t o c on ne c t, o r b r i dg e , o t h e r f un c t i on a l g ro u ps . E xa m p l e s o f a lk yl gr o ups a re il lu s t ra t ed in Fi gu re 8 - 9. a . A lk yl g r o up s c a n pa r tic i pa t e i n va n de r W aa l s i n t e r ac t i o ns (i . e ., in du c e d di po l e i n du c ed di po l e b on ds ) an d h yd r o p h o b i c b on d ing . b . M e t a bo l is m . O xi d a ti on is t he m a jo r ro u te of m e t a bo li s m . Al k y l si d e c hai n s a r e u s ua ll y o xi d i z e d at ei t her t h e t e r mi n a l ( ω ) o r p en u l t im a t e ( ω- 1 ) c a rb o n a t om s . 2 . Al k e n es , a ls o k no wn a s ol e f in s , a r e u ns a t u rat e d an al o gs of al k y l g r oup s (s ee F i g ur e 8 - 9 ) . a . Th e bi nd i ng ab il i t y of a l k e n es i s s i m i l a r t o t ha t o f s a tu r a te d a lk y l g ro ups . P.164
Figure 8-9. Examples of drugs that contain alkyl groups and alkenes as part of their chemical structure. For the sake of clarity, only certain functional groups have been highlighted.
b . M e t a bo l is m . A lk e ne s a r e s om e wh a t m o re r ea ct i ve t ha n a lk y l gr o up s a nd a r e s u bj ec t to m e ta b ol ic h yd r a t i o n , e po x i da t i on , pe ro x i da t i o n, an d r ed u ct i on . 3 . Mo s t a r om a ti c h yd r o c a r b o ns ar e an al o gs o f e i t he r be nz e ne o r n a ph th a l en e ( s e e F ig u re 8 -1 0 f o r e xa m p le s ). W he n a t ta c h e d to a d r u g m o l ec ul e , b en z e n e i s r e f e r re d t o a s a p he n yl g r o u p .
a . S im il a r t o a lk y l g ro up s a n d a lk en es , a r om a ti c hyd r o c a rb on s c an pa r t ic ipa t e i n va n d e r W aa l s i n te r a c ti o ns a n d h yd r o p h o b i c b o n din g . A dd i ti on a ll y , a ro m a t ic r in gs ca n p a r ti c i p a te i n ch a r ge - t r an s f e r in t e r ac t i on s . E l ec t r o n - ri ch a ro m a t ic ri n gs (i . e ., t ho se wi t h e l ec t ro n - do na t in g g ro u ps ) c a n f o rm d i po l e- l ik e i nt e r ac ti o ns wi t h e le c tro n - po o r a r o m a t ic ri ng s (i .e . , t h os e wi t h el ec t r on - wi t h d ra wi n g g ro up s ) . b . M e t a bo l is m . O xi d a ti on is t he pr im a r y r ou t e o f m e ta b ol is m f o r a r om at ic h yd r o ca r bo ns , wi t h h yd r o x yl a t i o n , ep o xi d a t io n , a n d d i o l f o r ma t i on c o m p r i si ng t he t h r e e m o s t c o m m on pa t hwa y s . 4 . E t he r f un c t i on al g ro up s c on t ai n a n o xy g e n a to m b o un d o n b o th s i de s b y e i th e r a l k yl o r a r om a ti c c a r b ons . Th e y c a n b e p r es en t as ei t he r a t e rm in a l f un c t io n al g r o up , s uc h a s t h e m e tho x y g r o u p o f n a pr o xe n , o r as pa r t o f a c e n t ra l c h ai n /b ac k b o ne , s uc h a s t h a t s e e n i n g em fi b ro zi l ( F i gu r e 8 - 1 0) . a . Th e c o nt r ib u ti o n o f e th e r s t o d r ug bi nd i ng is m i n i m al ; ho we v e r , t he s e fu n c t i on al g r o up s c an pa r t ic ip a te in d i p ol e - in d u ce d d i p ol e i n t e r ac t i o ns an d c an s er ve a s h yd r o g e n - b o n d a c ce p t or s . b . M e t a bo l is m . Me t h y l an d et h yl e t he r s c an un der g o O - de a lk yl a t i o n , wh i le t ho se l a r ge r do no t g e ne r al l y un d e rg o m e ta bo l ism . W hile e th e rs us ed as o rg an ic s ol v e n ts ( e . g ., di e th y l e th e r ) c an fo r m p e r o xi d es an d m a y e x p lo d e, t hi s p ro p e rt y is ge n e ra ll y n o t p r es e nt in d ru g m ol ec u le s . 5 . Al k yl a n d a r o ma t i c ha l i d es ar e e l ec t r o n -w i thd r aw i n g f u nc ti o na l g r o up s . Th e y a r e of t en us ed t o “ lo c k ” a d r ug m o le c u le in a d es i r e d c on f or m a t io n a n d/ o r t o d e c re as e a r om a ti c o xi d at i o n o f t h e d ru g . F l uo r in e i s t h e s m al l es t h al o ge n , wi t h i ts s i z e ve r y s im il a r to th a t o f h y d ro g en . Ch l o ri ne is t h e s ec o nd s m a l le s t , fo llo we d b y b r o m i ne an d i o di ne , r es pe c ti v e l y . S ee Fi gu r e 8 - 10 f o r s p e ci fi c e xa m p l es . P.165
Figure 8-10. Examples of drugs that contain an aromatic hydrocarbon, ether, and/or alkyl or aromatic halide as part of their chemical structure. For the sake of clarity, only certain functional groups have been highlighted.
a . W it h t h e e xc e p ti o n o f f l u or i ne , wh i ch c a n s e r v e a s a h y d ro ge n - bo nd ac c e p t o r, h a li d es d o no t d i re c tl y pa r t ic ip a t e in t he bi nd i ng o f d ru gs to t he i r r ec e pt o rs o r o th e r m ac r om o le c u le s .
b . M e t a bo l is m . A r om a ti c h a li de s a r e n o t n or m a l l y m e ta bo l i z ed . Al k y l h al i de s c an u n d er g o o x id a t i ve d e ha lo g e na t i o n t o f o rm al de hyd e s .
II. BIOCHEMISTRY A. I n t r o d u c t io n . B i oc hem is t r y is th e s t ud y o f c he m ic al p ri nc ip l es th a t sup p o r t li f e p r o ce s s es . I t i n fl u en c e s d r u g m et a bo li sm , t h e ra pe u t ic e f f ec ti v e n ess , an d b i o tr a ns f or m a t io n . Bi oc he m ic al l y s i gn i fi c a n t m o l ec u le s i nc lu d e am i no ac ids , c a r bo h yd ra t es , l i pi ds , p y r i m i d in es , p u r in es , a n d bi o po l y m er s —p r o te in s a nd e n zym e s , wh i c h a re bu i lt f r om am in o a ci d s; po l y sa c c h a ri de s , wh i c h a r e b ui l t f r om c a r bo h yd ra t es ; a n d n uc le i c ac i ds , wh ic h a r e b ui l t f r om p y r im id i ne s a nd pur i n es . B . Am i n o a ci d s a r e t he m o no m e r ic un i ts o f pr o tei n s a nd en zy m e s a nd hav e t h e f o l lo wi n g g e ne r al f o rm ula :
1 . W it h t h e e xc e p ti o n o f g l y c in e , n at u r al l y oc c u r rin g am in o a ci ds a re L, α -a m in o a c id s. P r ot e in s a r e m a d e u p o f th e 2 0 d i ff e r en t am i no ac id s , wh i c h d if f e r in t he si de c h ai n ( R ) a tt ac h ed t o P.166
t h e α -c a r bo n . Th e 20 di f fe r e n t s i d e c h a in s v a r y i n s i ze , s h a pe , c ha r g e, h yd r o ge n b o n di ng c a pa c i t y , an d c he m ic al r ea c t i v i t y . A p ro t ei n c a n b e h yd r ol yz e d in to i ts c om p on e nt α - am i no ac ids b y ac id s, ba se s , o r e n zy m e s . a . Am i no ac id s wi t h a ci di c s id e c h ai n s i nc lu d e as p a rt ic ac id an d g l ut am ic a ci d . b . A m i no ac id s wi t h b as ic s i de ch a in s i nc l ud e a rg i ni n e, l y si ne , an d h is t am i ne . c . Am in o ac id s wi t h p ol ar , n o n io n ic s id e c h ai n s i nc l ud e g l y c i n e, s e r in e , c ys t ei ne , t h r e on in e , t y r o s i ne , as par a g in e , a nd gl u ta m i n e. d . A m i no ac id s wi t h n o np o l a r , h yd r o p h o b i c s i de c ha i n s in cl u de al a ni ne, v a l in e , l e uc in e , i s o le u c i ne , ph eny l a l an i ne , m e th io n in e , p ro l in e , a nd t r y p to p ha n . 2 . Am i no ac id s h a v e a z w i t te r i o n s t r u ct u r e , wh i c h a c c o un ts fo r t he i r h igh m e l ti n g p o in t an d l o w wa t e r s o l ub i li t y . Am i no ac id s i n so lu t i on ha v e th e fo ll o wi n g g e n er a l f o r m u l a:
3 . I on i z a t i on of am in o ac i ds to th e z wi t t e ri o n f o rm o r o th e r f o rm s d ep e nds on p H ( F i gu r e 8 - 1 1) . C . C a r b o h yd r a t e s . Th e s e a r e p ol y h yd r o xy a l d ehy d e s o r k e t on es . Th r ee m a jo r c l as s e s o f c a r b oh y d r a te s e xi s t . 1 . M o n os a cc h a ri d es ( s im p le s u ga r s ), s u c h as g lu c os e o r fr uc t os e , co n s is t of a s i ng le po l y h y d r o xy a l d ehy d e o r k e to ne un i t . a . Al d e h yd i c m o n os ac c ha r i de s a r e r e du c i n g su g ar s .
b . Mo n o s ac c h a ri de s c an b e li nk ed t og e th e r b y g l yc o s id i c b o n ds , wh ic h a re h yd r o l yz e d b y a c i ds bu t n o t b y b as es . 2 . O l i go s ac c ha r i de s , s uc h a s s uc r os e, m a l to s e , a n d l ac t os e, co ns is t o f sh o r t c h ai ns of m o n os ac c h a ri de s j o in ed c o v a l en t l y. a . S uc r o s e c a n no t b e a bs o r be d b y t he in t es t in e un t i l i t is co n v e r te d b y suc r as e i n to i t s c om po ne n ts , g l uc os e a n d f r uc t os e . b . M a l t os e i s h y d r ol y z e d b y m al t as e i nt o t wo m o le c ul es of gl uc o s e . c . La c t os e ( o r m il k s ug ar ) c an no t be ab s o r be d by t h e in t es ti n e u nt i l i t is c o n ve rt e d b y l ac t as e i n to it s c om pon e n ts , g al ac t os e a n d g luc os e . 3 . P o l ys a c c h a r i de s , s uc h as ce l l ul o se an d gl yc o g e n , c o ns is t of lo n g cha i ns of m o no sa c c ha r i de s . D . P yr i m i d i n e s a n d p u r in e s . Th es e a re ba s es t ha t , wh e n b o nd ed wi t h ri bo s e, f or m n u cl e os id es , wh ic h wh e n s ub s e q ue n tl y b on d ed to p h os ph o ri c a c i d f o rm n u cl e ot id e s— t he s t r uc t u ra l bu il d in g b lo c k s o f n uc le i c ac i ds . 1 . P yr i m i d i n e b a se s i nc l u de : a . C yt o s i n e ( C ) , f ou n d in d eo xy r i b o n u cl ei c a c i d (D N A ) a n d r i bo nu c l e ic a cid ( R N A ) b . U r a ci l ( U ) , f ou n d i n RN A o n l y c . Th ym i n e ( T) , f o un d i n D N A o nl y
Figure 8-11. Amino acid ionization in solution. The carboxyl and amino groups are either in ionized or unionized form depending on the pH of the solution.
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2 . P u r in e ba se s i nc l ud e : a . Ad e n i ne ( A ) , f ou n d i n D N A a n d R N A b . G u a ni n e ( G ) , fo u nd in D N A a n d R N A 3 . P y r im i di ne s a n d p ur i ne s e xh i b i t ta u t om e r is m ( a f o rm o f s t e re oi s o m e r is m ) a nd c a n e xi s t in ei t he r k e t o (l a c t am ) o r e no l (l ac t im ) fo r m s . E . B i o po l ym e r s 1 . P r o te i n s a re p ol y m ers o f am i no ac id s t ha t ar e l i nk ed to g et h e r b y pe p t id e b on d s ( i . e ., li nk s b e t we e n c a r bo n y l c a r bo ns an d a m i n o n i t ro g en s [ F ig u re 8 -1 2 ] ). P r o t ei ns h a ve fo u r s t ru c tu r al le v e ls .
a . P r i ma r y s t r u c tu r e r e fer s to t he s e qu e nc e o f a m i n o a c i ds an d l oc a ti o n o f d is u lf i de b o n ds i n t h e p r ot e in . b . S ec o n da r y s t r u c tu r e re f e rs to t he s p at i al a rr a ng e m e n t o f s eq u en ce d a m i n o a c i ds ( f o r e xa m pl e , α - c on f o rm a t i on [h e li c a l c oi l ] o r β -c o n f o rm at i on [p l ea t ed s h ee t ] ) . c . Te r t i a r y s t r u c t u re re f er s to t he th r e e- d im en si on a l s t ru c t u r e o f a s i ng le p r o t ei n . d . Q u a te r n a r y s t r u c t u re r e f e rs to t he ar r a ng em e nt o f i nd i vi du a l su b un i t c ha i ns in t o c om p le x m o l ec ul es . 2 . E nz ym e s a r e p r ot e in s c ap a bl e o f a c ti ng as c a ta l y s ts fo r bi ol o gi c r e ac tio n s . Th e y m a y be s i m p le o r c om pl ex a n d m a y r eq ui r e c of a c to r s o r c o en z y m e s f o r b iol o gi c a c ti vi t y. a . A n e n z y m e e nh a nc es t h e ra t e o f a s p ec if ic c h em ic a l r e ac ti o n b y lo we r i ng t he a c t i va t i on en e r g y o f t h e r e ac t io n . I t d o es n o t c ha n g e t he r ea ct i on ' s e q ui li b r iu m p o in t , a n d i t is n ot us ed u p o r p er m a n en t l y c h an ge d b y th e r e ac t io n . b . A c o fa c to r m a y be an i n o r g an i c c o mp o ne n t (u s ua ll y a m e ta l i o n ) o r a n o n p r o te i n o r g an i c m o le c u le . A c of ac t o r m a y be b io lo g ic al l y in ac t i v e wi t h o ut an a p o en z y m e (t h e p r ot e in p o r ti o n o f a c om p le x e n z ym e ) . A c of ac t o r f i rm l y bo u n d t o t h e a p oe n z y m e i s c a l le d a p r o st h e t ic g ro u p . A n o r g an ic c o f ac to r th a t i s no t fi r m l y b o u nd bu t i s ac t i v el y i n vo l v e d d u ri n g c a t al ys is is c a ll ed a c o en z ym e . c . A c om pl e te , c a ta l y t ic al l y ac t i ve e n z ym e s ys t em i s r e fe r r ed t o as a h o l oe n z ym e . d . E n zy m es fa ll in t o s i x m a jo r c l ass es . ( 1 ) O x i do r e du c t as e s ( e .g . , de h y d ro g en as es , o xi d a se s , p er o xi d a s e s ) a r e i m po r t an t i n th e o xi d a t i v e m e ta bo l is m o f d r u gs . ( 2 ) T r an s f e ra s es c a ta l yz e t h e t r an s fe r of g ro u ps , s uc h as ph os p ha t e a nd a m i n o g r o up s . ( 3 ) H yd r o l a s e s ( e .g . , p ro t e ol y t ic en z y m e s , am y la s es , e st e r as es ) h y d r ol y z e t h ei r s u bs t ra t es . ( 4 ) L ya s e s ( e . g. , de c a r bo xy l a s e s , d e am in as es ) ca t a l yz e th e r e m o va l o f f un c ti o na l g r o up s b y m e a ns ot h er th a n h y d r ol ys is . ( 5 ) L ig a se s (e . g. , D N A l ig a s e , wh i c h bi nd s n uc leo t i de s t og e th e r d u ri n g D N A s yn t he s i s ) c at a l y z e th e c o u pl i ng of t wo m o l ec ul es . ( 6 ) I so m e ra s es c a ta l y z e v a r i o us i so m e r i za ti o ns , s uc h a s t h e ch a ng e fr om D t o L f o r m s o r t he c h an ge f r om c i s i s o m e r s t o t r an s i s om e rs . 3 . P o l ys a c c h a r i de s (a ls o c a l le d g l y ca ns ) a re l o ng - c ha in po l y m e r s o f c a rbo h y d r a te s a n d m a y b e l i ne a r o r b r an c he d . Th e y a r e c la ss if ie d as h om o po l ys a c c h ar id e s o r h e t e ro po l y s a c c h ar i de s . a . H o mo p o l ys a c c h a r i des ( e .g . , s ta r c h , g l y c og en, c el lu l os e ) c o n ta i n o nl y o n e t yp e o f m o no m e r ic un i t. ( 1 ) S t a rc h (a r es e r v e f oo d m a te r i al of pl an t s ) is c om p os ed o f t wo g lu c o s e p o l ym e r s —a m y lo s e (l i nea r a nd wa t e r s ol u bl e ) a nd am y l o pe ct i n ( h ig hl y b ra n ch e d a nd wa t e r i ns o lu bl e ) . I t y ie l ds m a in l y m a l to s e ( a gl u c o s e d is ac c h a ri d e) a ft e r en z ym a t ic h yd r o l ys i s wi t h s a li v a r y o r p an c r e a ti c am y l as e ; on l y g lu co s e af t e r c om pl et e h yd r o l ys i s b y s t r o ng ac ids .
Figure 8-12. Peptide bond formation occurs as a result of the condensation of the carboxyl group of one amino acid with the amino group of another. Water is eliminated during this process.
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( 2 ) G l yc o g e n , l ik e a m y lop e c t i n, is a h ig hl y b r an ch e d , c o m p a c t c h ai n o f D- g l uc os e . Th e m ai n s t or a ge po l y s ac c h a r id e o f a n im al c e ll s , i t i s f o un d m os tl y i n l i v er a n d m us c l e a n d c an be h y d rol y z e d b y s a li va r y o r p a nc r e a ti c a m y la se in t o m al to s e a nd D - g l uc os e . ( 3 ) C e ll u l os e (a wa t e r -i ns o lu bl e s t r uc tu r al po l ys ac c h a r id e f o un d i n p la n t c e l l wa ll s ) i s a li n ea r , u n br a nc he d c h a in o f D - g lu co s e . It c a nn o t b e d i ge st e d b y h um an s b e ca us e th e h um an in t es t i n al t ra c t se c re t es n o e nz y m e c ap a bl e o f h y d r ol y zi n g it . b . H e te r o p o l ys a c c h a r i de s ( e. g ., he p a ri n , h ya lu ro n ic ac id ) c o nt a in t wo o r m o re t yp e s o f m on om e r ic u n its . ( 1 ) H e pa r i n (a n a c i d m uc o po l y s a cc ha r i de ) c o ns is t s o f s ul f at e d e ri va t i ves o f D g l uc u ro n at e , D -g lu c o s am i n e a nd L -i d u ro na t e . I t ca n be is ol a te d f r om lu n g t i ss ue an d i s u se d m ed ic a ll y t o p r e ve n t b l oo d c lo t fo rm a ti o n. ( 2 ) H ya l u r o n i c a c id , a c o m po n en t o f b a ct e ri a l cel l wa l ls as we l l as o f t he v i t r e o us h u m o r an d s y n o v ia l f l ui d, c on s i st s o f a l te r na t in g u n i ts o f N - ac et y l - D - gl uc os am i ne a n d N -a c e t y l -m u r am i c a c i d . 4 . N u cl e ic ac i d s a re li ne a r po l ym e r s o f n uc le o tid e s —p y r i m i di n e a nd pu r in e ba se s l i nk ed t o r ib o s e or de o xy r i b os e s ug a rs (n u c l eo si de s ) a n d b ou n d t o p ho sp ha t e g r o up s . Th e ba c k bo n e o f t h e n uc le ic ac id co ns is ts o f a lt e rn a ti n g p ho s p h ate a nd p e n to se un i ts wi t h a pu r in e o r p y r im id i ne ba se at ta c he d t o e a c h . a . N uc le ic ac i ds a r e c lo s e l y as s o ci a t ed wi t h c e ll ul a r c at i o ns an d s uc h b as ic p r o t ei ns as h i s to n es a nd p r o ta m i ne s . b . Th e t wo m a in t y p es o f n uc l ei c ac i ds a r e D N A an d R N A. R N A e xi s t s i n th r e e forms. ( 1 ) R i bo s om a l R N A ( r RN A ) f u nc ti o ns as a f ra m ewo r k t o bi nd bo t h m es s en g e r a nd t r a ns f e r R N A . I t is c om p ri s ed of nu m e r o us s ub u nit s wi t h t h e 4 0 S a nd 60 S b e in g th e m os t we l l k no wn . ( 2 ) M e ss e n ge r R N A (m RN A ) s e r ves a s t h e t em pla t e fo r p r o te i n s y n th es is a n d s p ec if i es a po l y p ep t id e ' s a m i n o ac i d se q ue nc e .
( 3 ) T r an s f e r R N A ( t R N A) c a rr i es ac ti v a t ed am in o a c i ds t o t he r ib os om es , wh e r e t h e a m in o a c i ds a re in c o r po ra t e d i nt o th e g r o wi n g p oly p e p t id e c ha i n. c . In bo t h D N A a nd R N A , t h e s ucc es s i v e n uc le o tid e s a r e j oi ne d b y p h os ph o d i es t e r b o n d s b et we e n th e 5 ′ - h yd r o xy g r o u p of on e n uc l eo t i de ' s p e nt os e a n d t he 3 ′ - h y d r o xy g r o up o f t he ne xt n u c le ot i d e 's pe n to s e . d . D N A di f fe r s f r om R N A i n t h at i t l ac k s a h yd r o x yl g r o u p a t t h e p en t os e ' s C 2 ' p o si t io n , a nd it c o n ta in s T r a t h e r t h an U . e . D N A s t r uc t ur e c on s i s ts o f t wo α - h e li c a l D N A s tr a n ds c o il ed a ro u nd th e s am e a xi s t o f or m a do ub l e h el i x. T h e s t r an ds a re an t ip a ra l le l — t he 5 ′, 3 ′ -i n te r nu cl e ot i d e p h os p ho di es t e r l in k s ru n i n o p po s i t e d i re c t i on s. ( 1 ) H yd r o g e n b o nd i ng be t we e n s p ec i fi c b as e p air s A - T a nd C - G ho l ds t he t wo D N A s t r an ds t og e th e r. Th e s t ra n ds a re c om p le m e n ta r y ( t h e b as e s eq ue nc e of on e s t r an d d e t e rm in es th e b as e s equ e nc e o f th e o t he r ) . ( 2 ) Th e h yd r o p h o b i c bas e s a r e o n t h e i ns id e o f t h e h e li x; t h e h ydr o ph i li c d e o xyr i b o s e- p ho s p h at e b a c k bo n e is on t he ou ts id e .
III. BIOCHEMICAL METABOLISM A. O ve r vi e w . B io c h em ic a l m e ta b ol is m is t he re vie w o f p a th wa ys t h at le a d t o th e s yn t he s i s o r br e ak do wn o f c o m p ou n ds im po r ta n t t o t he l i fe o f a n o r ga ni sm . 1 . C o n t ro l o f m et a b ol i sm . Me t a b ol is m i s c o n t ro ll e d b y s u b st r a te c o nc en tr a t io n , e n zym e s ( c o ns t it u ti v e o r i n du c e d ) , a ll os t er ic ( r egu l a to r y ) en z ym e s , h or m on e s, an d c om p a rt m e n ta t io n . 2 . C a ta b o li s m is t he s um o f d eg r ad a ti o n r ea c ti on s th a t us u al l y r el ea s e en e r g y fo r u s ef u l wo r k ( e. g . , m e c h an i c a l , os m o t ic , b i os y n th et i c ). 3 . An a b o l is m i s t he s u m o f bi os yn t he t ic (b ui l d -u p) r e ac t io ns th a t c on s u m e e n e rg y t o f o r m n e w b io c h em ic a l c om p ou n ds (m et a bo li t es ) . 4 . Am p h i b ol i c p a thw a ys a r e t ho s e t ha t m a y b e u s ed fo r bo t h c at a bo li c as we l l a s a n a bo li c p u rp os es . K r ebs c yc l e b r e a k s d o wn m et a b ol i te s p ri m ar i l y t o re le a s e 90 % o f t he to t al en e rg y o f a n o r g an is m . I t a ls o d r a ws o f f m e ta b ol it e s t o f o rm c o m po u nd s s uc h a s a m i n o ac i ds (e . g. , as p ar t ic , g l ut am ic , al an i ne ) . H em og lo b in ha s i ts he m e m o ie t y f or m e d f ro m s u c c i n y l c o en zy m e A (s ucc i ny l C o A ) an d g l y ci n e f ol l owe d b y a c om p le x s e t of r ea c ti on s . P.169
B . B i o e ne r g e ti c s 1 . S u bs t r a te le ve l p ho sp h o r yl a t i o n en t ai ls t he fo r m at i on of on e u n it of ad e n os in e t r i ph o sp ha t e ( A TP ) p e r un i t o f m e ta b ol it e t ra ns f orm e d ( e .g . , s uc c i n y l C o A t o s uc ci n at e , p h os ph oe n ol py r u v a t e t o p yr u v a te ) . The s e r e ac ti o ns d o n o t n eed o xyg e n . 2 . O x i da t i ve ph o sp h o r yl a t i o n e nt ai ls t he fo r m a t io n of on e - an d -a - h al f o r two - a n d - a h a l f u ni ts o f A TP p e r u nit o f m et a bo li t e t r a ns fo r m e d b y o xi d o r e d uc ta se enz ym e s ( e . g ., de h y d r og e na s e s ); t h es e e n z ym es us e f l a v in A di n uc le o ti de ( F A D ) fo r m ed f ro m +
t h e vi ta m i n r i bo f la v i n , o r n ic o ti n am id e A d in uc le ot i d e ( N A D ) f ro m t h e v i t am i n n i co t in am id e a s c of a c t o rs . Th e re ac t io ns a re c o up l ed t o t he el ec t r on t ra ns p o rt s ys t em , a nd t he en e rg y re l ea s ed i s u s e d t o fo r m A TP i n t he m i to c ho nd r i a.
C . C a r b o h yd r a t e m e t a bo l i sm 1 . C a ta b o li s m. Th is p roc es s re le as es s t o r ed ene r g y f r om c a rb o h y d ra t es . a . G l yc o g e n o l ys i s i s the b r ea k d o wn o f g l y co ge n i n to gl uc os e p h os ph a te i n th e l i ve r a n d sk e le t al m u s c le . I t i s c on t r ol l ed b y t h e h o rm on e s g lu c a g on an d e pi n eph r i ne . b . G l yc o l ys i s i s t he br ea k do wn o f s u ga r ph os pha t es ( e. g . , g lu c o s e , fr u cto s e, g l yc e ro l ) i nt o p y r u v a t e (a e r ob ic a ll y ) o r l ac t at e (an a e ro b ic al l y) . 2 . An a b o l is m . Th i s p r oc e s s c o ns um es en e r g y to b u il d u p c om pl e x m o l ec ul e s f r om s im p le r m o le c u le s . a . G l yc o g e n e s i s i s t he fo r m at i on of gl yc og e n i n th e li v e r an d m us c l es fr om gl uc os e c o ns um ed in t he di et ; it s s y n t he s i s is c o n t ro ll e d by t h e pa nc r ea t ic ho rm o ne i ns ul in . b . G l u co n eo g e ne s is is th e fo r m a t io n o f g l uc os e fr o m n o nc a rb oh y d r a te s ou r c es , s uc h a s l ac t at e , a la n in e , p y r u v a t e , a nd K re bs c yc l e m e ta b ol i te s ; f at t y ac ids c a nn o t f o r m g lu c o s e . D . K r e b s c yc l e . Th i s p ath wa y i s al s o k n o wn a s t he c i t r ic a c i d c y c le , s e r v es bo t h b r e ak do wn a n d s y n th e ti c p u r po s e s, an d o c c u rs in t h e m it oc h on d ri a l c o m pa r t m e n t. 1 . C a ta b o li s m. Th is p ath wa y c o n v e r ts p yr u vat e ( g l y c ol y s is ) , ac e t y l Co A ( f a t t y ac id d e g ra d at i on ) , a n d am i no a c i ds t o c a r b on di o xi d e a n d wa t e r wi t h a r e le as e o f en e rg y. Th e c yc le is s t ri c tl y o xy g e n - de p en d en t (a e ro b ic ) . Ma t u r e r e d b lo o d c el ls l ac k m i to ch o nd r ia ; he nc e , t her e is no K r eb s c y cl e a c t ivi t y. 2 . An a b o l is m . Th i s p at hwa y f o r m s a m i n o ac i ds s u c h as as p ar t a te an d g lut a m a t e f r o m c yc l e i n te r m e di a te s ; a ls o , t he po r ph yr i n ri n g o f he m e (e . g ., he m o g lob i n , m yo g lo b in , c y t oc h ro m e s ) i s f o rm ed f ro m a c y c l e in t e rm e di a te . 3 . An a p l e r ot i c re a ct i o ns . B ec au s e m e t ab ol i te s a r e us ed to m a k e am in o a c id s o r h e m e ( e. g ., s u c c in y l C oA ) , t he m e t ab ol i te m u s t b e r ep la c e d b y i n te r m e dia t es f ro m o t h e r so u rc es ( e. g . , gl u ta m at e fr om t he b re ak down o f p r o te in f or m s α - k et o g lu t a ra t e) . 4 . E le c t r o n t r a ns p o r t . Th e el ec t r on t ra ns p or t s ys t e m a c c ep ts el ec t r on s an d h yd r o ge n f ro m t he o xi d a ti o n o f K re bs c y c le m e t abo l i te s a nd c o up l es t h e en e r g y r e l ea se d to s y n t he s i z e ATP i n t he m i t oc ho nd r i a. E . L i pi d me t ab o l is m 1 . C a ta b o li s m. T r ig l yc e r i d e s (t r ia c y lg l yc e r o ls ) st o r e d i n f at ce ll s ( a di p oc yt e s ) ar e h yd r o l yz e d b y h o rm on e -s e ns it i v e l i pa s e s i nt o th re e fa t t y ac id s a nd gl y c e ro l . a . F at t y a c i d s a r e b r ok en d o wn b y be t a o xi d a t io n t o ac et y l C o A ( t wo c a rbo n un i ts ) , wh i c h en t e r t he K r eb s c yc l e t o c om pl e te th e o xi d a t i on to ca r bo n d i o xi d e an d wa t e r wi t h r e l ea s e of c o ns id e ra b le en e r g y . To o r ap i d br e a k d o wn o f f a tt y a ci ds le a ds to k e to n e b od i es (k et o ge n es is ) as i n d i ab e te s m el li tu s . b . G l yc e r o l e n te rs gl y c ol y s is an d i s o xi d i ze d to py r u v a t e an d , v ia th e K reb s c y c le , t o ca r bo n d i o xi d e a nd wa t e r . c . S te r o i ds m a y b e c o n ve r t e d t o o th e r c om po u nds su c h as b i le ac id s , v i t am i n D , or s t e ro i da l h o rm on es ( e. g ., c or t is on e , e s t r o ge ns , an d r og e ns ) ; t h e y a r e n o t b r o ke n d o wn c om pl e te l y . 2 . An a b o l is m . B i o s yn t h e s i s f o rm s f at t y ac i ds , s te r o id s , a nd ot h er t e rp ene - r e la t ed m e ta b ol i te s . a . F at t y a c i d s a r e f o rm ed i n t he c yto p la s m , a nd u n s a t u ra t io n o c c u rs i n t he m i to ch o nd r ia P.170
o r e nd op l as m ic r e ti c u lum . H um an s c an no t m ak e l i no le ic ac id ; th us , i t is im p o rt a nt t h a t i t b e i nc lu d ed in th e d i et ( es s e nt i al fa t t y ac id) . b . T e rp e ne c om p ou n ds a r e de r i v ed f ro m a c e t yl C o A v i a m e v al o na t e a nd i n c l ud e : ( 1 ) C h ol es t er o l a nd ot h er s te r o id s ( 2 ) F at - s o lu b le v i ta m i ns ( i . e ., A , D, E , K) ( 3 ) B il e a c i ds c . S ph i n go l i pi d s c o n ta in s p h in g en in e fo rm e d f r om pa lm i to yl C o A a nd s e ri n e . S p h in g en i ne fo r m s a c e ra m id e b ac k b o ne wh e n j oi n ed t o f a tt y a ci ds . Th e ad d i ti on o f s u ga r s , s i al ic ac id , or c ho l in e p h os ph a te f or m s co m po u nd s s u ch as c e r ebr o s id es , g a n gl io s i d es , o r s ph i ng om y e l in fo u nd in ne r ve ti s s u es a n d m em br a ne s . d . P h os p ha t i d yl c o m p ou n d s , s u ch as ph os p ha t id yl ch o li ne ( le c i t hi n ) , p ho s ph a ti d y l s e r in e , o r e t ha no l am in e , a r e al s o im po r ta n t p a r ts o f m e m b r an es . F . N i t r o ge n m e ta b o li s m. N i t ro g en m e t ab ol is m i nvo l ve s a m i n o a ci d m et a bo l is m a nd n u cl ei c a c i d m et a bo l is m ( s e e C h ap t e r 9 f o r a di s cu s s i on of t he nu cl ei c a c id r ol e i n c e ll ac ti v i t y ) . 1 . C a ta b o li s m a . Am i n o a c i ds . Th e am i n o g r ou p i s r em o v e d b y a t r an s a m i n as e e n z ym e. Th e c a r bo n sk e le t on is b r ok en d o wn t o ac e t y l C o A (k e t o ge ni c a m i n o ac i ds ) o r t o c i t ri c a c id c yc le in t e rm ed i at es ( g l y c og en ic am in o a ci d s) a n d o xi d i z e d t o c a rb o n d i o xi d e a n d wa t e r f o r e ne r g y . G ly c o g en ic am in o a c i ds f orm gl uc os e a s n e ed ed v i a g l uc o ne og e ne s i s ; s o m e a m in o a c i ds a re bo t h k e to g e ni c a nd gl y c og e ni c ( e. g . , t yr o s in e ) . b . P u r i ne s a r e s al v a ge d ( 9 0 %) , an d t h e r em ai n ing 1 0% a re de g ra d ed in a s eq u en c e t h a t i nc lu d es xa n t hi n e oxi d a s e fo r m i n g u ri c a c i d i n hu m a ns . c . P yr i m i d i n es a re c a tab o li z e d to β - al an i ne , a m m o ni a , a nd c a r bo n d io xi d e . 2 . An a b o l is m a . Am i n o a c i ds ar e fo r m e d f ro m t he ci t ri c a c i d c yc l e i nt e rm e di a te s ( s e e I I I D 2 ) ; o t h e rs m us t b e e a te n d a il y i n d i et a r y p ro t ei ns . The l at t e r a r e c a l le d e s s en ti a l a m i no a c id s ( p he n y la l an i ne , v ali n e , t r yp to p ha n [ P V T] ; t hr e o ni n e, is ol e uc in e , m e th i on i ne [ TI M] ; h i s t i di ne , a r g in in e i n i n fa n ts , l y s in e , l eu c i ne [ H A LL ] ) . b . P u r i ne s a r e f o rm ed by c o m p le x r e a c t io ns us ing c a r b am o y l p ho s p h at e , a s pa r t at e , g l u ta m i ne , gl y c in e , c a r bo n di o xi d e , a n d f o rm y l t et r a h yd ro f ol a te . c . P yr i m i d i n es a re fo r m e d f ro m a s p a rt a te an d c a r b am o y l p ho s ph a te in a m ul t is t ep p r o ce s s . G . N i t r o g en ex c r e ti o n . E xc e s s ni t r og en m u s t be e l im in a te d b ec a us e i t is t o xi c . H u m an s p r im a ri l y e xc r e te u r ea bu t a ls o e xc r e t e ur i c a c i d . 1 . U r e a s yn t h e s i s . Th e K r e b s - H e ns e le i t p a t hw a y i s u se d to fo r m u r ea p r i nc ip a ll y i n th e l i v e r . Th e am m o nia is r em o ved f ro m a m i no a c i ds b y am in o a c i d t r an s fe r as es ( t r a ns am in a s e s ) t ha t u s e p y r i d o xa l ph os p ha t e ( v i ta m in B 6 ) as a c oe n z ym e. G l u t a m in e i s f o rm ed f rom gl u ta m a t e ( a n i nt e rm ed i a te ) an d a m m on ia ; gl u ta m in e a n d c a r bo n d io xi d e f o rm c a rba m o y l p ho sp h at e , wh ic h e n t e rs t h e u r ea c yc l e a nd a f te r s e ve r al s t ep s f o rm s u r ea. 2 . U r i c a ci d s yn t h e s i s . A l t h ou gh m o s t pu r i ne s ar e s a l v a ge d , h um an s e xc r e t e t h e r e m ai ni n g p u ri ne s a s u ric ac id .
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STUDY QUESTIONS D i r e c t i on s : E a c h of t he n u m b e re d i t em s o r i nc om p le t e s ta t em en ts in t his se c t i on is f o l lo we d b y an s we r s o r by c o m p le t io ns o f t he s t a te m en t . Se le c t t he o ne l et t e r ed a n s we r o r c o m p l et i on tha t is be s t i n e ac h c as e. 1 . W hi c h o f th e fo l l ow in g f u nc t i on a l g r o u ps ca n r ea c t w i th h yd r o c h l o r i c ac i d t o f o r m a s a lt ? ( A ) Te r t i a r y a m i n es ( B ) C a r bo xy l i c a c i ds ( C ) A m id es ( D ) E t h er s ( E ) S ec o nd a r y al c o h ol s V i e w A n s we r 1 . T h e a n sw e r i s A [] .2 . T h e c om po u n d s h ow n c o n ta i ns al l o f t h e f ol l ow i ng f un c t i on al g r o u ps E X C E P T :
( A ) a ph en o l ( B ) a s u bs ti t ut e d p he n y l r i n g (C) an ester ( D ) a n a li c y c l ic ni t r og en ( E ) a k e to n e V i e w A n s we r 2 . T h e a n sw e r i s C [] .3 . W h ic h o f th e f o ll ow i ng f u nc t i on a l g r o u p s i s m o st s us ce p ti b l e to h yd r o l ys i s ? (A) R—CO—R (B) R—COOR (C) R—O—R (D) R—NH—CH3 (E) R—COOH
V i e w A n s we r 3 . T h e a n sw e r i s B [] .4 . M o no m e r u n i t s o f p ro t e in s a r e know n as ( A ) m on os ac c h a ri d es ( B ) p r os th e ti c g r ou ps ( C ) a m i n o ac i ds ( D ) p u ri n es ( E ) n uc le os i de s V i e w A n s we r 4 . T h e a n sw e r i s C [] .5 . W h ic h o f th e f o ll ow i ng f o r mu l as r e p r e se n t s t h e z w i t te r io n f o r m o f a n a m i no aci d ?
V i e w A n s we r 5 . T h e a n sw e r i s D [] .6 . G lu c os e is a ca r b o h yd r a t e t h a t c a n no t be h yd r o l yz e d i n t o a s i mp l e r s u bs t an ce . I t i s b e s t d es c r i be d as ( A ) a s u ga r ( B ) a m o no s a c c ha r id e ( C ) a di s a c c ha r id e ( D ) a po l y s a c c ha r i de
( E ) a n o li g os ac c h a ri de V i e w A n s we r 6 . T h e a n sw e r i s B [] .7 . Al l o f t h e fo l l ow i ng ca r b o h yd r a t e s a r e co n s id e r ed t o b e po l ys a c c h a r i de s E X C EPT ( A ) h ep a ri n ( B ) s ta r ch ( C ) g l yc o g en ( D ) m al t os e ( E ) c el lu l os e V i e w A n s we r 7 . T h e a n sw e r i s D [] .8 . W h ic h o f th e f o ll ow i ng c om p ou n ds a r e co n s id e r ed t he b ui ld i n g b l o ck s o f nu c le i c a c i ds ? ( A ) N u c l eo t id es ( B ) N u c l eo s i d es ( C ) Mo n o s ac c h a r id es ( D ) P u r in es ( E ) A m i n o ac i ds V i e w A n s we r 8 . T h e a n sw e r i s A [] .P . 17 2
9 . W hi c h o f th e fo l l ow in g t e rm s be s t d es c r i bes a c o f ac t o r th a t i s fi r ml y b o u n d t o a n a p oe nz ym e ? ( A ) H o lo e n z y m e ( B ) P r os t he t ic gr o up (C) Coenzyme ( D ) Tr a n s fe r as e ( E ) H e t er o po l y s a c c h ar i de V i e w A n s we r 9 . T h e a n sw e r i s B [ an d] . O 10 . En z ym e s t h a t u nc o up l e p ep t i d e l i n k ag e s a r e b es t cl a ssi f i e d a s ( A ) h yd r ol as es ( B ) l ig as es ( C ) o xi d o r e du c t a s e s ( D ) t r a ns fe r as es ( E ) is o m e r as es V i e w A n s we r 1 0 . T he a nsw e r i s A [] .1 1 . T he s ug ar t h a t is in h e r en t in t he n u c le i c a c id s R N A a n d D N A i s ( A ) g lu c o s e ( B ) s uc ro s e ( C ) r i bo s e ( D ) d ig i to xo s e ( E ) m al to s e V i e w A n s we r 1 1 . T he a nsw e r i s C [] . Di r e c ti o ns : E a c h i te m b el o w c o nt a in s t h r e e su g ge s t e d a ns we r s o f wh i ch on e o r m o r e is c o r re c t . C ho os e t h e a nswe r . 1 2 . W h i ch o f t h e f o l low in g f u nc t i on a l g r o u ps ca n f o rm a h yd r o g e n b on d ? I . An a r o m at i c a m in e I I . A t e r t i a r y h yd r o x yl I I I . An a r om a t ic h yd r o c a r b o n
A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 2 . T he a nsw e r i s C [] .1 3 . W hi c h o f t h e f ol l ow i ng f un c t i on al g r o u p s c om m on l y u n d er g o e s c o nj u g at i o n w i t h g l u cu r o n ic ac i d ? I . A c a r b o x yl i c a c i d II. A primary amine I I I . A p h en o l A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 3 . T he a nsw e r i s E [] . Q u e s ti o ns 14- 1 6 Th e f o ll o wi n g q u es ti o ns r e f e r t o t h e d r ug m o le c u le s h o wn b el o w.
1 4 . Th e fu n c ti o na l g ro up s t ha t en h an c e t h i s c om p o u nd ' s a b il i t y t o c r o s s ce l l m e m b ra n es i nc l ud e : I . t h e p he n yl r i n g s I I . t he ce n t r al a lk yl c h ai n I I I . th e s e co n d a r y a n d t e r t i a r y h yd r o x yl s A if I only is correct B i f I I I o nl y i s c o r r e c t C i f I a n d I I a re co r r e c t D i f I I a n d I I I a r e c o r r ect E i f I , I I , a nd I I I a r e c o r re c t 1 5 . Ba s ed u po n t he f unc t i o na l g ro u p s p r es e n t, t h i s d r u g w ou l d b e e x pe c t e d t o b e ab l e to f o rm : I . va n de r W aa l s i n te r ac t i o ns
I I . i on i c b o nd s I I I . h yd r o g e n b o n ds A if I only is correct B i f I I I o nl y i s c o r r e c t C i f I a n d I I a re co r r e c t D i f I I a n d I I I a r e c o r r ect E i f I , I I , a nd I I I a r e c o r re c t 1 6 . Po s si b l e m et a b ol i c p a t hw a ys f o r t h i s d r ug i n c l ud e : I . r e du c t io n o f t h e c a rbo x yl i c a c i d I I . h yd r o l yt i c c l e a va g e I I I . a r o ma t i c o x id a t io n A if I only is correct B i f I I I o nl y i s c o r r e c t C i f I a n d I I a re co r r e c t D i f I I a n d I I I a r e c o r r ect E i f I , I I , a nd I I I a r e c o r re c t V i e w A n s we r 1 4 -1 6 . T h e a n s w e r s a r e : 1 4 - C [] , 15 -E ( I , II , an d I I I )[ ] , 1 6 - B ( I I I )[ ] . P. 1 73
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is A [ I C 2 c ]. S u b st a nc es th a t r e ac t wi t h ac id s t o f o rm sa l ts m us t be ba se s . O n l y o r g an ic c om p ou n ds th a t c o n ta i n t h e n i t ro g en -c o nt a in i ng a m in e g r ou p a r e b as es . W hile a m id es c o nt a in ni t r og en , t h e a dj ac e nt c a r bo n y l g ro u p d ec r ea s es t h e b as ic it y; t h e r ef o re , th e y a re es s en t i al l y ne u tr a l. 2 . T he an sw e r is C [ F igu r e s 8 -4 , 8 -7 , 8 - 8 , 8 -1 0 ] . A s sh o wn in F ig u re 8 -8 , e s te r s h a v e a c a r bo n yl at o m d i re c t l y bo n de d to an o xy g e n a t om . Th is s t r uc t ur a l f eat u r e i s n ot p re s e n t i n t his co m p o un d . H o we ve r , th e c om p ou n d d oe s h a v e t h re e s u bs ti t u te d p h en y l ri ng s , t wo p h en o ls , a te r ti a ry a l ic y c li c n i t ro g en , a k e t on e , a nd a n et h e r. 3 . T he an sw e r is B [ I E 2 b ] . H yd r o l ys is i s a do u bl e de c om po s i t io n re ac t io n i n wh i c h wa t e r i s o ne of t he r e a ct a nt s . E s t e rs , p a r ti c u l a rl y s i m pl e e st e rs , c om m o nl y u nd e rg o h y d r o l ys is . C e rt a in t yp e s o f e t he r s s uc h as g l y c os id es al so un d e rg o h y d r o l y si s , bu t th e y us ual l y r eq u i re s t r on g l y a lk a li ne c o nd i ti on s o r a c at al ys t s uc h a s a n en z ym e . Ke t on es , a m i n es , o r c a r bo xy l i c ac i ds d o n o t un d e rg o h y d r o l ys is . 4 . T he an sw e r is C [ I I B 1 , II E 1 ] . P r o t ei ns a re la r g e m o l ec u l es wi t h m ol ec u la r we i gh t s r a ng i ng f ro m 5 00 0 t o m o re th a n 1 m i l li on da l to ns . Al l p r ot e i ns a r e c om po s e d o f c h a in s o f a m i n o ac i ds a n d c an be h yd r o l yz e d t o y ie l d a m i xt u r e o f th ei r r es pe ct i ve am i no ac id s. Th e r e a r e 2 0 α - a m in o a c id s, wh i c h a re c o m m on l y f ou n d i n p r ot e in s. A ll t h e n a tu r al l y oc c u r r in g a m in o a c i ds i n pr o t ei ns ar e L - e na n ti om e rs , wi t h t h e e xc e p t io n o f gl y c in e . A ll ha ve a t l ea s t o ne a m in o g r ou p a n d o ne c a rb o xy l g r o u p . Th e am in o a c id s a r e l in ke d t o ge t he r t h r ou g h
t h e a m i n o g r ou p o f o n e a m in o a c i d a n d t he c a r bo xy l g r o u p of an o th e r a m i n o a ci d wi t h t h e s pl i tt i ng ou t o f a wa t e r m ol ec ul e to fo r m a n am id e l in k a g e , wh i c h i n a p r o t ei n i s r e fe r r ed to as a p ep t id e . Mo n o s ac ch a rid e s a r e s i m p l e, no n h yd ro l yz a b l e s u ga r s . P u ri ne s a n d p y r im i di ne s a r e o r ga n ic b as e s , wh il e a p ro s th e ti c g ro u p i s a c o fa c to r th a t is f ir m l y b ou n d t o a n a p oe n zy m e . 5 . T he an sw e r is D [ I A 1 a , I I B 2 , 3 , II E 1 , Fi gu r e s 8 -2 , 8 -1 1 , 8 -1 2 ] . A zwi t t e r i o n is a s in gl e s p e c i es c o n ta in i ng bo t h ne g a ti ve an d p os i ti v e ch ar g e s . I t s om e ti m e s i s r e fe r r ed to a s a n i n te r n al s a lt . Am ino ac i ds h a ve an am in o gr o u p a nd a c a r bo xy l g r o u p i n t h e s am e m ol ec u le . Th e a m i no g r o u p , wh ic h i s b as ic , at t r ac t s t he p r o t on f ro m t he c a r bo xy l g r o up an d b ec om es po si t i v e l y c ha r g ed , wh i le th e c a rb o xy l g r o up be c o m es n e ga t i v ely c h a rg e d wh e n it do n a te s i t s p ro t on t o t he am ino g r ou p . A m i no ac id s e xi s t as z wi t t e r io ns at ne a r n e ut r a l pH s uc h a s o c c u rs wi t hi n a c e l l o r i n t h e b l oo ds t r ea m . 6 . T he an sw e r is B [ I I C 1 ] . W hile gl uc os e i s a s ug a r, i t i s m o r e s pe c i f ic al l y a s im pl e s ug a r t h at c a n not b e h yd r o l yz e d i n to m o r e s im p le s u ga r s —t h us , i t i s c l as s i fi e d as a m on os acc h a ri de . S u g a rs m a y be s i m p le , s u c h as gl u c o se , o r c om p le x, s u c h as su c ro s e , a n d a r e c l as s i fi e d as di s a c c h ar i de s o r ol i go sa c c ha r id es , re s pe c t i v e l y . Po l y sa c c ha ri d es c o ns is t o f l o ng c h ai ns of m on os a cc ha r id es su c h a s c el l ul os e a n d g l yc o gen . 7 . T he an sw e r is D [ I I C 2 b , 3 , E 3 a , b ] . P o l ys ac c h a ri de s a r e l ong - c ha in po l y m e r s o f s uga r s . A s t h e p r ef i x “ p o l y” in d ic a te s , t h e r e a re m a n y s u ga r uni t s i n t he m o le c ul e . Ma l t o s e is c o m p os e d o f t wo m o le cu l es o f gl uc os e a n d is c l as s i f ie d as a di s a cc h ar i de o r a n ol ig os a c c ha r id e . 8 . T he an sw e r is A [ I I D, E 4 ]. N u c le ic ac id s a r e l in e ar p o l y m e r s o f n uc le o ti d es t h a t c on s i s t o f t h re e d i ffe r e n t m o le cu l es t h at a re c o v a le n t l y l i nk ed to f or m o ne u n i t: ( 1 ) a n o rg a ni c b as e o f ei th e r a p u r in e o r a p y r im i di ne ; (2 ) a 5 - c a r bo n s ug a r (e . g., p en t os e ); a nd (3 ) a p hos p ho r ic a c id g ro up . A n uc l eo s i de c on s i s ts o f th e o r ga n ic b a se an d t h e p en t os e . A m o no sa c c ha r i de is a s im p l e n on h yd r ol yz a b l e ca rb o h y d ra t e , wh i c h m a y b e c o ns id e re d a b ui ld i ng blo c k o f p ol y s ac c h a ri d es . P u r i ne s a r e h et e r oc y c l ic b a se s . A d e ni n e a nd gu a ni ne a re t h e t wo p u ri n es fo u nd in d e o xyr i b o nu cl e ic ac id (D N A ) a n d r i b on uc l ei c ac i d ( R N A ) . A m i no ac id s a r e t he bu ild i n g bl oc ks of p ro t ei n . P.174
9 . T he an sw e r is B [ I I E 2 b , c a nd d ]. C o m pl e x, o r c o nj u ga t ed , e n z y m es c o n ta in a n on pr o t ei n gr o up c a ll e d a c ofa c to r , wh i c h is re q ui r ed f or bi o lo g ic ac ti vi t y . In m a n y c as es , th e c o fa c t o r i s q ui t e f i rm l y b o u nd to th e p r o te i n. In o t h e rs , t he bi n di n g oc c u rs on l y du r i ng th e re ac t ion t ha t th e e n zym e c a ta l y z e s . C o fa c t o r s t ha t a re fi r m l y b ou nd t o t h e p ro t ei n a r e k no wn as p r o st h et ic g ro u ps , wh e r ea s th os e t h at a re ac ti v e ly b o u nd to t he p ro t ei n on l y d u ri ng c a ta l ysi s a r e r e fe r r ed t o a s c oe n z ym es . A h o lo en z y m e is a c o m p le t e , c at a l y ti c a l l y a c ti ve en z y m e s ys t em . A t r an s fer a s e is an e n zym e th a t c a t al y z e s the t r an s f e r o f gr o up s f r om o n e s u b st a nc e t o a no t he r , s u ch a s c a te c h o l- O - m et h y l t r an s fe r as e ( C O MT) . A h e t er o p ol ys ac c h a ri d e is a
p o l ysa cc ha r i de th a t c o n ta i ns t wo o r m or e d i f fe r ent m on om e ri c u ni t s , s uc h a s h e p ar i n. 1 0 . Th e a n sw e r i s A [ I I E 2 d] . A p e pt i de li nk ag e i s a n am i de fu nc t io n al g ro up f orm e d f r om th e l os s o f a m o l ec ul e o f wa t e r f r om t wo am i no ac i d s . U nc o up li n g t hi s l in ka g e i s t he r e ve rs e o f t h is r e ac t io n , a h yd r ol y s is re ac t io n . A h y d r o la se is an en zy m e th a t c a ta l yz e s h y d r ol y s is r e a c t i on s . Mo r e s p ec i fi c t e rm s f o r an e n z y m e t ha t c a ta l y ze s t h e h yd r o l ys is o f p ro t ei ns a re a m id as e o r pe p ti da s e. A l i ga s e ca t al yz e s th e c oup l i n g o f t wo m o le c u l es . A n o xi d o r e d uc ta s e c a t al y z e s o xi d a ti o n r e ac ti o ns . A tr a n s f e ra s e c a t al yz e s th e t r a ns fe r o f g ro u ps f r om on e s u bs ta n c e to an o th e r . A n i s om e r as e c a t al yz e s th e i n t er c on v e r s i on o f o ne is o m e r t o a no t he r . 1 1 . Th e a n sw e r i s C [ I I E 4 ] . N u c le ic ac id s a r e b io p oly m e r s c on si s t i ng of lo n g c h ai ns of nu c l e ot i de s . Nu c le o ti de s c o nt a in a p en t os e m on os a c c h a ri de as on e o f th ei r t h r ee c o ns ti t u en ts . R N A c on t ai ns , a s th e n am e s ug g es ts , th e m o no s a cc ha r i de ri b os e , wh e r e as D N A c on t ai ns d e o xyr i b o s e. Th e o n l y d if f e r en c e be t we e n th es e two s u g a rs i s t h e a bs en c e o f o xyg e n i n th e 2 p os it io n o f t he ri b os e r i ng . G lu cos e , a ls o k no wn a s d e xt r o s e , i s a h e xo s e . D ig i to xo s e is a d e o xy h e xo s e p r es e nt in t h e d i gi t al is gl y c os id es . S u c r os e a n d m al t os e a r e d is ac c ha r i de s . 1 2 . Th e a n sw e r i s C ( I , II ) [ I C 2 b, D 1 a , F 3 a ]. H yd r o g e n b on ds a re a s p e c i al i z e d t y p e o f d i po l e b o n d in wh i c h a h y d r oge n at om s e r ves as a b ri d ge be t we e n t wo e l ec t ro n eg a ti v e a t om s . H yd r o ge n -b o nd do n o rs i n cl ud e h y d r o xy l g r o u ps , p h en ol s , am i ne s , an d am i de s. H y d r og e n -b o nd ac ce p to r s i n cl ud e h y d r o xy l g r o u ps , p h en ol s , u ni o ni ze d n i tr og e n a t om s , k e to n es , a n d e t he r s. H yd r o c a rb o ns , r e ga r dl es s i f t he y a r e a li ph a ti c , a li c yc li c , o r a r om a ti c , a re no t c a pa b le of fo r m i n g h y d r og e n b o nd s . 1 3 . Th e a n sw e r i s E ( I , II , a nd II I ) [I B 2 e , C 2 d , D 2 d] . G l u c ur o ni d e c o n ju ga t io n i s th e m os t c om m o n p has e II m e ta b ol ic pa t h wa y fo r t wo r e a so ns : (1 ) Th e b o d y ha s a r ea d il y a va il ab l e sup p l y of gl uc u r on ic ac id , a n d (2 ) t h e r e a re a l a rg e n um b e r o f fu nc t io n al gr o up s t h at c an re a c t wi t h th is c om p o u nd . I n cl u de d a m o n g t he s e f un c ti o na l g r ou ps a re ca r bo xy l i c a c i ds , p ri m a r y , s ec o nd a r y a n d t e r ti a r y am in es , a n d p h e no ls . 1 4 - 16 . Th e a n sw e rs a r e: 1 4 - C ( I , II ) [I A 1, D 1 b, F 1, 3 ], 15 - E ( I, I I, an d I I I ) [I B 2 b , C 2 b , D 1 a , F 1 a , 3 a ] , 16 - B ( II I ) [ I B 2 e, E 2 b , F 3 b ] . L i po p hi li c f u nc ti o na l g r ou p s i nc r ea s e a d r ug ' s a bi l it y t o c r os s ce l l m e m b ra n es . Th e t h r e e a ro m a t ic ph e n y l r ing s , a s we l l as th e a li p ha ti c b u t y l c ha in co nn e c t i ng t h e c e nt r a l p he n y l r i ng to t he n it r o ge n o f t h e p ip e ra di n e r i ng , a r e a l l li p op h il ic ( i . e. , h yd r o ph o bi c ) a nd c o nt r i bu t e to th e d r ug ' s pa s s age t h ro u gh c e ll m em b r an es . Th e h yd r o xyl g r o u ps , a s we ll a s th e a c i di c c a rb o xyl i c a c id an d t h e b as ic al ic y c l i c am i ne , a r e al l h y d r op h il ic a n d en h a nc e t he o ve ra ll wa t e r s ol u bi li t y o f t he co m p o un d . Th e p h en y l r in gs , a s we ll a s t h e ce n t ra l a lk y l c h ai n a nd th e m e th y l g ro up s , a r e c a pa b le of fo r m i n g v a n de r W aals in t e ra ct i on s wi t h a r om at ic an d a l ip ha t ic h yd r o ca r bo n re g io ns on r e c ep t or m o le c ul es . Th e c a r b o xy l i c ac i d a nd th e ba s ic n i t ro g en a re c a pa b le of fo r m in g b o th io ni c a nd h yd r o ge n b o nd s , wh i l e t h e h y d r o xy l g r o up s a r e a ls o c ap ab l e o f f or m i n g h yd r og e n b ond s .
O f t h e m et a bo li c p a th wa y s l is t ed , a r om a ti c o xi d at i o n is th e on l y pl au s i b le c ho ic e . Th e t wo u n s u bs t it u te d ph e n y l ri ng s a r e v e r y s us c e pt i bl e t o h y d r o xy l a t i o n, e p o xi d a ti o n , a nd / or di o l fo r m at i on . Ca r b o xyl i c a c id s a r e n o t n o rm al l y r ed uc e d, bu t r a t h er c o nj u ga t ed wi t h eit h e r g l uc ur o ni c a c i d, gl y c i ne o r g lu t am in e . E s t e rs , a m i de s a n d t h ei r c y c li c d e ri v a t i ve s , l ac t on es an d l ac t am s , a r e t he p ri m a r y f un c ti on a l g r ou ps t h a t u nd e r go h y d ro l y s i s . N o n e o f th es e f u nc ti o na l g r o up s a r e p re se n t i n t he c om p ou n d s h o wn .
9 Microbiology G a i l G o o dm a n- S n i tk o f f
I. SCOPE OF MICROBIOLOGY. Mi c r o b i ol o g y i s t h e s t u d y o f or g an is m s f ro m t h re e d om a in s as we l l as a c e ll u la r e n t it i es t h a t a re no t c o ns i d e re d to be li v i ng in th e b i ol og ic a l s e n s e . A. D o m a i n s o f li vi n g o rg a n is m s 1 . Ar c h a e a i nc lu de p ro k a r y o t es wi t h c e ll wa l ls tha t a re bi oc h em ic al l y di f fe r e n t f r om b a ct e r ia an d t h at in h ab i t e xt r e m e en v i r on m e n ts of h ea t , c ol d , p H , o r s a lt s . A r c ha e a a r e no t a m e di c a l l y i m p or t a n t d om ai n o f m ic r oo r ga n i s m s . 2 . E uk a r ya c o n t a in s s om e m i c ro o rg a ni sm s — f o r exa m p l e , fu ng i ( y ea s ts a nd m o l ds ) , p r o t o zoa , a n d a lg ae — a lon g wi t h m ac r os co pi c o r ga n is m s s uc h a s m us hr o om s , p l an t s, an d a n im al s . D i mo r p h i c f u n gi a re th os e th a t c an e xi s t i n e i th e r t he u n ic el l ul a r ( y e a s t ) or t he f i la m e n to us (m o ld ) ph as e , de p en d in g o n t h e i nc ub a t io n t e m p e r at u re ( e .g . , H i s t op l as m a an d Bl as t o my c es ) . a . F un g i a r e c la s s if i ed in t o p h y l a b as ed on t he ty p e o f r e p ro d uc ti v e st r uct u r es o b se r v e d o r th e l ac k o f ob s e r v ab le s e xu a l r ep r o du c ti v e s t r uc t u re s . ( 1 ) As c o m yc o t a ( a s c u s ) ( e . g. , C an di d a a nd H is to p la s m a ) ( 2 ) B a si d i om yc o t a ( b a s id i um ) (e . g ., C ry p to c oc c us ) ( 3 ) Z yg o m yc o t a ( z y g o t e) ( e . g. , R hi zo p u s ) ( 4 ) D e u te r o m yc o t a ( a s exu a l , a ls o c al l ed fu n gi im p e r f ec ti ) (e . g ., C oc c i di o id e s ). R e c en t l y, s om e s e xu a l re p r od uc t i v e s ta t es ha v e b e e n id e n ti fi e d i n f un g i cl a ss if i ed a s b e lo n gi ng t o D e ut e r om y c o ta . b . P r o t oz oa , un ic el l ul a r , n o np h ot os y n t he t ic eu kar y o t e s c ha r ac t e r i ze d b y m o de of m o ti l it y , in c l u de th e fo ll owi n g : ( 1 ) M a s ti g o ph o r a (f l ag ell a t es ) (e . g. , G ia r di a ) ( 2 ) S a rc o d in a (a m o e ba e) ( e . g. , En t a m oe b a ) ( 3 ) C i l io p ho r a (c il i at es ) ( e . g ., B al a nt i di u m ) ( 4 ) S p o ro z oa (n o nm o ti le) ( e . g. , Pl as m o d iu m ) 3 . B ac t e r i a c o n ta i n a wid e v a r ie t y of p ro ka r y o t es , i nc lu d in g g r am - po s i t i ve a n d g r am n e g at i ve b ac t e ri a . S ec t ion s II - V I I ch a r ac te r i z e b ac t e ri a i n m o re de t ai l . B . N o n l i vi n g, bu t me d i ca l l y s i g n i f ic a n t e n ti t i es a r e t h e f ol l o wi n g 1 . V i r us e s ( s e e VI I I ) , wh i c h a r e c l as s i f ie d b y : a . C a ps i d s t r uc t u r e , wh i c h is t he pr o te i n co a ti n g a r o un d t h e n uc le ic ac id b . T yp e a n d s t r a nd e dn es s o f n u cl e ic ac i d , wh i ch c o u ld be D N A or R N A , e i t he r s i ng le o r d ou b le s t r an d ed c . P re se n c e or ab s e n c e o f a l i p id en ve l o p e s u r ro u n di ng t he pr o te i n ca p s i d d . P r es en c e o f e nz ym e s , wh i c h m a y b e e i th e r i nco r p o ra t ed in t o t he li p id en v e l o pe o r f ou n d i n t he c a ps id nea r t he nu c l e ic a ci d 2 . P r i on s , i n f ec t i ou s p r o t e i ns , ar e i m p l ic at e d i n s om e s po n gi f or m e n ce p ha lo p at h ie s ( e .g . , m a d c o w d i s ea s e , C re u tz f e l d t -J ak ob di se as e , a nd ku r u ) .
II. TAXONOMY AND NOMENCLATURE OF BACTERIA
A. T a x o n om y i s c la s s if ic a t i on o r o rd e r in g i n to gr ou p s b as ed on de g r ee of r e l at e dn es s . B ac t e ri a a re p r o ka r yo t e s t h at be l on g to t he B ac te r ia do m a in a nd th e E u b ac t e ri a k in gd om an d a r e gr o up e d a nd na m e d p r i m a r il y b y m o r ph o lo g y , b i oc h em ic al an d m et a bo li c d i ff e r en c e s, a nd i m m un o lo g ic a n d g en e ti c r e la ti o ns hi p s. D N A t e c h n ol og y h as le d t o t he re c l as si f ic a ti on o f s om e o r g an is m s b a s e d on D N A s e qu e nc es a n d h om ol o gy . B a c te r ia a re na m e d us i ng th e Li n na e an o r b in o m ia l s ys t em a s a ge n us a n d s p e c i es ( e. g ., H o m o s ap i en s i s t h e g en us an d s pe c i e s f o r h u m a ns ) . P.176
B . M o r ph o l og y i s t he c la s s i fi c a t io n o f ba c t e ri a by s h ap e an d s t ru c t u r e. 1 . C u l tu r a l m o r p ho l og y i s b as ed on t he s i ze , s ha p e , a nd te xt u r e o f c ol on i es th a t a r e gr o wn i n p u re c u lt u re o n a n a ga r pl a te . Ea c h c ol o n y o r i gi na t es f ro m a c o l on yf o r m i n g u n it ( C F U ) , c o ns is t in g o f a si n gl e c el l o r g r o up of ad h er e n t c e ll s . 2 . M i c r os c op i c m o r p ho lo g y d e s c ri b es ba ct e ri a on t he ba si s o f th e s i z e, s h a p e, an d a r r a ng em e nt o f t he c e ll s ( s e e I I . C a nd D ) . C . S t a i ns . Be c a us e o f the i r s m a ll s i z e an d re la t i ve t r an s p a r en c y, b ac t er i a m us t be s t ai n ed to be v i s i bl e u n de r t he li gh t m ic r os co p e. S t a i ni ng is al so us ed as a c l as s i fi c a t io n s y s te m . Th e m a j o r t yp es of s t ai n in g r e ac t io ns a re th e fo ll o wi n g : 1 . S im p l e s ta i n . A s i ng le d y e (e . g. , G e nt ia n v i ole t , s a f ra ni n ) t h a t c o l or s th e c e ll s . 2 . G r a m s t ai n . A d if f e ren t i al s t ai n in g p r oc ed u r e th a t d i v i de s b ac te r i al c e lls in t o e i t he r gr am - p os it i v e (p u rp l e ) o r g r am - ne g a ti v e (p in k ) . 3 . Ac i d - f as t s ta i n. A pr oc e du r e t h at s t a in s ce l ls th a t h a ve a n o u t er la ye r o f a wa xy l i pi d (a c i d fa s t ) bu t no t c e l ls th a t l ac k t ha t l a ye r (n o n -a c i d - fa s t) . 4 . S p o re s ta i n. A pr oc ed u r e t h at us es he a t t o he l p d ye en t e r t he s p o re . 5 . C a ps u le s ta i n . Two d y e s a re us ed t o s ta in t he c el l a n d t he ba c k g ro u nd, a ll o wi n g vi s u al i za ti on o f t he un s ta i ne d c a ps ul a r m a t e ri a l. D . B a c te r i a l c el l sh a pe a n d a r r a n ge m en t 1 . C o cc i a r e s ph e ri c a l an d e xi s t i n c ha in s (S t r ept o co c c us py og e ne s ), pa ir s o r d i pl oc o c c i ( S t re p to c o c c us pn e u m on i ae , Ne is s e r i a g o no r r ho e ae ) , c lu s t e rs ( s t ap h yl oc oc c i ) , a nd pa c k e ts of f ou r o r ei g ht (s a rc i na e ) . 2 . B ac i l l i a re c y li nd r ic a l a n d ro d -s ha p ed o rg an ism s ( p s e ud om o na ds , Es ch e r ic hi a ) . 3 . C o cc o ba c il l i a r e s ho rt r o un d ed ro d s ( B r uc el la ). 4 . S p i ro c he t e s a nd s pi ri l l a a r e h el ic a l, li k e a c or k sc r e w ( T r ep o ne m a pa lli d u m ) ; s p i ri ll a a r e r i gi d h el ic e s , wh e r e a s s pi r oc h et es a re f l e xi b l e h el ic es . 5 . F us o ba c te r i a h a v e tap e r ed en ds a nd ar e s li g ht l y c ur ve d (i . e ., fu si f o rm ; F u so b ac te r i u m m o rt i fe r um ) . 6 . F il a me n t ou s o r g an is m s a r e b r an ch i ng or g an is m s an d a r e a s s oc ia t ed wi t h m ol d l i ke ba ct e r ia ( Ac ti n o m y c e s b ov is ) . 7 . V i b ri o s a r e c om m a s ha p e d r od s (V i b ri o c ho le ra e ) . 8 . P le o m o rp h i c o rg a ni s m s e xi s t in v a r ie d f o rm s ( H a e m o p hi lu s , L eg io n el la , C o r y ne b ac te r ia ) . E . O t h e r c l as s i f ic a ti o n p a r a me t e r s 1 . P r es e nc e o r a bs e nc e o f
a . S p o re s u s e d fo r s u r v iv a l ( B ac il l us a n th r ac is ) . b . C a ps u le s o r s li me l aye r s u s e d fo r a d he r e nc e. C a ps ul e s a re al so an t iph a g oc y t ic ( S t r e p to c o c c us p n eu m o ni a e , N e is s e r ia m e ni ng i ti di s ) . 2 . M o t i li t y a n d t he t y p e o f f la g e ll a a . M o n o t ri c h ou s . A s i ngl e fl a ge ll um b . L op h o t r ic h o us . A t uf t o f fl ag e ll a a t o n e p ol e c . Am p h i t r ic h ou s . A f lag e ll um a t b ot h p o le s d . P e r i t ri c h ou s . F la g el la d is t ri b ut e d e v e nl y o ve r t h e e n ti r e ce l l e . Ax i a l fi l am e n ts . Pe r ip l as m i c f la g el la wr a p p ed a r o un d s pi r oc he t es f . G l i d in g m o t i li t y. A s de m on s t r a te d b y s li m e m ol d s P.177
III. STRUCTURE OF THE PROKARYOTIC CELL A. O ve r vi e w . P ro k ar y o t ic c e ll s ( b ac t er i a ) a re sma l l an d r e la t i v el y s im p l e ( F i gu r e 9 1 ) . Th e y ha v e t he fo l lo wi n g c h a ra c t e r is ti cs : 1 . C o n ta i n n o i n t e r na l m e m b ra n e b o un d o rg a ne l l es bu t ha ve c om p le x c e ll wa l l s t r uc t ur es 2 . La ck a t r ue nu c l e us , a n uc l ea r m em b r an e , a nd i n t ra c y t op l asm ic m e m b r an o us o r g an e ll es ( e. g ., pl as t id s , e nd o pl as m i c r e ti c u l um , va c uo l es ) 3 . Mu l t i pl y a s e xu a l l y b y b i n a r y f i s s i o n r a th e r t ha n b y m i to s i s o r m ei os is 4 . P r o te i n s yn t h e s i s i s m e di a te d b y 7 0s ra t he r th a n b y 8 0s ri b os om es . 5 . B ac t er i al ge ne t ic in f o rm a ti o n is a r ra ng e d o n a s i ng le s u p er co i le d c i rc ula r st r a nd o f do u bl e -s t ra n de d D N A ; t h e n u cl e o id is th e a r ea o f th e c el l c on t ai n in g t he t ig h tl y c o il ed c h r om os om e . 6 . S om e b ac t er i a c o n t ai n s t or a ge g ra n ul es , o r in c l u s i on bo d ie s , t he s t ai n in g of t he se g r a nu l es m a y al s o be us e f u l i n i de n ti f y i ng th e b ac t e ri a . B . E x t e r na l s t r u c tu r e s 1 . C a ps u le an d sl i me laye r a . Th e ca p su l e is an adh e r en t , s u rf ac e c o at m a de u p o f l on g c ha i n r e pe at s of c a r bo h yd ra t es o r p ep ti d es . Th e c ap su l e d if f e rs i n c om p os it i on am on g b ac te r i a o f d i f fe r e nt ge n us a n d s p ec i e s . A nt i ge n ic d i ff e r en c es am on g c a ps ul es c a n be us e d t o i d en t i f y s t ra i ns wi t hi n a s i ng le s p ec i es o f b a c t e ri a ( S t r ep t oc oc c us pn e u mo n ia e ) . C a p su l es a r e u s u a ll y p oly s a c c h ar i de in na t u re ; ho we v e r , t h e c ap su l e o f Ba c il lu s i s p o l yp ep ti d e . Th e c a ps ule h as s e v e ra l fu nc t io ns : ( 1 ) I nc r ea s e s t he vi r u l en c e (d e gr e e o f o r ga n is m p a th o ge n ic it y ) o f a m ic ro o r ga n is m ( 2 ) P r e v en t s p ha g oc yt o s i s o f th e o r ga n is m b y m a c r op ha g es an d n eu t r oph i ls ( 3 ) A id s i n a d he r e nc e o f t h e o r ga n is m to h os t c e ll s b . I f t h e p ol y s ac c h a ri de is no n ad h er e n t, it is c a ll ed a s l i me la ye r .
Figure 9-1. Structure of a procaryote cell. [Adapted with permission from Winn WC Jr, Allen SD, Janda WM, et al. Koneman's Color Atlas and Textbook of Diagnostic Microbiology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.]
P.178
c . T ra n s fo r m a ti o n f r om s m o o th t o r o ug h c ol on i es on m e di a i n di c a t es c ap s u le l os s . C o n cu r r en t l y , t h e re is a lo s s o f vi r ul e nc e . Th i s c ap s ul a r m at e ri a l is im m u no g e ni c, t h e r eb y i nd uc in g th e p r od u c t i on of a nt i b od i es , wh i ch ac t a s o ps on i ns t o en h a nc e p h a go c y to s i s ( o p so n iz a ti o n ) . 2 . F la g el l a a r e p r ot e in ac e o us , h e li ca ll y c oi le d or ga n s us e d f o r m o v em en t th a t e xt e n d o ut wa r d f r om th e c y t o pl as m t h r ou gh t he c e l l wa ll in t o t h e e n v ir o nm e nt ( F i gu r e 9 - 2 ) . F la g el la r ota t e e i th e r c lo ck wi s e o r c o u n te r c l oc k wi s e , al lo wi n g a s e ri es o f r un s a nd t um bl es in res p on s e t o c h em ic a ls i n th e en vi r on m e n t . Th e di re c ti o n o f m o vem e nt is c o nt r o ll ed b y a c o m p le x m e c ha n is m i n v o l v in g c he m o r ec e pt or s an d a n i n t ra c el lu l ar c a s c ad e o f m e th y l a ti o n a nd ph os p hor yl a t io n re ac t io ns , c a us in g ba ct e r ia t o m o ve to wa r d n ut r ie n t c h em oa t t ra c ta n ts a n d a wa y f r om r ep e ll an t s. a . S t r uc t u r e ( 1 ) Fl a ge l la ar e c om p os ed o f f l a ge l li n , a p ro t ei n c a ll ed H a n ti g en , wh i ch is a n t ig en ic a ll y d is ti nc t f rom o th e r f la g el la in eu c ary o t e s . ( 2 ) Fl a ge l la ha v e t h re e p a r t s : ( a ) B a sa l b o d y ( i ) A t ta c h es t he fl a ge ll a to t he c yto p la s m ic m em b ra n e a n d c e l l wa l l
Figure 9-2. Structure of a procaryote flagella from a Gram-negative organism. [Adapted with permission from Winn WC Jr, Allen SD, Janda WM, et al. Koneman's Color Atlas and Textbook of Diagnostic Microbiology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.]
P.179
( i i ) Th e n um b e r o f r i ng s t h a t m ak e u p t he ba s a l bo d y d if f e r i n g r am -p o si ti ve ( t wo ) a n d g r am - ne g at i v e (f o u r) o r g an is m s . Th e L a n d P r i ng s a r e a bs e nt in G r am - p os it i ve o r g an is m s . ( b ) H o ok ( c ) F il a me n t b . P e r ip l as m ic f la g e ll a , a ls o c al l ed ax i al f i la men t s , o c c u r i n s pi r oc he t es a n d a r e e m be d de d i n to th e c el l wa l l 's ou t e r m em br a ne . Bec a u s e t h e y c au se a c o rk s c re w t yp e o f m o t io n o n c on t r ac t io n , t h es e o r ga ni s m s ar e n ot hi n de r ed b y th e vis c o si t y o f m e di a . 3 . P i li ( f im b r ia e ) a r e p r ot e i na c e o us , h ai r - li k e e xt e n si o ns t h at a re s h o rt e r t h a n f l a ge ll a a n d c o m po s e d of r e gu l ar l y a r ra ng e d p r ote i n s ub u ni ts c a ll e d p i li n o r f i m b r i li n . Th e y a r e m o re c om m o n i n g r am - ne g at iv e o r g an is m s b u t c an be f o un d i n g r a m - p os it i v e o r g an is m s . Th e r e a r e t wo m o rp h olo g ic a l an d fu nc t io n al va ri e t ie s: a . C o mm o n ( a tt ac h m e n t) p il i ( 1 ) A pp e a r i n g re a te r num b e rs t h an s e x p i l i ( 2 ) H a ve a d he s i v e p ro per t i es , wh i ch ar e i m p o r ta nt i n t he f o rm at i on of bi o fil m s ( 3 ) A r e l ec ti ns , wh i c h a re r es p on si bl e fo r t ro ph ism , th e a b il it y o f th e o r gan i s m to b i nd t o sp ec i fi c r e c e p to rs on ho s t ce l ls b . S ex ( c o nj u ga t i v e o r F ) p i li ( 1 ) A r e l on g er t ha n c om m o n p il i ( 2 ) F or m i n g r ou ps o f < 1 0 ( 3 ) A r e i n v ol v e d i n t h e t ra n s p o r t o f D N A b et we e n d o n or an d re c i p ie n t c e l ls C . T h e c el l w a ll , pe r i p las m i c s pa c e, a nd c yt o p l a s m ic me m b ra n e 1 . Th e ce l l w a l l i s r ig i d. A l t h ou gh i t p ro v i d es th e g e n er a l s h a pe of t he c e ll, i ts f u nc t io n i s t o p r o te c t t he c el l f r om os m o t ic s ho c k . I f th e c el l wa l l is de s tr oy e d , t he b a ct e r ia l c el ls ar e s us c ep t i bl e t o a l te r a ti on s i n t he t on ic i t y of th e e n v i r onm e nt . Th e wa l l i s c o m p o s e d o f a bas ic p ep t i do g l yc a n l a ye r , wh i c h i n t u rn is c om p os e d of r e p ea t in g d is ac c ha r id e un i ts ( a p ol y m e r o f N- a ce tyl g l u c o s a m in e a n d N -
a c e t yl m u r a m i c ac i d ), wi t h a f o ur - am i no - ac id s i de c ha i n t ha t is c o val e nt l y l i nk ed t o a m in o a c i ds f ro m n ei g hbo r i ng di s a c c ha r i de un i ts , f o rm i ng a s ta bl e c r os s -l in k ed s t r uc t ur e . Mo s t b ac t er i a a r e de s i gn a te d a s e i th e r g r am - po s i t i ve o r gr am - ne g a ti v e , b a se d o n f u nd am e nt a l d if f e r en c e s i n t h e co m p o ne n ts o f t he ce ll wa l l . O wi n g to t he u n iq u en es s a nd t he im por t a nc e o f th e c el l wa ll t o b a ct e r ia l v ia bi l it y, i t is the t a rg e t o f m a n y an t ib io t ic ag en ts . a . G r a m -p o si t i ve o r ga n is m s h a ve a th ic k c el l wal l , wh ic h i s 9 0% pe p ti d ogl y c a n , wi t h e xt e n s i v e c r os s - l in k i n g t h at is ap p ro xi m a t el y 4 0 l a ye rs th ic k a n d f o rm s a l a ye r ed ne t wo r k a ro un d th e c y t o pl a sm i c m em b ra ne . W i t hi n th e c el l wa ll , a v a r i e t y of e l em e nt s s e r v e t o s ta bi l iz e t h e c el l wa ll , m a in t ai n i t s as s o ci a ti o n wi t h t he c yt o pl as m i c m em b ra ne , a n d a c t as r ec ep t o rs a n d a n ti g en ic de t e rm in an t s . Th e s e e l em e nt s i nc lu d e p ro t ei ns , po l y s a cc ha r id e s a nd te i c h oi c a c i d (g l y c e r ol o r r i b it o l p h os p ho di es t e rs ) . ( 1 ) T ei c ho i c a c id s (g l y c e r o l o r ri bi t ol ph o s p ho d ie s te r s ) ( a ) M e m b ra n e -a ss o c ia te d t ei c h oi c a c id s (l ip o te i c h oi c a c i d ) a r e c o v al ent l y l in ke d to g l yc ol ip i ds o f th e c y t o pl as m i c m em b ra ne . ( b ) W al l - as s oc i a te d te ic h o ic a ci d s a r e c o va l ent l y l in ke d to th e g l yc a n c h a in o f p e p ti do g l y c a n . b . G r a m -n e ga t i ve o r ga ni s m s' c e ll wa l ls a re m u lti l a ye re d wi t h a th i n p ep t id o gl y c a n l a ye r th a t h as no te ic h oic ac id s . E xt e r n a l t o th is is t he ou t e r m e mb r a ne , a c o m p l e x c e ll wa l l l a y e r , wh i c h is li n k e d t o th e p ep t id o gl y c a n la y e r b y t h e l i po p r o te i n l a y e r . Th e o u te r m em b r an e a c ts as a h y d r op ho b ic d i f fus i on ba r r ie r an d c on s i s t s o f ( 1 ) P h os p ho l i pi d , a bi la y e r s i m i l ar t o t he c y to p la s m ic m e m b r an e wi t h p ro t e in c h an n el s , c a ll e d p o r in s , f o r n u t ri e nt t ra ns p o rt . Th e ph os p ho li p id la y e r of t h e o u te r m em b r an e f ac es t he c y t o p la s m ic m em b r an e . ( 2 ) Th e li p o po l ys a c c h a r i d e ( LP S ) c om p on e nt p ro j ec ts f ro m t h e c e l l s u r f ac e a n d is b o t h t o xi c an d a n ti ge n ic ( O a n t i ge n ) . I n a gr a m - ne g a ti v e o rg an is m , t he L PS b l o ck s d i f f u si o n o f l o w m ol ec u la r we i g h t su bs t an c es i n to t he c e ll , s o a n ti b io ti c s a n d c h em ic al s t ha t at t ac k t he c el l wa l l ( e .g . , l ys o zy m e, p en ic i ll in ) c a nn o t e as ily p a ss t h r o ug h . L P S , a ls o k n o wn as e nd o t ox i n , is to xi c t o hu m a ns a nd i s c om pos e d o f t h r e e p ar t s : ( a ) L ip i d A: t o xi c p o r ti o n t h a t c a n e i th e r s lo u gh of f in t ac t c el ls o r b e r e le as e d i nt o c i rc u la ti o n u po n l y s is of t h e c el l , c au si ng no n s p ec i fi c i nf l am m a ti o n, in cl u di n g d i a r rh e a, fe v e r , an d s ep ti c s ho c k P.180
( b ) C o r e p o l ys a c c h a r i de : s i m i la r wi t h in ge n e ra ( c ) O - s pe c i fi c s i d e c ha in : s p ec i es s p ec if ic ( 3 ) P r o te i n 2 . Th e pe r i p la sm i c s p ac e , a n a r e a b et we e n th e c e ll wa l l a nd t he c y t o pl as m i c m em b r an e , c o n ta i ns a ge l of s e v e r al t y p es o f m ol e cu le s (e . g. , h y d r o l y ti c e n z ym e s , p e r ip l as m ic - b in di n g p r ote i ns ) th a t p r oc es s m o le cu l e s be f o re th e y en t e r t he c yt o pl as m . I t a ls o c on t ain s p r o te i ns t h a t ac t a s c h e m o r ec e pt o rs fo r c h em o t a xi s ,
o t h e rs t h at ac t a s c a rr i e rs o f n ut r ie n ts (s im il a r t o c a r ri e rs in th e c y t o pl as m i c m em b r an e ), a nd an t ib io t ic - i na c t i va ti n g e n z y m e s . 3 . Th e c yt o p l a s m i c m em b r a ne is a p ho sp h ol ip id b il a ye r m at r i x o f a f a tty a c id c o r e ( h y d r o ph o bi c ) a nd gl y c e ro l ph os p ha t e ( h y d ro p hi lic ) . In th e p r es e nc e o f p ro t e in s e m be d de d i n t h e m a t r i x, t h es e m em b ra n es a r e a c t i ve l y an d p as s i v e l y e nga g e d in s e ve r al ce l lu l a r fu n c ti on s . a . T r an s po r t a t io n of nu tr i e nt s t h r ou gh ( 1 ) P as s i v e di f fu s i o n ( 2 ) F ac il it a te d d i f fu s i on ( 3 ) A ct i v e t r a ns po r t (t h is m e th od is th e o n l y o n e th a t a c ti v e l y us es e n e rg y b e c a us e m o le cu l es a r e m o v in g i n to t he c e ll ag a in st a c on c e n t r at i on gr a di e nt ) b . Th e s i te o f r e sp i r a t ion p r o t ei n s u s e d f o r e l ect r o n t r a ns p o r t a nd en e rg y f o r m a t io n c . E nz ym e s i n v o l v e d i n th e as s e m b l y of th e c el l wa l l c om po n en ts d . S ec r e t i on o f e xo t o xin s an d o t he r s u bs t an c e s f o r th e b r ea kd o wn o f m ac r om o le c u le s D . I n t e rn a l s t r u ct u r e s 1 . S t o ra g e g r a n ul e s a re i nc l us io n b o di es us ed for f o od o r e ne r g y s t o ra g e ( e . g ., p o l yp ho s p ha t e c om pl e xe s , c a r bo h y d ra t e ). 2 . R i bo s om e s a r e c e l lu la r u ni ts th a t s yn th es i ze p r o t ei n b y t he t ra ns l at i on o f m es s en ge r R N A (m R N A ) b as e s e qu en c e s i n to am i n o a c i d p r o te in s e qu e nc e s . Th es e r i b os om es , u n li k e th os e in e uk a r yot ic c e ll s , a re 70 s u n it s a nd a re no t as s o c ia t ed wi t h m em b ra n es s uc h a s m it o c h on d r ia or r ou g h en d o pl as m i c r e ti c u lu m . 3 . Th e nu c le a r r eg i o n of b ac t er i a is a c on d en s ed a r ea (a nu c l e oi d ) c on ta i ni n g t he b a ct e r ia l c hr om o s o m e , wh i c h la ck s a n uc l ea r m em b r an e a nd c o ns is t s o f a l on g , d o u bl e -s t ra n de d , s u p e rc o i le d , c ir c ul a r D N A m o lec u le . 4 . S om e o r ga n is m s c on ta i n p l as m id s , c ir c ul a r do u bl e -s t r an d ed pi ec es of D N A t h at a r e fo u nd ou ts i de of t he b a c t e r ia l c hr om o s o m e . Th e s e s t r uc t ur e s a re au t on o m o us ( n o t c on t r ol le d b y t h e b ac t e ri al c h r om os om e ) , c on t a in in f or m at io n fo r he av y m e t a l a n d a n ti bi o ti c re s i s t a nc e, a r e c o n ju nc t i v e , a nd c ar r y g e ne t ic el em e nt s c a l le d t r a n s po s o ns .
IV. MICROBIAL PHYSIOLOGY A. N u t r i t i o n a l t yp e s 1 . Au t o t r o p hs us e c a rb on d io xi d e as th e i r s o l e o r m ai n c a rb o n so u rc e . a . P h ot o a ut o t r o ph s u s e l i gh t a s a n e ne r g y so u rc e . b . C h em o au t o t r op h s o x i d i z e o r ga n ic o r in o rg a nic c o m p o un ds to p ro d uc e e n e rg y. 2 . H e te r o t r o ph s u s e o rga n ic c om p ou n ds a s t h ei r m ai n c a rb o n s o u rc e . a . P h ot o h et e r o t r op h s us e l i gh t a s a n e ne r g y s ou r c e. b . C h em o he t e r o t r op h s o xi d i z e o r ga n ic a n d i no rg a ni c c om po u nd s t o p r od u ce e n e rg y. 3 . P r o t ot r o p hs a re pa r en t c e ll s t h at ha ve no s p ec i al nu t ri t io n al r eq ui r em en t s . Th e y r e q ui r e t h e s a m e n ut r ie nt s as t h e m aj o r n um be r of t h e n at u ra l m em be r s o f t h e s p ec ie s .
4 . Au x o t r o p hs ar e m u tat e d s o t h at t he y c a n no t sy n t h es i z e th e s am e e s s en t i al n u t ri e n ts (u s u al l y am in o a c id s ) as t he i r p a re n t c e l l . 5 . S u bs e ts a . H o lo p h yt i c . O r g a n is m s wh o s e n ut r ie n ts m us t be i n a s ol u bl e , d if f us ib l e f o r m b . H o l oz oi c . O rg a ni s m s t h a t n ee d c om pl e x n u t r ien t s , o ft e n s ol id m a te r i al s t h a t a re i n ge s te d a n d t he n b r ok en d o wn c . S ap r o p h yt i c . O r g a n is m s wh os e n u t ri en t s a r e o b t ai ne d f ro m d ea d o r de c a y in g o r g an ic m a t te r P.181
d . P a r as i t ic . O r ga ni s m s wh o s e nu t r ie n ts a r e o b tai n ed f r om a n d a t t he e xp e n se of a l i vi ng o rg a ni s m (h um a n p a t ho g en s ) B . N u t r i t i on a l r e q ui r e me n t s . B ac t e ri a u se a wi d e v a r i et y o f n u t ri en t s t o o b t ai n e n e rg y a nd t o c o ns t r uc t n e w c e ll u la r c om p on en t s . Th e s i x e l e m e n ts us ed a s th e m a in c om p on e nt s o f c a rb o h y d ra t es , l i pi ds , p r o te in s , a nd nu c l e ic a ci d s a re c a rb o n, o xyg e n , h y d r o ge n , n it r o ge n , p h os ph o r us , a nd su lfu r . S e ve ra l m in o r a nd t rac e e l em e nt s as we l l as c at io n s p la y va r i ou s r o le s i n t h e m ic ro o r ga ni s m s . C . T e mp e r a tu r e r el a t ion s 1 . P s yc h r o p h i l e , a n o r ga n is m t ha t gr o ws we l l at 0 ° C , ha s o p ti m a l g r o wt h a t 15 ° C o r l e ss , a nd a m a xi m um g r owt h t e m pe r a tu r e o f 2 0 ° C 2 . M e s op h i le : a n o r g an is m wi t h o pt im a l g r o wt h at 2 0 ° -4 5 ° C , m i n im um g r owt h t e m p e r at u re s b e t we e n 15 ° a nd 20 ° C , a n d a m a xi m um g ro wt h t em p e ra t ur e o f a p p ro xi m a t el y 4 5 ° C (h um a n p at h og e ns ) 3 . T he r m op h i le : a n or g an i s m th a t ca n g r o w a t 55° C o r g re a te r , wi t h a m ini m um g r o wt h t em pe r a tu r e o f ap p r o xi m a te l y 45 ° C . D . O x yg e n r e q u i r em e n ts . H o w o r ga n is m s u se oxy g e n c an be a m a j or f ac t o r i n t he i r c l as s i fi c a t io n . 1 . Ae r o b e s h a v e t h e a bi li t y t o g r o w i n t h e p r es enc e o f at m o s p h e ri c o xyg e n . a . O b l ig a t e a e ro b es de pe n d c om pl e te l y on o xy g e n f o r g r o wt h . O xy g e n se rv e s as t e r m i n al e l ec t ro n a c c e pto r in a er o bi c r es p ir a ti o n. b . F ac u l ta t i ve ae r o be s h a v e th e a b il i t y to gr o w wi t h o r wi t h ou t m o le c u la r o xyg e n . 2 . An a e r o be s h a v e th e a b il i t y to g ro w wi t h o u t o xyg e n . a . O b l ig a t e a na e r ob e s d o no t to le r a te o xy g e n at a ll an d d i e i n i ts p r es e nc e . Ma n y s t r ai ns la c k c a ta l as e a nd s up e r o xi d e d is m u t as e, wh i c h p ro t ec t c el ls f ro m t h e d e st r uc t i v e o xi d i z i n g c a pa b il i ti es o f h yd r og en pe ro xi d e a n d s u p e ro xi d e ion s , wh ic h a r e no rm a ll y p r od uc e d un d e r a e ro b ic c on d it i on s . b . F ac u l ta t i ve an a e ro b es d o n ot r eq u ir e o xy g e n b u t g r o w b e t te r i n i t s p res e nc e. 3 . M i c r oa e r o ph i le s re q ui r e o xy g e n l e v e ls be lo w n o r m a l a tm os p he r ic pr e ss u r es fo r g r o wt h ( e .g . , He li c o b ac te r py l or i ) 4 . C a pn o p hi l es r eq ui r e h i gh e r l e ve ls o f c a rb o n di o xi d e t ha n a r e f o un d a t n o r m a l a t m o s p h e ri c p r es s u r es fo r g ro wt h ( e . g. , N ei ss e ria s p . an d St r ep t oc oc cu s p n e u m on ia e ) . E . B a c te r i a l g r ow t h c u rve . B a c te r ia l g r o wt h is de f i ne d a s a n i nc r ea se in t h e n u m b e r o f c el ls p re s e n t. B e c au se ba c te r ia r ep r odu c e b y b in a r y f i s s i o n, gr o wt h c an
b e pl o tt e d as t he lo g o f th e c e ll nu m b e r v e rs us t im e to pr o du c e a c ur ve wi t h f o u r d i st i nc t p ha s e s (F ig u r e 9- 3 ) . 1 . L ag ph a se . A t r an s i t io n pe r io d d u r in g wh ic h th e ba c t e r ia ar e re p li c a t in g D N A an d t h e e n zy m es ne e de d f o r t h e n e w e n v i r on m e n t a r e b e in g i nd u c e d . Th e c e lls a re i n c re as in g i n s i z e b u t n ot i n n um be r . D ur i ng th is p h as e o f g r o wt h , th e c el ls a re m o st p e r m e ab l e. 2 . L og a r i th m ic ( l og ) pha s e . D i vis i on oc c u r s a t co n s t a nt an d m a xi m a l r a te , an d th e n u m b e r o f c el ls in c re as es in a g eo m e t r ic p r o g re s s i on . Th e g en e r at i on ti m e , wh i ch va r i e s am o ng s p ec ie s , is u s u a ll y 1 5 -2 0 m in u te s (E s c h e r ic hi a ), bu t m a y be h o u rs ( My c o b ac t e ri u m ) . Be c a us e th e c el l wa ll is be in g s y n t he si z e d s o ra pi d l y , ba c te r i al c e ll s a r e m o s t s u s c ep t ib le t o c el l wa l l in h ib i to rs du r i ng t hi s p ha s e . 3 . S t a ti o na r y p h a s e . The g r o wt h ra t e t ap e rs o ff a n d g r o wt h an d d e at h rat e s a r e n e a rl y e qu a l. A fa i rl y c on s ta n t p op u la t io n o f v ia bl e c e ll s r es u lt s. D u ri n g th i s p ha se , c e ll ul a r m et a bo l it es a re p o ll u ti n g t he en vi r o nm ent . 4 . D ea t h ph a se . W hen th e c o nc en t r at i on of vi ab le ce l ls d ec r e as es b e ca us e o f th e a cc u m u la t io n o f to xi c wa s t es an d a u to l y t ic e n z y m e s .
V. METABOLISM AND ENERGY PRODUCTION. Mi c r o o r g an is m s de r i v e en e r g y f ro m n ut r i en ts b y a se r i es o f c h em ic al re ac t io ns b y wh i c h th e en e rg y s to r ed i n c h em ic al bo n ds i s t r ans f e r re d t o n e wl y f o r m e d c h em ic al b o n ds t o p r o v i de en e rg y s t o ra g e i n a u se f ul f or m , s uc h a s a de n os in e t r ip ho s ph a te ( A TP ) . P.182
Figure 9-3. Growth curve of bacterial culture. [Reprinted with permission from Winn WC Jr, Allen SD, Janda WM, et al. Koneman's Color Atlas and Textbook of Diagnostic Microbiology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.]
A. AT P g e n e r at i o n 1 . S u bs t r a te - l e ve l p h osp h o r yl a t i o n r el e as es e ne r g y t h ro u gh di r ec t t r an s f e r of h i gh - e ne r g y ph os p ha t e gr o u ps f ro m a n i nt e rm e dia t e m e ta bo l ic c om p ou nd t o a d e no s i ne di p ho s p h at e (A D P ) . N o m ol e cu la r o xyg e n o r ot h er in o r ga ni c f in a l e le c t ro n a cc e pt o r i s r e qu i re d .
2 . O x i da t i ve ph o sp h o r yl a t i o n r em o ves el ec t r ons f ro m o r ga n ic c om po u nd s a n d p a ss es th es e e l ec t ro ns th r o ug h a s e r ie s o f e l ec t ro n ac c e p to rs al o ng an ele c t ro n t r a ns p or t c h ai n , wi t h m o le c ul a r o xyg e n o r s om e ot h e r i n or g an ic c o m p ou n d a s t h e f i n al acc e pt o r . B . F e r me n t at i o n r e fe r s to e ne r g y- p ro d uc in g o xi d a t i v e s eq u en ce s , i n wh i ch o r ga ni c c om p ou n ds s e r v e a s b oth e le c t r o n d on o rs an d a c c e pt o rs . Th is p ro c e s s o cc u rs in th e a b se nc e o f e xt e r na l e l ec t r o n a c c ep t o rs . 1 . G l yc o l ys i s i s th e fi rs t s t ep in fe r m e n ta t io n a nd r e s p i ra t io n a n d ca u s e s th e o xi d a t i on o f g lu c o s e to py r u v i c ac id wi t h a y i e ld of t wo m ol es o f A TP . Th e re a r e d i f fe r e nt pa t h wa y s fo r p yr u v i c a c i d p r o du c t i on i n m ic r o or g an is m s : a . Th e Em b d en - M e ye r h o f ( g l yc o l yt i c ) p a t hw a y i s th e m aj o r p at h wa y . b . Th e E n tn e r - D ou d o r o ff p a t hw a y i s a n a l te r na te . c . Th e h e xo s e m o no p hos p h a te sh u n t u s e d wi t h t h e g l yc o l y t ic pa t h wa y i s a n a l t er n a ti v e . 2 . S ec o n da r y f e r m e n t a ti o n p r oc es s . Ma n y b ac te r i a u s e p y r u v at e t o o xi d i ze r e d u ce d ni c o ti n am i d e ad e n i ne di n u cl e o ti d e ( NAD H ) , p r o d uc e d i n g l yc ol ys is , to m a nu f ac tu r e a v a r ie t y o f f i n al pr o du c ts . a . L ac t ic ac i d fe r m en t at i o n . Th e s i m p l es t p r oc es s , wh i c h c on v e r ts p y r u va t e to l a ct a te ( La c t o ba c i l lu s , S tr e p t oc oc c us ) . b . Al c o h o l f e r me n t at i o n. P y r u va t e i s co n v e r te d to e th a no l a n d ca r bo n di oxi d e ( S a cc h ar o m y c es ) . c . M i xe d a c i d f e r me n ta ti o n . A co m bi na t io n o f l ac t ic , f o rm ic , an d a ce t ic ac i ds i s p r o du c e d wi t h e t ha n ol , hy d r o g en , an d c a rb on di oxi d e ( E s c h e ri c h i a c ol i ). d . B u t an e di o l fe r m en t a ti o n . P y r u v at e i s c on v e r te d to ac e to in , wh i c h is re d uc e d t o 2 , 3 - bu t an ed i ol ( En t e ro b ac t e r ). e . B u t yr i c a c id f e rm e n ta t i o n . B u ta no l , i s o p ro p an o l , a nd ac et o ne a re p rod u c e d ( C l o st r id i u m ) . P.183
f . P r o p io n i c a ci d fe r m en t a t i on . P y r u v a te is c onve r t e d t o o xa l o a c e t a te wi t h t h e a d di t io n o f c a r bo n d io xi d e a nd th e n t o p r op i on ic a c id ( P ro p io ni b ac t er i u m ). C . R e s pi r a t i on r ef e rs to e n e rg y - p r o du ci ng o xi d a tive s eq u en ce s , i n wh i c h in o r ga n ic c om p ou n ds a c t as t he las t el ec t ro n a c c e pt o r i n a s e r ie s o f r e ac ti o ns . Th is p r o c e ss i n cl ud e s g l yc o l ys i s , t h e t r i c a r b ox yl i c a c i d ( T C A) c yc l e , a nd th e el e ct r on t r a n s po r t s ys t e m , wh i c h y i e ld s A TP wh e n c ou ple d wi t h o xi d a t i v e p h os p ho r y l a ti o n . 1 . Ae r o b i c re s pi r a t i on . O xy g e n s e r ves as t h e f ina l el ec t r on ac c e pt o r . a . P y r u v a te is c o n v e rt e d t o ac e t yl c o e n z ym e A a n d c a r bo n d io xi d e a nd wa t e r t h r o ug h t h e T C A c yc l e . b . Th e el e c t ro n t r an s por t s ys t e m p la ys a r ol e i n t h e t r an s p o r t o f e l ec t ro ns al o ng a s e r ie s o f c ar r i er s f o un d in t he c y to p la sm ic m em b ra n e , e ac h wi t h su c c es si ve l y h ig he r o xi d a t i on p ot e nt i al s . Ma j o r c o m p o ne n ts o f th e e l ec t r on t ra ns p o rt s ys t em i nc l ud e ( 1 ) C yt oc h r om es ( 2 ) Fl a v o p ro t ei ns ( 3 ) U bi q ui n on es
2 . An a e r o b ic r es p i r at i on . A n i no r g an ic el ec t r on a cc e pt o r o t he r th a n o xyg e n ( e. g ., n i t ra t e , s u l fa t e , c a r b on a te ) s e r v e s a s t he fi n al el ec t r on ac c e p to r .
VI. GENETICS A. D e f i n i t i o n a nd t e rm s. G e n et ic s i s t he s t u d y of wh a t g en es a re , h o w t he y c a r r y i n f or m at io n , a n d h o w t hey a r e r ep li c a t ed an d pa ss e d o n. 1 . C h r om o s om es a re bod i es c om p os ed o f D N A th a t c on t ai n g e ne t ic i n fo rm a ti o n. B a c te r ia h a v e o nl y o ne c h r o m o so m e — a s in gl e , co n t in u o u s ( c l os e d) , do ubl e s t r an d ed , c i rc ul a r p ie c e o f D N A . a . D u pl i ca t i o n oc c u r s by s e m i c o ns e r v a ti ve r ep lic a ti o n, in wh i ch t he t wo s t r an ds o f t h e h e li x s e p a ra t e ( o r i gin ) a nd at t hi s p oi n t ( tw o r e p l i ca t i on f o rk s ) n e w s t r a n ds a r e s yn t he s i z e d , b i di r ec ti o nal l y , wi t h th e o r ig i na ls s e rv i n g as te m p la t es . b . S t r u ct u r e . Th e c e ll m e m b ra ne is at t ac he d to th e c h r om os om e; as th e c e ll gr o ws , i t se pa r a te s t h e d au gh t er c h ro m o s o m e s . Th e r e for e , ea ch da u gh t e r ce l l ha s o n e o r i gi n al an d o ne ne w s t ra n d . 2 . G e ne s a r e D N A s eg m e n ts t ha t a r e p r oc es se d in t wo s te ps t o p r od uc e va r i ou s p r o t ei ns . A n o rm al ba c t er i a l c e l l is h ap l o id . B . R e g u la t i on an d ex p re s s io n o f g en e t ic i nf o rm a t i on 1 . D N A h a s m an y f u nc t io n s . a . I t is d up l i ca t ed f or t ra n s f e r t o p r o ge n y du r in g c el l d i v is i on . b . I t i s t r a ns c r ib e d i n to R N A , wh i c h c an be t ra n s l a t ed in t o a p r o te in . c . It co n ta in s c o n t ro l sig n a ls , wh i ch ul t im at e l y c o n t r ol th e s yn t he s i s o f p ro t e in . d . I t c an be mu t a te d to a l t er s p ec i fi c ch a r ac te r ist i cs en co d ed b y g e ne s . e . I t ca n b e du pl ic a te d an d t ra ns f e r re d t o o t h e r ba c t e r ia l c e l ls in pr o ce s s e s o t he r t h a n ce l l d i v is io n (e . g. , c o n ju g at i on ) . 2 . D N A r e p l i ca t i o n, t r ans c r i p t io n , a nd t r a ns l at io n a ff ec t c e ll ul a r g r o wt h a n d d e ve l op m e n t. a . B ac t er i al r ep l i ca t i on in v o l v e s a c c ur a t e d up li cat i o n o f c hr om o s o m a l D NA , wh i c h e n a bl es th e f o rm a ti o n o f t wo i d e nt ic a l d au g ht e r c e l ls . b . T r an s c r ip t i on o f i nf o rm a ti o n f r om D N A t o R N A i s t h e f i rs t o f t wo s t ep s n e e de d t o p r o du c e ne c es s a r y p ro t ei n s . O n e g en e c an be t ran s c r i be d i n to m a n y c op i es o f R N A . S i m pl is ti c al l y , R N A p ol y m e r as e l oc at es t he be gin n in g o f th e g e ne ( pr o m o t o r ) , a nd t h is a re a u n de r go es lo c al i z e d u n wi n di n g t o a ll o w R N A p o l y m e r as e t o t ra ns c r i be R N A ( c al l ed m R N A) f r om t h e D N A t em pl a te . Th e R N A i s n o t p r oc ess e d, as in e u ka r y o t es . Th er e a r e no i nt r o ns a n d e xo n s , n o c a pp i ng of th e 5 ′ en d , a nd n o p o l ya de ni n e t ai ls ad d ed t o t he 3 ′ e nd . c . T ra n s la t i on is th e p r oc es s i n g o f g e ne ti c i n fo rm a ti o n t o s yn th es i z e p r ot e i ns . B e f o re t r an s c ri p ti o n is c o m pl e te d , a ri b os om e wi l l a tt a c h to th e 5 ′ en d o f th e m es s ag e . Th e 70 s P.184 b a ct e r ia l ri b os o me is c om p os ed of t wo s ub un i ts , 3 0 s a nd 50 s . Th e r ib os om e t r a n s la t e s t he m e s s ag e i n t o p r ot ei n b y re ad i ng th e t r i pl e t c o do n ( th r ee n u cl e ot id e s ) wh i c h c o d e f o r a s p e c i fi c a m i no ac i d. Th i s a m i n o ac i d is c a r rie d to t he s i te b y t r an s fe r R N A ( t R N A) a n d p ai r s wi t h t he c o d o n b y an an t i co d o n. A m i no
a c id s a r e j oi ne d , a nd t he r i bo s om e m o v e s t o t h e n e xt c o d on . Th is c on t in ue s u n ti l t h e c om p le t e p r ot e in is s y n th e s i z e d . 3 . R e gu l a ti o n . Th e p ro du c ts of ce ll u la r g r o wt h m u s t b e p r od uc e d i n c o r r ec t p r o po r t io ns fo r t he c e ll to l i v e a nd fu nc t io n . Th e two m o s t c o m m o n m e ch an i s m s o f m e ta b ol ic an d g e ne t ic reg u la t io n a r e a s f o ll o ws : a . F ee d ba c k i nh i b i ti o n o f en z y m e ac ti vi t y ( m e t ab o li c r e gu l at i on ) i n hi bi t s t h e s yn t he s i s o f th e c el l g r owt h p r o d uc t . Th e p ro d uc t b i nd s wi t h an al l os te r ic s i te on t he e n zym e , t h e re b y in ac t i v at i n g t he ac t i v e s i t e. b . R e p re s si o n o f e n z y m e ac t i v i t y (g en e ti c re gu l at i o n) in h ib i ts th e s y n th e s i s o f th e e n zym e at th e tr a ns c r i pt io n al le ve l . c . In d u ct i o n o f e n z y m e a c ti v i t y ac t i va te s t he s y nt h es is o f t he en zy m e at th e t r a ns c ri p ti on le v e l . C . O t h e r me t h od s o f DN A t r a n s f e r . Mi c r o o rg ani sm s c an c h an g e t he i r ge n e ti c c o ns ti t u ti on b y th e tr a ns fe r o f g en e ti c m a t e ri a l f r om a d on o r c h ro m o s o m e to a r e c ip ie n t c hr om o s o m e ( re c om bi n at i on ) . Re co m b in a t io n o c c u rs b e t we e n ho m ol o go us s e gm en t s ( t ho s e th a t h av e s im il a r n uc l eo t id e s equ e nc es ) . Th e re a re th r e e g e ne r al m ec h an is m s : 1 . T r an s f o rm a t io n i n v o lv e s t he r ec ip ie n t c el l t aki n g u p c el l -f r e e, f ra gm e nt e d (i . e. , n a ke d ) D N A a nd r ec om bin i ng ge n e ti c el e m e n ts . a . Th i s p ro c e s s is p ri m i ti ve a n d oc c ur s n a tu r al l y wi t h i n on l y a f e w g e ne r a. b . R e qu i re m e n ts in c l ud e c om pe t en t r ec ip ie n t c el ls ( e xh i b it i ng D N A re c e p to r s ) o r a “ l ea k y” b a c t e r i a l c el l w a l l , s o t ha t D N A c a n b e in t r o du c e d i n to th e c el l . c . It is ge ne r a ll y as s o c i at e d wi t h re c om b i na n t DN A t e c h n o l o g y o r c l o n in g , a t e ch n iq u e t o am p li f y a s p e c i f ic g e ne in p re pa r a tio n fo r an a l ys is . In th is pr o c es s , th e b a ct e r ia l c el l wa l l s a r e m a d e l ea k y b y c h em ic al t re a tm e nt . ( 1 ) C lo n in g i n v o l v es s pl ic i ng a g en e i n to a p la s m i d D N A ( ve c to r ) . Al l v ec to r s s ha r e s e ve r al c om m o n c h ar ac te r i s t ic s : ( a ) Ty p i c al l y s m a l l, we l l -c h a ra c t e ri z e d m o le cu le s o f D N A ( b ) C o nt a in at le as t on e r e p li c o n a n d c a n b e re p lic a te d wi t hi n th e h os t e v en wh e n t h e vec t o rs c on t ai n f o r eig n D N A ( c ) C o de fo r a p he no t y p ic t ra i t t h at c a n b e u s e d to d et ec t th e p r es e nc e o f f o r ei g n D N A , wh i c h c an o ft e n b e u s e d to di s t i ng ui sh pa r en t a l f r om re c o m b i na n t vec t o rs ( 2 ) S e le c ta b le ma r k e r s a r e us ed to fi n d c el ls th at c on t ai n t h es e ve c to r s. ( 3 ) P l as m id s c an n ot m a in t a in s t ab i li t y un l es s t hey a r e be n ef ic i al to th e h os t , s o t h e p l as m i d s ho u ld c o nt a in a g e ne es se n ti al fo r c e ll u la r s u r vi va l —e i th e r a n e nz y m e r e q ui r e d in a m et a bo li c pa t h wa y o r a g en e th a t r es i s t s c e r t ai n a n ti bi o ti cs (s e e I I I . D .4 ) . 2 . C o nj u g at i o n is an im p o r t an t m ea ns o f g en e t ra n s f e r , p a rt ic u la r l y am ong g r am +
n e g at i ve o r ga n is m s . Th is p ro c e ss in vo l ves t wo m a ti n g t y p es — t he do no r ( F ) a nd -
r e c ip ie n t ( F ) c e l ls — an d t h e e xt r a c h r om os om al pie c e kn o wn a s t he s e x o r f e r t il i t y f a c to r (F f ac t o r ) . Th e F fa c to r ( e. g . , F p l asm i d o r e p is om e ) i s n ot un d e r t he c o n t ro l o f t he c h ro m os om e a nd c a n r e pl ic a te au t on om o us l y . Pl a sm i d -m e di a te d exc h a n g e o f g e n et ic in f o rm at i on c a n o c c u r o n l y th r ou g h t he exp r e s s i on of t ra ns f e r g ene s . Th e g e n es e nc o de d o n t h e p la s m i d r es u lt in th e tr a ns fe r o f a s in g le s t r an d o f DN A t h r o ug h t h e s e x p i l us in to t he r ec ip i en t c el l . Th e F f ac t o r h as s e v e ra l g e ne s th a t
c o de fo r fo r m a t io n a n d ai d in do no r a tt ac hm e nt of s e x p i li . D ur i ng th is p roc es s , a +
c o p y i s m ad e , a s in g le s tr a n d i s t r an s f e r re d , a nd th e r ec ip ie n t b ec om es F . R p l as m i ds al s o e xi s t , wh i c h e nc od e f o r re si s t a nc e to c e r t ai n a n ti b io ti cs o r he a v y m e ta ls . W he n a n F p l as m i d i nt e gr a t es i n to th e c e l lu l a r ch r om os om e , t h e b a c t e r ia l s t r ai n i s s a i d t o b e a hi gh - f r e q ue n c y r e c o m b i n at i o n ( H f r ) s t ra in . D u ri ng t h e c o nj u ga l t r an s fe r i n v o l v in g an H f r s t ra in , de pe n din g on th e a m o u nt o f t im e, t h e wh o l e b ac te r ia l c h ro m o s o m e m a y b e t r a ns fe r r ed . A n t i b i ot ic - r es is ta n ce gen e s a r e o f t en pa r ts o f t r a ns p os on s (s e e I I I. D . 4 ) , wh i c h ar e r es po n si bl e f o r a d di t io n s , d e le t io ns , an d i n v e rs io ns o f l a r ge ( 4- 8 0 k i l ob as es) s eq u en c e s . W hen d i ff er e n t t r a ns p os on s “ j um p” in t o tr a n s f e ra b le pl as m i ds , c on t a gi ou s re s i s t a nc e t o m u l t ip le a n t ib io t ic s c a n o c c u r . 3 . T r an s du c t io n is t h e t ra n s f e r o f g e ne t ic m a te r ial b y b ac t e r io p ha g es ( vi ru s es th a t i n f ec t b ac t er i a ). S uc h v i ru s es c a n b e c l as si f ie d i nt o t wo g r ou ps : P.185
a . L yt i c p h a g e s e nt e r t he c e l l, r ep li c a t e , a nd pa c k a ge th e i r D N A ; th e y t hen l ys e t he c e ll to r el ea s e m a t u re in fe c ti v e vi r io ns . b . L ys o g e n i c ( t em p e ra te ) p ha g es c a n a l te r na t e b e t we e n t wo pa t h wa y s : ( 1 ) Th e l y ti c p at h wa y ( 2 ) Th e l ys o ge ni c p a th wa y- i n t eg r at i ng in t o t he ho s t D N A a nd r em ai ni n g do r m an t ( a ) Th e v i ra l D N A d o es no t r ep li c at e b u t is in t eg ra t e d i nt o th e h os t g e no m e a nd is k n o wn as p r op h ag e . ( b ) Th e p ro ph a ge s u pp r es s e s t h e l y t ic s t at e b y s yn t h es i z in g a p ro t ei n k nown a s a r e p r es so r , wh ic h p r o te c ts t he c e ll f ro m f u rt h e r i nfe c ti o n b y a v ir u s . ( c ) S om e p r op h ag es c a n c ha n ge th e c el l ' s p he n ot yp e ( p ha g e o r l ys o g e n ic c o n ve r s i on ) , wh ic h a l lows t h e o rg an is m t o e l abo r a t e m a t e ri al s ( e xo t o xi n s o r vi r u l en ce f ac to r s ) t ha t a re d et r im e nt a l t o t he hu m a n ho s t . L ys o ge n ic c on v e r s io n t h e r eb y i nc r ea s e s t he v i ru l en c e o r t h e s y m p t om s o f a s pe c i f ic p a th o ge n — fo r e xa m p l e , C o ry n eb ac t e ri um d i p ht h e ri ae ( di p ht h er ia t o xi n ) , S tr e pt oc o c c us py o ge n es ( e r yt h r og e ni c t o xi n in s c a r l et f e v e r) , an d Cl os t r idi u m t e ta ni ( te t an us t o xi n) .
VII. EXAMPLES OF UNIQUE BACTERIA A. C h l a m y d ia ar e o b li g at e in t r ac el lu l a r p a ra si t es t h a t 1 . L ac k t h e a b il i t y t o g e n e r a t e AT P ; h e n c e t h e y m us t ob t ai n i t f r om th e ho s t c el l 2 . H a ve a tw o - ph a se li fe c yc l e a . Th e i n fe c ti o us f o rm , or e l em e n ta r y b o d y, i s a d e ns e , n on r e pl ic at i ng c el l th a t is r e s is ta n t t o d r y i ng in t he e n v i r on m e n t. b . Th e r e ti c u la t e b o d y f o r m s f ro m e ng u lf e d e le m e n t a r y b o d y a n d u nd e rg oe s b i na r y f i ss io n . A f t e r m u l ti pl e d i vi s io ns , th e r e ti c u l at e b o di e s b ec om e t h e d en s e , el e m e n ta r y b o di e s, wh i c h a re r el ea s e d f ro m t he ho s t c e l l ( e .g . , C hl a m yd ia t r ac ho m a t is , wh i ch c a us es bl in d ne s s a n d s exu a l l y t r a ns m i t te d d is e as e s ) . B . R i c ke t t s ia , o bl i ga t e in t r ac e ll ul a r p a ra si t es t ran s m i t te d b y a r th r op o ds , a p p ea r to h a ve th e a b il i t y to ge ne ra t e A TP , bu t i ns t ea d u s e t h e ho s t c e ll p r od u c ts , i n c lu d i ng
AT P , a m i n o a c id s , n i cot i n a mi d e a de n i ne d in u cl e o t i de ( N AD ) , a n d c oen z ym e A ( e . g ., R ic k e t ts ia r ic k e t ts ii , wh i c h c a us es R oc k y Mo u n ta in sp o tt e d f e v e r ). C . My c o p l a sm a , t h e s m a l le s t b ac te r i a, a re un iq ue i n t ha t 1 . Th e y l ac k a ce l l w al l . 2 . Th e pl as m a m em b r ane c o n ta i ns s t e r o ls fo r add e d s t re n gt h (e . g. , My c op l as m a p n e u m on ia , wh i c h c a us es an a t y pi ca l o r wa l k i ng p n e um on ia ) .
VIII. VIRUSES A. V i r a l s t r u ct u r e 1 . Th e ba s i c s tr uc t u re o f a v i r us i s t h e vi r i o n o r n u c le o ca p s id . Th is s t r uc t u re is c om p os ed o f a p r o te in c o a t , wh ic h s u rr o un ds t he v i r a l g e no m e . Th e s h a pe o f t h e n u cl e oc ap s i d i s o ne c om p o n en t t h at de t e rm in es th e c l ass i fi ca t io n o f th e vi r u s . As n o t ed in I .B . 1 .b , th e v ir a l g e no m e is c om p os ed of e i t he r R N A o r D N A an d m a y be s i ng le o r d ou b le s t r an d ed . Th e nu cl eo c a p s i d o f vi r u s e s t ha t i n fe c t h um ans ha s t wo b a si c sh a pe s . a . I co s ah e d ra l . A r eg u lar g e om e t r ic s t r uc t u re wi t h 12 o r m o r e fa c e s ; r ese m bl es a s oc c er ba l l b . H e li c al . Th e p r o te i ns t h a t m ak e u p t he s t r uc t ur e wr a p in a h el ic a l f as hio n . He l ic al c a ps id s o f te n h a v e c on e o r b ul le t s h ap es . P.186
Table 9-1. The Multiplication of Animal Viruses NumberStep
Action(s)
1
Attachment (adsorption)
Virus attaches to a protein or polysaccharide molecule (receptor) on the surface of a cell
2
Penetration
Entire virus enters the cell, in some cases because it was phagocytized by the cell
3
Uncoating
Viral nucleic acid escapes from the capsid
4
Biosynthesis
Viral genes are expressed, resulting in the production of pieces or parts of viruses (i.e., viral DNA and viral proteins)
5
Assembly
Viral pieces are assembled to create complete virions
6
Release
Complete virions escape from the bacterial
cell by lysis or budding Reprinted by permission from Burton GRW, Engelkirk PG. Microbiology for the Health Sciences, 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2004.
2 . Th e v i ri o n m a y h a v e a l i p id e n ve lo p e, wh i c h is p ro d uc ed wh e n th e v iru s b u ds f r o m t he ho s t c e l l. Th e en v e l o pe i s c om po se d o f th e ho s t c e ll pl as m a m e m b r a ne an d vi r a l l y c o de d g l y c o p ro t ein s . B . V i r a l re p l ic a ti o n . V i ru s es a r e n o nl i v in g e n ti t ie s th a t m u s t e nt e r a ho st c el l t o r e p l i ca t e . O n c e in th e ho s t c el l , t he v i r us i s a bl e t o re p li c a t e i ts ge no m e a n d p r o du c e m o r e v ir us e s , wh i c h wi l l i n fe ct o th e r c e l ls . Th e s te p s i n t he m u lt ip l ic a ti on o f a n im al v i r us es ar e ou tl i ne d in Ta b le 9- 1 a n d i n volv e : 1 . Th e v i ru s a t ta c h es ( a tt a c h me n t ) t o t h e h os t c el l us in g vir a l p r ot e in s o r g l yc op r o te in s , wh i c h b ind t o r ec e pt o rs on t he hos t c e ll s u r fa ce . 2 . Th e v i ri o n t he n e n t e rs ( p e ne t r a t io n ) th e h os t ce l l . E n t r y m a y be acc om p l is he d b y f u si o n o f a v i ra l e n v e lo pe wi t h t he c e ll m em b r ane o r b y u pt a ke of th e v i rio n in t o a n e n d oc yt ic v es ic l e. I f t he v i r u s e n te r s t he c e ll t hr ou g h a n e n do c y ti c v es ic le, t h er e a r e s e ve r al wa y s f o r i t t o l eav e t h e e nd o c y ti c v e s ic le a n d e n te r th e c yt o pl as m o f t he h o st ce ll . 3 . O nc e i n th e h os t c el l , t h e v i ru s u n co a ts , an d th e nu c l ei c a ci d i s r e le ase d f ro m t h e c ap s i d . Th e f r ee nu c le i c ac i d t he n i s a bl e to be g in t he p ro ce s s o f re p ro d uc t io n . 4 . P r o te i n s yn t h e s i s o c c u rs in t wo s t a ge s . E a r l y p r o t e in s a r e n ec es s a r y f o r th e s yn t he s i s o f a ne w v i r a l g e n om e a nd ar e s y n t he s i z e d im m e di a te l y af t e r i nf e c ti on . L a t e p r o t e in s a r e s y n the s i z ed af t e r t h e v i r al ge no m e h as b e en c o pi e d; t he s e a r e t h e p r o te i ns n ec es s a r y fo r t he as se m b l y of th e ca p s i d , g l yc o p ro t ei ns fo r th e e n ve l op e , a nd an y e n z ym es in c l u de d i n t h e n uc le o c a p s i d. a . F or vi r us es wi t h a si ng l e - s t ra n de d R N A g e n om e , th e R N A m a y b e a pl u s ( + ) s t r an d o r a m i n us ( -) s t ra n d . P l us -s t r an d R N A g en o m e s a r e m R N As an d ar e t r a ns l at e d d ir ec t l y to p rot e i ns . Mi n us - s t r an d R N A g e no m e s h a ve a n R N A -d e p en de n t R N A p o l y m e r as e t h at c op i es th e g e no m e in t o a s t r a n d o f m R N A f o r tr a ns c r i p ti o n. b . D o u bl e -s t r a n de d R NA g e n o m e s us e a n R N A -d e p en de n t R N A p ol y m e ra s e t o t r a ns c ri be t he m i nu s s t ran d of R N A in t o a m es s a ge f o r t r an s l a ti o n. c . S om e p lu s - s t ra nd R NA v i r u s e s a r e m e m b e rs of t h e r e t r o vi r u s f am il y (e . g . , h um an i m m u no d ef ic i en c y v i ru s ). Th e s e v ir u se s h a ve a n e n z y m e c a ll ed r e v e rs e po l ym e ra s e , wh i c h t ra ns c ri b es th e RN A t o do ub l e -s t ra n de d DN A . Th e d ou bl e -s t r an d ed D N A i s i n t eg r a te d i n to th e h os t c e ll c h r om os om e ( a p r o vi r u s ) an d t h en t ra ns c ri bed t o
m R N A us i ng ho s t c e ll enz y m e s . Th e vir a l m R N A is t he n t r an sl a t ed i n t o v i ra l p r o t ei ns . d . I n vi r us es wi t h a D N A g e n om e , t he D N A m a y b e do u bl e s t ra nd e d o r s in g le s t r an d ed . I n ei th e r c as e , t h e D N A is t ra ns c ri b ed to m R N A a n d t he n t r a ns la t e d i nt o p r o t ei ns . 5 . A f te r ge no m e an d p r o te i n s y n th e s i s , th e vi ru s is as s em b le d in t o n e w v ir i o ns . 6 . A f te r as s em b l y , t h e v ir i o ns ar e r el e as e d f r om t h e h os t c e ll . F o r n o ne n ve l op e d vi r u s es , t h e v i r io ns a re re l ea s ed wh e n t h e h os t ce l l l y s es . E n v e lo p ed vi r us es a re r e l ea se d fr om t he ho s t c e l ls b y b u dd i ng ou t o f the h os t c el l m em b ra ne . P.187
IX. TRANSMISSION OF INFECTIOUS AGENTS A. I n f e c ti ou s a ge n ts a re f o u nd in a n um be r of di f fe r e n t e n vir o nm en t s , c a lle d r e s e r vo i r s . 1 . H u ma n s a re r e se r vo ir s f o r d is ea s e s t h at a re o b li g at e h um a n p a th og en s , wh ic h i n cl ud e a lm o s t al l v ir a l in f ec t io ns an d m a n y b ac te r i al di s e as es . W he n h um a ns a r e t h e re se r v o i r f o r t h e d is ea s e, t he y a r e s a i d t o b e c a r r i e r s. a . As ym p t o m a t i c c a r r i er s h a rb o r a n i n fe c t i on but h a v e n o s ym p t om s . S om e a s ym pt om a ti c c a r r ie r s c a r r y t h e i nf ec t io us ag e nt a s p a rt o f t he i r n o rm al flo r a ( S t r e p to c o c c us p y og en es ) . b . S ym p t o m a t i c ca r r i e rs h a v e o b vio us si gn s a nd s y m p t om s o f d is ea s e . 2 . A n a n im a l r e se r vo i r e xi s t s wh e n t h e p r im a r y h o st is an an im al . S uc h a n im al s m a y be wi l d (e . g ., fo xe s , r a c c oo ns ) o r d om es ti ca te d (l i ve s t oc k a nd pe t s ). 3 . E n vi r o nm e n ta l r es e rvo i r s i nc lu d e s oi l, la ke s , a n d p la n ts . B . Th e t r a ns m is s io n o f i n f e c ti o us a ge n ts de p en d s o n t he s o u rc e o f i n fec t io n . F o r d i se as es wi t h hu m a n re s e r v o i rs , th e m ec ha n is m s o f t ra ns m i s s io n i nc lu d e 1 . C o n ta c t a . D i r ec t co n t ac t re q ui re s p h y si c al c o nt ac t be t we e n a n i n fe c t e d i nd i v i dua l an d a s us c ep ti b le in d i v id ua l (s e xu a l l y t r a ns m i tt e d d is eas es ) . b . I nd i r e ct c on t ac t in v o lv e s a s us c e p ti bl e i n di vi du a l c om in g i n c on t ac t wi th a c o nt am i na t ed s u r fa c e ( m a n y v i r us es an d b a ct e ri a) . F om i t es a re s u r fa ce s t h a t c an b e an d f r e qu en t l y a re c on t am i na t ed wi t h m ic r oo rg a ni s m s ( d oo r k n ob s, cou n t e rs a n d o t h e r su r f ac es , c om pu t e r k e y bo a r ds , t o y s ). 2 . D r o p le t t ra n sm i ss i o n. I n fe c t e d d r op le t s a r e f or m e d wh e n an in f ec te d in d i v id u al c o ug hs o r s n e e z es . Th e i n f ec te d d r o pl e ts t r a nsm it t h e di s ea se to a s usc ep t i bl e i n di vi d ua l wh e n t he y c om e i n c on t ac t wi t h t h e m u c ou s m em br a ne s o f t h e i n di v i du a l 's n o se , m ou t h , o r e y e s ( m e a s l es ) . 3 . Ai r b o r n e t ra n sm i ss i on . W hen s m a ll c o nt am i na t e d d us t p a r ti c l es or t he r es i du e f r o m d r ie d d r op l et s ( d r opl e t n uc l ei ) re m a i n s u sp en d e d in t he ai r fo r lo ng pe r i od s o f t i m e , th e y c a n t r an s m i t di s ea s e ( in f lu en z a , pn eum o ni a , t ub e rc u lo s i s ). The s e sm al l n u cl ei ca n i n fe c t bo t h t he u pp e r a nd t he lo we r r es p i ra t or y t r ac t . 4 . F oo d a n d w at e r co n ta m i na t i on . Fo o d o r wa t er c on t am in a te d wi t h b ac te r i a f r om h u m a n o r an im al f ec es le a ds to t ra n s m is s i on of d i s e as e t h r ou g h t he fe c al - o r al ro u t e.
C . V e c to r s ar e a n im al s c a pa b le of t ra ns m i t ti n g di s ea se s . Th e m os t c om m o n vec t o r f o r di se as e i s t h e m o s q ui t o (m al a ri a ) , b ut o th e r in s ec ts ( fl e as , t ic k s a n d fl i es ) a r e a l so vec t o rs ( R oc k y Mo u n t a in s p ot t ed f e v e r) . In ad d i ti on , m am m a ls ( do gs , m ic e a nd r a t s ) c a n b e v ec t o rs f o r d i s e as e . D . E n t r y i n t o a ho s t . B ac t e ri a c an en t e r a h os t th r o ug h i n ge st i on of f oo d o r wa t e r , i n ha l at i on of d ro p le ts o r d u s t pa r t ic le s , in j ec ti o n b y a n i ns e ct vec t o r , o r by c o nt am i na t io n o f a wo u nd .
X. MECHANISMS OF PATHOGENICITY A. Mi c r o o r ga n is m s c au s e d is ea s e in di f fe r e nt wa ys . A l th o ug h s ig ns an d sy m p t om s o f t h e d is e as e a r e o f te n t he r es u lt of t he ho st r es po n se , m ic r oo r g an is m s c an d am ag e t i ss ue t hr o ug h th e p r od uc t io n o f e xo t o xi n s a n d en d o to xi n s , a n d b y d ir ec t e f f ec ts . In a d di t io n , m ic r ob ia l v i ru len c e f ac t o rs c on t r ib u te to t h e a bi l it y o f a m ic r o or ga n is m t o i n f ec t a ho s t an d c au s e d i s e as e . 1 . V i r ul e nc e fa c t o rs a re t h e c ha r ac t er is t ic s o f a n o r g an is m t ha t a l lo w i t t o e i th e r d a m a g e t he ho s t o r e v a de h os t d e fe ns es . a . E xo t o xi n s a r e t o xi n s t h a t a r e s e c re t ed b y th e m ic r o or g an is m e it h e r i nto t he e n vi r on m e n t o r af t e r c o lo n i z a ti on o f a h os t . ( 1 ) E xo t o xi n s s e c re t ed int o f oo d o r wa t e r t h at a re t h e n i ng es t ed b y a h os t c a us e i n t o xi c at i on ( bo t ul is m a nd s ta ph y l o c o cc al fo o d p oi s on in g ) . ( 2 ) E xo t o xi n s p r od uc ed a f t e r i nf ec t io n a n d c ol on iz a t i o n i nt e r fe r e wi t h c e l l f u nc t io n o r p h ys ic al l y da m a g e t he c e l l ( B o r de t el la pe r t us s is , C o r y n e ba ct e r iu m d ip h the r i ae , V i b r io c h ol e ra ) . P.188
Table 9-2. Important Human Pathogens and Their Diseases Infectious Agent
Typical Infection
Bacteria Gram-positive cocci Staphylococcus aureus
Abscess, skin infections, toxic shock
Streptococcus pyogenes
Strep throat, erysipelas, rheumatic fever
Streptococcus pneumoniae
Pneumonia
Gram-positive rods Bacillus
Anthrax
Clostridium
Gas gangrene, tetanus
Corynebacterium
Diphtheria
Acid-fast rods Mycobacterium tuberculosis
Tuberculosis
Mycobacterium leprae
Leprosy
Nocardia
Nocardiosis
Gram-negative cocci Neisseria gonorrhoeae
Gonorrhea
Neisseria meningitidis
Meningitis
Gram-negative rods Bordetella
Pertussis
Brucella
Brucellosis
Escherichia coli
Sepsis, diarrhea, urinary tract infection
Haemophilus influenzae
Meningitis
Legionella
Legionnaires disease
Pseudomonas
Opportunistic lung and burn infections
Salmonella
Typhoid fever, salmonellosis
Shigella
Dysentery
Vibrio cholerae
Cholera
Yersinia pestis
Plague
Spirochetes Borrelia
Lyme disease
Treponema pallidum
Syphilis
Mycoplasma
Pneumonia, urinary infections
Rickettsia
Rocky Mountain spotted fever
Chlamydia
Urethritis, vaginitis
Fungi Systemic mycoses Aspergillus
Aspergillosis
Blastomyces
Blastomycosis
Candida albicans
Candidiasis
Coccidioides immitis
Valley fever
Cryptococcus neoformans
Cryptococcosis
Pneumocystis (carinii) jiroveci
Pneumonia (PCP)
Sporothrix schenckii
Sporotrichosis
Protozoa Entamoeba histolytica
Amoebiasis
Giardia lamblia
Giardiasis
Plasmodium
Malaria
Toxoplasma gondii
Toxoplasmosis
Trichomonas vaginalis
Trichomoniasis
Trypanosoma brucei
Sleeping sickness
Helminths Ascaris
Acariosis
Cestodes
Tapeworm
Schistosoma
Schistosomiasis
Various fluke infections Various roundworm infections
Adapted with permission from Cowan MK, Talaro KP. Microbiology: A Systems Approach. 1st ed.: McGraw-Hill, 2005. With permission of The McGraw-Hill Companies, Inc.
P.189
Table 9-3. Important Human Virus Families and Their Diseases Family
Virus
Disease
DNA viruses Poxviridae
Variola and vaccinia
Smallpox, cowpox
Herpesviridae
Herpes simplex 1 virus (HSV-1)
Fever blister, cold sores
Herpes simplex 2 virus (HSV-2)
Genital herpes
Varicella zoster virus (VZV)
Chickenpox, shingles
Human cytomegalovirus (CMV)
CMV infections
Human adenoviruses
Adenovirus infection
Adenoviridae
Papovaviridae
Human papillomavirus (HPV)
Several types of warts
JC virus (JCV)
Progressive multifocal leukoencephalopathy (PML)
Hepadnaviridae
Hepatitis B virus (HBV; of Dane particle)
Serum hepatitis
Parvoviridae
Parvovirus B19
Erythema infectiosum
Poliovirus
Poliomyelitis
Coxsackievirus
Hand-foot-mouth disease
Hepatitis A virus (HAV)
Short-term hepatitis
Human rhinovirus
Common cold, bronchitis
Calciviridae
Norwalk virus
Viral diarrhea, Norwalk virus syndrome
Togaviridae
Eastern equine encephalitis virus
Eastern equine encephalitis (EEE)
Western equine encephalitis virus
Western equine encephalitis (WEE)
RNA viruses Picornaviridae
Yellow fever virus
Yellow fever
St. Louis encephalitis virus
St. Louis encephalitis
Rubella virus
Rubella (German measles)
Dengue fever virus
Dengue fever
West Nile fever virus
West Nile fever
Bunyamwera viruses
California encephalitis
Sin Nombre virus
Respiratory distress syndrom
Rift Valley fever virus
Rift Valley fever
Crimean-Congo hemorrhagic fever virus (CCHF)
Crimean-Congo hemorrhagic fever
Filoviridae
Ebola, Marburg virus
Ebola fever
Reoviridae
Colorado tick fever virus
Colorado tick fever
Human rotavirus
Rotavirus gastroenteritis
Influenza virus, type A (Asian,
Influenza, flu
Flaviviridae
Bunyaviridae
Orthomyxoviridae
Hong Kong, swine) Paramyxoviridae
Parainfluenza virus, types 1-5
Parainfluenza
Mumps virus
Mumps
Measles virus
Measles (red)
Respiratory syncytial virus (RSV)
Common cold syndrome
Rhabdoviridae
Rabies virus
Rabies (hydrophobia)
Retroviridae
Human T-cell leukemia virus (HTLV)
T-cell leukemia
HIV (1 and 2)
AIDS
Arenaviridae
Lassa virus
Lassa fever
Coronaviridae
Infectious bronchitis virus (IBV)
Bronchitis
Enteric corona virus
Coronavirus enteritis
SARS virus
Severe acute respiratory syndrome
Adapted with permission from Cowan MK, Talaro KP. Microbiology: A Systems Approach. 1st ed.: McGraw-Hill, 2005. With permission of The McGraw-Hill Companies, Inc. P.190
b . E n do t o xi n s ( s e e II I . C. 1 . b ) a r e i nt e gr a l p a rt s of t h e o ut e r m em b ra ne o f g r a m n e g at i ve b ac t e ri a . D u r ing a n i nf ec t io n , e nd o to xi n s a re ab l e t o i nd uc e fe ver a n d s h oc k in t he ho s t . c . C ap s u le s ( s e e II I . B. 1) a r e u se d f o r a d he r en c e t o ho s t s u r fa c e s a n d h elp t he b a ct e r ia e v ad e p h ag oc y to s is b y t h e h os t c el ls . 2 . M e c ha n is m s o f d i se as e . Th e re a re th r e e m a i n p a t te r ns b y wh i c h m ic r oo r g an i s m s c a us e d is ea s e : a . I n to x ic a t io n [s ee X. A . 1 . a .( 1 ) ] b . I n fe c t io n i s s uf f ic ie n t t o c a us e d is ea s e fo r som e m ic r oo r ga n is m s , e s pe c ia ll y f o r d i se as es s u c h as p n eu m o n ia , in wh i ch th e c a ps ule su r r ou n di n g t he ba c te ri a s t im ul a te s a s t r on g i n fl am m a t o r y re s p o ns e . Th i s r e s po ns e i s r es p on s i bl e f o r m a n y of t h e s ym pt om s o f th e d is e a s e . In s om e c as es , i n fe c ti o n m a y b e f o ll o we d by t o xi n p r o du c ti on ( s e e X. A . 1. a .( 2 ) ) , a s i n d ip h th e r ia . c . In va s i o n o f h o s t t i ssu e s a n d t he n g r o wt h in th e ti ss ue is th e m ec ha n is m o f d i se as e i n fe c t i on b y v i rus es an d ba c t e ri a s uc h a s My c o b ac t e ri a . S om e b ac t e ri a ( e . g ., S hi g el la s p . ) a r e ab l e t o p r o du ce to xi n s a fte r t he in v a si o n o f h os t t is su e .
XI. DISEASES CAUSED BY INFECTIOUS AGENTS A. D i s e a s es ca u se d b y b a c t e ri a , f u n gi , p ro t o zoa , a nd he l mi n t hs ( Ta b le 9 - 2 ) B . D i s ea s es ca u se d b y vi r u s e s ( Ta bl e 9 - 3 ) P.191
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 12 : E a c h qu e st io n , st a t em en t , o r in co m p le t e s t a te m e n t i n th is s e c t i on c a n b e c or r e c tl y a ns we r e d o r c om p l e te d b y o n e o f t he su gg e s t e d a n s we r s o r p h r as es . Ch oo s e t he b es t a n s we r . 1 . C e ll w a l ls o f b o th g ra m - p os i t i ve a n d g r a m- ne g a t i ve b a c te r i a a r e c om p o se d of c o m pl e x m ac r o m ol e cu le s . W h i ch o f t h e f o l low in g s ta t e me n ts d es c r ib es b o th t yp e s o f c e ll w a l ls ? ( A ) Th e y c on t ai n s ig n if ic a n t a m o u nt s o f te ic ho ic a c id . ( B ) Th e y c on t ai n p o re s m a de f ro m p r ot e in s . ( C ) Th e i r a n ti g en ic s p ec if i c i t y is de t e rm in ed b y the p ol y s ac c h a ri d e O a nt i ge n . ( D ) Th e y c on t ai n p e pt i dog l y c an . V i e w A n s we r 1 . T h e a n sw e r i s D [ se e] . 2 . W h ic h o f t h e f o l low i n g d e s c ri p t i on s b e s t c ha ra c t e r iz es se x p i l i? ( A ) Th e y e n ab le D N A t ran s po r t b e t we e n b ac t er i a d u r i n g c on j ug a ti o n. ( B ) Th e y p l a y a r ol e i n t he a dh es i on of ba c te r ia to t h ei r ta r g et c e ll s . ( C ) Th e y a r e n um e r ou s on t he ba c te r ia l c el l s u rf ac e . ( D ) Th e y a r e f o un d o n l y o n g ra m - p os it i v e or g an is m s . V i e w A n s we r 2 . T h e a n sw e r i s A [ se e] . 3 . T h e m od e o f g e ne t r an s f e r i n w h ic h na ke d D N A i s t ake n u p i s c a ll e d ( A ) t r an s fo r m a ti o n.
( B ) t r an sd u c t io n . ( C ) c on j ug a ti on . ( D ) c el l f us i on . V i e w A n s we r 3 . T h e a n sw e r i s A [ se e] . 4 . Ba c te r ia t h a t m ak e e i t he r a f e r m e n ta t i ve o r r e sp i r at o r y s e t o f e nz ym e s a r e k n ow n a s ( A ) o bl i ga t e a na e ro b es . ( B ) o bl i ga t e a er o be s . ( C ) m ic r oa e ro p hi le s . ( D ) f ac u lt a ti v e o rg a ni s m s . V i e w A n s we r 4 . T h e a n sw e r i s D [ se e] . 5 . W h ic h o f t h e f o l low i n g s t a te me n t s d e s c ri b es p la s mi d s? ( A ) Th e y a r e s in gl e -s t r and e d D N A m ol ec ul es . ( B ) Th e y c a r r y o p ti o na l ge n es . ( C ) Th e y c a r r y g e ne s e s s e nt i al fo r g ro wt h . ( D ) Th e y a r e a l wa y s f oun d in li ne a r f o rm . V i e w A n s we r 5 . T h e a n sw e r i s B [ se e] . 6 . Al l o f th e f o ll ow i ng s ta t e me n ts d e s c ri b e th e n u cl e a r bo d y e x c e p t w h ic h o n e? ( A ) I t i s r e fe r r ed t o as nuc l eo id . ( B ) I t i s f r ee o f r ib os o m es . ( C ) I t i s c om po s e d o f ri bo s om es . ( D ) I t l a c k s a n uc le a r m em b r an e . V i e w A n s we r 6 . T h e a n sw e r i s C [ se ea n d] .7 . Ba ct e r i a th a t g r ow a t t e m p e ra t u r es as hi g h as 5 5 ° C a r e k n ow n a s ( A ) p s yc h r op hi l es . ( B ) t h er m o p hi le s . ( C ) m es op h il es . ( D ) a u xo t r o ph s . V i e w A n s we r 7 . T h e a n sw e r i s B [ se ea n d] .8 . W h ic h o f t h e f o l low i n g o r g a n is m s c an us e on ly m o l e c u l a r o x yg e n a s t h e f in a l a cc e p to r ? ( A ) o bl i ga t e a na e ro b es ( B ) f ac u lt a ti v e an a er o bes ( C ) o bl i ga t e a e ro b es ( D ) s t ri c t an a e ro b es V i e w A n s we r 8 . T h e a n sw e r i s C [ se ea n d] .9 . Vi ru s e s a r e c l as s if i e d b y a l l o f t h e f ol l ow i ng ex c ep t b y ( A ) s t ru c t u r e o f c a p s i d. ( B ) t yp e o f n u c l ei c a c i d. ( C ) o xyg e n r e q ui r em en ts . ( D ) p r es en c e o f l ip id en v e l op e . V i e w A n s we r 9 . T h e a n sw e r i s C [ se e] . 1 0. P r o t oz o a a r e c l as s i fi e d b y ( A ) s ha pe . ( B ) c el l wa l l t y p e. ( C ) s e xu a l re p ro d uc ti v e s t r uc t ur es . ( D ) m od e o f m o ti li t y .
V i e w A n s we r 1 0 . T he a nsw e r i s D [ se e] . 1 1. W hi c h o f t he f o ll ow i n g i s n o t p a r t o f t h e vi r us e 's i n fec t i o us c yc l e ? ( A ) a t ta c h m e n t ( B ) u n wi n di n g ( C ) r e pl ic a ti o n o f t h e g en o m e ( D ) p r o te in s y nt h es is ( E ) r e le as e V i e w A n s we r 1 1 . T he a nsw e r i s B [ se ea n d] .P . 19 2
1 2 . In f ec t i o us ag e n ts ar e t r a ns m i t te d to p eo p le f r o m r e se r vo i r s . Th e se r e s e r vo i r s i n c lu d e ( A ) d r op le t s . ( B ) a ni m a ls . ( C ) f om i te s . ( D ) c on t am in a te d f o od . V i e w A n s we r 1 2 . T he a nsw e r i s B [ se ea n d] . Di r e c ti o n s fo r q ue s ti o n s 1 3- 20 : Th e q u es ti o ns a n d i nc om p l e te s t a te m e n ts i n t h is s ec t io n c a n b e co r r ec t l y a n s we r e d o r co m p l et e d b y o ne o r m o r e o f th e s ug g es t ed an s we r s . Ch o os e t he c o r re c t a ns we r , A-D. 1 3 . G r am - n eg a t i ve a n d g r a m - po s i ti ve c e ll w a lls s ha r e w h ic h o f t he f ol l ow i n g c h a r ac t e r is t i cs ? I . p ep t i de c r os s - li n ks be tw e e n p o l ys a c c h a r i d es I I . h yd r o l ys i s b y l ys o z ym e I I I . r ig i d p o l ys a c c h a r i de f r a mew o r k A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 3 . T he a nsw e r i s E [s e ea n d] . 1 4. A d e c l in i ng g r ow t h r a t e o c c u rs d u r in g w h ic h o f t h e fo l l ow in g ph a se s of b a c te r i al ce l l g r ow t h ? I . l ag p ha s e I I . ex p on e n t ia l p h as e I I I . de a th p ha s e A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 4 . T he a nsw e r i s B [ se ea n d] .1 5 . T he p ep t i d og l yc a n b a c kb o ne o f a ba c t e ri a l c e l l c on t a in s I . d ip e p t id e c h ai n s . I I . N - ac e t yl m u r a m i c ac id . I I I . N -a c e t yl g l u c o s am i ne .
A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 5 . T he a nsw e r i s D [ se e] . N N 1 6 . E n ti t i e s t h a t a r e a ce l l ul a r d o n o t f i t t h e c la s si c al d e fi n i t i on o f l i vi n g th i ng s . T h e y a r e I . vi r u s es . I I . f un g i . I I I . p ri o ns . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 6 . T he a nsw e r i s C [ se ea n d] .1 7 . D im o r p h ic f un g i h a ve I . a ye a s t p h a se . I I . a s ex u al p ha s e. I I I . a m ol d p h as e . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 7 . T he a nsw e r i s C [ se ea n d] . Bl a s to m y ce s , C o c c i di o i de s , Hi s t op l asm a 1 8. T ra n sm i ss i o n o f a n i n fe c ti o u s d is e as e by t h e f ec a l- o r a l r o u t e o ccu r s w h e n I . i n fe c t io u s a ge n t s a r e d e p os i t ed on s u r fa ce s s u c h a s d o o r k n ob s . I I . an i nd i vi d u al co u g hs o r s ne ez e s a n d d r o pl e ts w i t h in f ec t i o us ag e n ts a r e e x p el l e d. I I I . fo o d o r w a t e r i s c o nt a m i na t e d w i t h h u ma n o r a n im a l f e ce s . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 8 . T he a nsw e r i s B [ se ea n d] .1 9 . V ir u l e n ce f ac t o r s t h at e n h an c e m ic r o b ia l pa t ho g e n ic i t y i n c l u d e I . c ap s ul e s. I I . en d o to x i ns . I I I . e x o to x i ns . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t
E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 9 . T he a nsw e r i s E [s e e] . 2 0. O n F rid a y, J a n u a r y 1 3 , a n u m be r o f p a t r o ns o f M o m ' s D i n e r b e ca me i ll 2- 6 h r af t e r e a t in g at t he r e s t a u ra n t . T h e h ea l t h d e p a r tm e n t w a s c a ll e d i n t o i n ve s t ig a t e. D u r ing t h e i n ve s t i ga t i o n, i t w a s fou n d t ha t a l l th e in d i vi du a l s w ho be c am e i l l h ad e a te n b a n an a c r e am p ie , M o m' s s pe c ia l i t y, b u t h a d no t e a te n a n yt h i n g e ls e in c o m mo n . T h e i n ve s ti g at o r s f ou n d n o vi a bl e pat h o g en s in t he p ie , b u t t e s t s i n d i ca t e d t h e p r es e nc e o f s t ap h yl o c o c c a l co n ta m i na t i on o f th e c r e am p i e . I l l n es s re s u lt i n g f r o m th i s co n t am i na t i on w o u ld b e c o ns i de r e d a n I . i n fe c t io n . I I . i n vas i o n. I I I . in t o xi c at i o n. A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 2 0 . T he a nsw e r i s B [ se e] . S t a ph y loc o c cu s a u r e us P . 19 3
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is D [ s ee I I I . C .1 ] . Th e c el l wa l l o f g r am - pos i ti v e ba c te r ia is a t hi c k l a y e r of pe p ti d og l yc a n wit h a l a rg e a m ou n t o f t e ic ho ic ac id s ( s u r fa ce an t ig e ns ) . G r a m - n e ga t i ve b ac t e ri a h a ve o n l y a s m a l l am o un t o f pe p ti dog l y c an , n o te ic ho ic ac i d, a n d a n o u te r m em b r an e c om p os ed o f li p op r ot e in an d l i po po ly s a c c h ar i de , o f wh i c h the p ol y s ac ch a ri d e m a k e s u p th e O a n t ig en . 2 . T he an sw e r is A [ s ee I I I . B. 3 .b ] . S e x p i l i ar e fo un d o n l y on g r am -n e ga t i ve o r ga n is m s a nd in v e r y s m al l n um b e rs (< 1 0 ) . Th e y a c t as f ra g il e tr a n s p o rt t ub es fo r D N A exc h a n g e . Co m m on pi li a re a d h es io ns . 3 . T he an sw e r is A [ s ee V I . C . 1] . O f t h e t h re e m e th o ds o f D N A t r a ns f er , on l y t ra ns fo r m at i on ta ke s u p D N A wi t h o u t a n i n t er m ed ia r y . 4 . T he an sw e r is D [ s ee I V . D . 1. b ] . F a cu l ta t i v e o r ga n is m s c an g r o w wi t h o ut ai r an d m a k e e it h e r a f e rm e nt a ti v e o r a r e s pi r at o r y s e t o f e n z y m e s , d ep e nd i ng on th e c on d i ti on s . 5 . T he an sw e r is B [ s ee I I I . D .4 ; VI . C . 2] . Th e c h ro m o s o m e c a r r ie s a l l o f t he ge n es es s e nt ia l fo r g ro wt h , wh e r e as p la sm i ds a r e e xt r a c h r om os om a l, do u bl e - s t r an d ed , c i rc ul a r p ie ce s o f D N A th a t c a r r y o pt io n al g e n es t h at ad d e xt r a pr op e r ti e s . 6 . T he an sw e r is C [ s ee I I I . D .2 an d 3 ] . R i b os om es a re fo u nd in t h e c y t o pl as m , no t in th e n uc l eo id ( a l on g , c ir c u l ar , d ou b le s t r an d ed D N A wi t h ou t a n u c l e ar m e m b r an e ) .
7 . T he an sw e r is B [ s ee I V . C . 1, 2 a nd 3 ]. Th e r m o ph il es g ro w a t 5 5° C a n d a r e f ou n d i n h ot s p r i n gs an d c om po s t pi l es . Me s o p h i le s g ro w a t a pp ro xi m a t e l y 3 7 ° C , p s yc h r op h il e s g ro w a t 1 5 ° C a nd l o we r , a nd a u xo t r o p hs a re m u ta n t or g a ni s m s. 8 . T he an sw e r is C [ s ee I V . D . 1 a nd 2] . O b l i ga t e a e ro b es re qu i r e o xy g e n a n d l ac k a n a lt er n a ti v e f e rm en t at i ve p a thwa y . O b l i ga t e a na e r ob es ar e s t r ic t a na e r ob es th a t c ann o t l i v e i n t h e p r es en ce o f o xyg e n . F a cu l ta t i v e a na e r ob es c a n us e o xyg e n a s t he fi na l ac c e pt o r o r to p ro vi d e a n a l t er n a te fe r m e n ta t i v e pa t h wa y . 9 . T he an sw e r is C [ s ee I . B . 1; V I II . A ] . V i r us e s a re c l as s i f ie d b y t h e s t ru ct u r e o f t he c a ps i d, t he t ype an d s t ra n ded n es s o f t h e n uc l ei c ac i d, t he p res e nc e o f a li pi d e n ve lo pe , an d th e p r es en ce o f en z ym e s . V i r us e s d o n ot ge n er a t e t h e ir o wn e ne r g y , h e nc e t h e r e is no ne e d f o r o xyg e n . V i r us e s us e t h e e ne r g y in t he ho s t ce l l. 1 0 . Th e a n sw e r i s D [ s ee I . A .2 . b] . P r o t o zo a a re un ic e ll ul a r , n o np h ot os y n t he t ic eu k ar y o t e s t h at a re c l as s i fi e d b y t h ei r m o de of m o t il it y o r la c k o f m o t il it y. Th e t y p es o f m o ti l it y a r e f la g el la , c il i a, a nd a m oe b oi d m o v em en t . 1 1 . Th e a n sw e r i s B [ s ee V I I I. B . 1, 2 , 3 , 4 , 5 an d 6 ] . Th e v i r a l i n fe c t i ou s c y c l e c on s i s ts o f at t ac hm en t , e n t r y , u n c o a ti ng ( no t u nwi n d i n g ), p r o t ei n s y n th es is , ge nom e re p li ca ti o n , as se m b l y, a nd r el e as e. 1 2 . Th e a n sw e r i s B [ s ee I X. A . 1 , 2 an d 3 ] . I n f ec t io us ag en t s c a n b e f o un d i n m an y d i ff e re n t e n vi r on m e n ts , i nc l ud in g p e o pl e, a n im al s , a nd th e n a tu r a l e n v i r on m e n t . A n im al s a re a re se v o i r ; f om i te s , d ro p le t s a nd c o nt am i na t ed fo o d o r wat e r a re m ec h an is m s o f t ra n s m is si on . 1 3 . Th e a n sw e r i s E ( I , II , I I I) [s e e I I I. C . 1 a n d 2 ]. P e p t id og l y c a n i s t h e b as i c l a y e r o f th e c el l wa ll i n b ot h g r am - p os it i ve a n d g r am n e g at i ve o r ga n is m s . I t p ro v i d es a r i gi d f r am e wo r k t h a t is s u sc ep t ib le t o t he ac t io n o f l ys o zym e . G r a m -p os i ti v e c el ls a re de f ic ie n t i n l ip i d s ; h o we v e r , g ra m - n eg a ti v e ce l ls a r e ri c h in c o m p le x l i p i ds ( e. g . , l ip op o l ys a cc ha r id e ) . Bo t h t y p es of ce ll wa l ls ha v e c r os s -l in k s be t we e n p o l ys ac c ha r id es . P.194
1 4 . Th e a n sw e r i s B ( I I I) [ s e e I V. E . 1, 2 , 3 a n d 4 ]. D u r i ng t he la g p ha s e, the c e l ls p r e pa r e f o r g r o wt h , so th e re is no ac tu a l gr o wt h . G r o wt h i s m a xi m al du r i ng t he e xp o n en t ia l p h as e a n d l e v el s o u t d u ri ng t he s t at i on a r y p h as e wi t h n o n e t i nc re as e i n c el l n um b e r. Th e r e i s a de c l i ne in o rg an is m n u m b e r d u r in g th e d ea t h p ha s e be c au s e t he r e a r e m o r e or g a n i sm s d yi ng th a n a r e b e in g p r o du c e d . 1 5 . Th e a n sw e r i s D ( I I , I I I ) [s ee I II . C . 1] . Th e c el l wa l l o f b o th gr am - p os it i ve a n d g r am -n e ga t i ve o r g an is m s i s c om po s ed of r e p ea t in g d is ac c ha r id e un i ts . Th es e u n it s c on t ai n N - a c e t yl gl uc os a m i ne and N a c et yl m u r am ic ac id , to wh i c h te t r ap e pt i de c h ai ns a r e c r os s -l in k e d . On l y g ra m p o si t i ve o r ga ni s m s h a v e t e ic h oi c ac i d.
1 6 . Th e a n sw e r i s C ( I , II I ) [s e e I . B .1 an d 2 ] . V i r us e s a re ba s i c al l y p r ot e i ns a n d n uc le ic ac id s , wh e r e a s p r io ns a re p ro t ei n s, n e i th e r o f wh ic h a r e c el ls . B ac te r ia a re p ro k a r yo ti c c el ls , an d f u ng i a r e e uk a r yo ti c c e ll s. 1 7 . Th e a n sw e r i s C ( I , II I ) [s e e I . A .2 . a. ( 1 ) , ( 2 ), (3 ) a nd (4 ) ] . D i m o rp hi c f u ng i l ik e Bl as t o m y c e s, C oc c i d io id es , an d H is to p la s m a c an be gr o wn i n e i t he r a y e as t (u n ic el lu l ar ) o r m ol d (f i la m e n to us ) p h as e , d ep e nd in g o n th e t e m p e r at u re o f i nc ub a ti on . F un gi a re pl ac e d i n ph y l a ba s e d o n t h e t y p e of s e xu a l r e p r od uc t io n o bs e r v e d: ei t h er as cu s , b as id iu m , o r z y g o t e . F u ng i i m p e r fe c t i c on s i s t o f sp ec ie s wi t ho u t o bs e rv a b l e s e xu a l re p ro d uc ti v e s tr u c t u re s . 1 8 . Th e a n sw e r i s B ( I I I) [ s e e I X. B . 1, 2 , 3 a n d 4 ]. Th e f e ca l -o r al r ou t e o f t ra n s m is si on in v o l v es c o n ta m in a ti on o f f oo d o r wa t e r wi t h a n im al f ec es . 1 9 . Th e a n sw e r i s E ( I , II , I I I) [s e e X. A . 1 ] . C a p su l es a c t as v i r ul e nc e f ac t or s b y i nh i bi ti n g p ha g oc y t o si s a nd ac ti n g t o a t t ac h m ic r o or g an is m s to ho s t s u r fa c e s . E xo t o xi n s a r e s ec r e te d b y m ic r oo r ga n is m s an d e i t he r al te r c e ll fu n c t i on s o r c a us e c el l d ea t h . E ndo t o xi n s i n du ce s h oc k i n m am m a l ia n h os ts t h ro ugh t he li p id A c om po n en t o f t he m o le cu le . P ep ti d og l yc an is t h e b ac k bo ne o f t he ba c te r i al c e ll wa l l . 2 0 . Th e a n sw e r i s B ( I I I) [ s e e X. A . 1 .a . ( 1) ; X. A . 2 ]. S t a p hy lo c o c c us au r eu s c a n p ro du ce a n e xo t o xi n , wh i c h r es ul ts in ga s tr o int e s ti na l d i se as e . W hen th e re is di s ea s e in th e a bs e nc e o f i n fe c ti on o r i n vas io n o f th e ti s s ue s b y a li v e o rg a ni s m , t h e di s ea s e is c al l ed an in t o xi c a ti o n.
10 Immunology G a i l G o o dm a n- S n i tk o f f
I. THE PHYSIOLOGY OF THE IMMUNE SYSTEM A. I m m u n o ge ns , an t i gen s , an d h a p te n s 1 . I mm u no g en s a r e c hem ic a l c o m p o un ds t ha t c au s e a s p ec if ic i m m u ne r es po ns e . 2 . An t i g e ns a re c h em ic al c o m p o un ds t ha t b in d to p r o du ct s o f a n i m m u ne r es po ns e . W hen t h e a n ti ge ns a re r ec og ni ze d b y a n ti b od y o r ac t i vat e d c el ls , t h e y c a n be el im in a te d b y a s pe c if ic im m u ne r e s po ns e . 3 . I mm u no g en - a n ti g en s. C o m p o un ds ass oc i at e d wi t h o r s ec r e te d b y p a r as it ic ba c te r ia , p r ot o z o a , f u ng i , a nd v i r us es a n d o f m ol ec ul a r we i g h t (m o l wt ) > 5 00 0 da l t on s m a y a c t as bo t h im m u n og e ns a n d a n t ig en s . a . Mo l e c u l a r c o m p l e xi t y is as im po r t an t a s m o l ecu l a r we i g h t i n d e t e rm in in g th e s ta t us of a c o m p ou n d a s a n im m un o g en . F o r a m o le cu l e t o b e im m u n oge n ic , i t m us t c o nt ai n p r o te i n o r pe p ti de . Th e r e f o re , pr o te i ns , g l y c o p r o te in s , li p op r o te i ns , an d nu cl e op r ot e in s a r e th e m os t p o te n t im m u n o ge n -a n ti g en s. b . D r ug s o f s u ff ic i en t m ol e c u la r we i g ht ( e. g . , i ns ul i n ) c a n ac t as i m m u no g en - an t ig e ns . Th e c e l ls o f an o th e r i nd i v i du a l a nd t he c e ll s o f on e ' s o wn b od y ( s ee II I ) c a n a ct as im m u no g en - a n ti ge ns . I m m u no g en - an t ig e ns c a n b e c on t ac t ed en v i r on m en t a ll y ( e .g . , p o ll e ns ) . 4 . H a pt e ns a re lo w m o lec u la r we i gh t c om p ou n ds t h a t a c t as i m m u no g en s a ft e r c o v al en t l y bi n di ng t o a l a rg e r m o l e c u l e o r c el l s u r fa ce . A ft e r t h e y s t im ul a t e t he im m u ne s ys t em in t hi s c om pl e x, t h es e c om p ou nd s c an ac t a s a nt i ge ns in th e u n bou n d o r bo un d s t a te . a . H ap t e ns m a y be pr es en t in th e en v i r on m e n t ( e .g . , p e n ta d ec ac at ec h ol of poi s on i v y ) . b . S e ve ra l t y p e s o f d r ugs ac t a s h ap t en s (e . g. , pe n ic il l in ) . 5 . T ol e r o ge n s a re c h em ic a l c o m p o un ds t ha t e li ci t s pe c i f ic n o n re sp o ns i v en es s . Th i s s pe c i f ic no n re s p o ns i v ene s s m a y b e c a us ed b y th e a b il it y o f th e c om p ou n d t o b e b r ok e n do wn b y t h e b o d y o r b y t he ro u te o f ad m in is t r at io n of th e c om p o u nd (e . g ., o ra l a d m i ni s t ra ti o n o f te n c aus es s p ec i fi c n on r es p on siv e n e ss ) . 6 . I n t hi s c h a p te r , t h e t e rm an t ig e n is us ed f o r c om p ou n ds a n d c e l ls t h a t a r e b ot h i m m un o ge ns an d a n ti g en s. B . C e l ls o f t h e i m mu n e s ys t e m
1 . B l ym p h o c yt e s a n d T l ym p h o c yt e s a r e th e p ri m a r y c el ls of s p ec if ic im m u ne r es po ns e s . Al l B an d T l y m p h oc yt e s a r e a nt i ge n s p ec if ic be c au s e th e y hav e s pe ci f ic an t ig en r ec ept o r s em b ed d ed in t h e ir pl a s m a m e m b r a ne s . I n t h is c ha p t er , th e t e rm s B ce ll a nd T c e ll ar e us ed in s t e ad of B l y m ph oc y t e an d T l y m p h oc y t e . 2 . An t i g e n r e ce p t o r s o f B c e ll s a r e a n ti b od y m ol e c u le s . a . B c el ls ha v e t ho us a nds o f i de n ti c a l a n ti bo d ie s i n th e ir m em b r an es th a t a ll o w t he m to bi nd t o a s m a ll g rou p of c h em ic al l y r e l at e d a n ti ge ns . Th is g ro u p d e fi n es t h e a nt i ge n s p ec if ic i t y of ea ch B c el l . D i f fe r en t B c el ls h a v e di f fe r e nt an t ig e n spe c if ic i ti es , bu t e a ch B c el l h as on l y on e s pe c i f ic i t y. B c e ll s t h at re c og n i z e s p ec i fi c a n t ig en s d i v i de to fo r m ne w B c e ll s ( m em o r y B c e l l s ) a nd p la sm a c e l ls ( an t i b od y- f o r m i n g c e l ls ) , wh ic h s ec r et e fre e , s ol u bl e ( h u m o r al ) an t ib od y m ol ec u le s i nt o e xt r a c e ll u la r flu i ds ( Fi gu r e 1 0 - 1) . b . V i rg i n B c e ll s h a v e n ot r es p on d ed to an an t ig en s i nc e th ei r r e l ea se in t o t h e c i r c u la t io n f ro m b on e m a r ro w. T h e i r m em br a ne a n t ib od i es ar e o f th e i m m u no g lo bu l in M ( I g M) a n d D ( I g D) cl as s e s (see I.D). c . Me m o r y B c el ls a re der i v e d b y c el l d i v is i on f rom an o th e r B c e l l t h a t h as re s po nd e d t o a n a n ti g en . Th ei r m em b r ane a nt i bo di e s a re o f im m u no g lo b ul in c l as s e s A ( I g A ), E (I g E ) , o r G ( I g G ; s e e I . D ) . P.196
Figure 10-1. B cells: antigen specificity and activation.
3 . An t i g e n r e ce p t o r s o f T c e l l s h a ve t wo m em b ra n e p r o te in s ( α a n d β o r γ an d δ ) , wh ic h d e f in e t h e a nt i ge n s pe c i fi c it y o f e ac h T c e ll , a n d s e v e r a l o th e r i nt e g r al m em b ra n e p r ot e ins k n o wn as C D 3 +
c o m pl e x. Th e r e fo r e, T c e l ls ar e C D 3 . E ac h T c el l ha s t ho us a nd s o f id e nt ic a l a nt i ge n r e c ep t o rs in it s m em b ra ne . Di f f e re n t T c e ll s o f d i f fe r e nt an t ig e n s p ec i fi c i t i es d i ff e r i n t h e c on f orm a ti o n o f t h ei r a n t ig en r ec ep t o rs .
a . M a j o r h i s to c om p a ti b il i t y c o m p l e x ( M H C ) p r ot e i n s. Th e an t ig en r e c ep t or s o f T c e l ls d o no t r ec og n i z e a nt i ge ns alo n e . R a t he r , t h e y n o r m a ll y r ec o gn i z e p e p t id e ep i t o pe s (f r ag m e n ts o f an t ig e n ) t ha t a r e c h em ic al l y c om b in e d wi t h MH C p r o t e i ns o n the s u r f ac e o f o t he r b o d y c e ll s ( F ig u re 10 - 2 ) . MH C p r o t e i ns a re di v i ded i nt o tw o m aj o r c l a ss e s : ( 1 ) C l as s I p r o te i ns , wh ic h a r e p r es e nt on th e s ur f a c e s o f a lm os t a l l b od y c el ls ( 2 ) C l as s I I p r ot e i ns , wh i c h a re pr e s e n t o nl y o n t h e s u rf a ce s o f s p ec ia l a n t ig e n -p r e se n ti n g ce l ls ( AP C s ) b . T h ym u s g l a n d. T c el ls do no t en t e r t he c i rc u la t i on di r ec tl y f r om b o n e m a r r o w b u t f i rs t e nt e r th e th y m us g l an d t o m a tu r e . Mo s t d e ve l op in g T c e ll s d ie in t h e t h ym u s . Th e c e ll s t ha t di e e i th e r d o n o t re co g ni z e no r m a l s elf - a n ti g en s o r p r od uc e a re s po ns e a g ai ns t n o r m a l s el f -a n ti g en s . ( 1 ) T c el ls th a t a r e r e le as e d f r om th e t h y m u s i n to t h e c ir cu l at i on a r e vi r g i n T c e l ls . ( 2 ) T c el ls th a t o r ig i na t e t h r o ug h c el l d i v is io n fr om t he re s po ns es of o t h e r T c el ls a re me m o ry T c e l l s o r e f f ec t o r T ce l l s . c . G l yc o p r o t e i n s . Mo s t T c e l ls c a n b e c l as si f ie d b y t h e p r es en c e o f a m e m b r a ne gl y c op r o te in k n o wn a s C D 4 — th e hel p e r , o r T H c e ll — o r t h e p r es e nc e o f C D8 — t he c yt o t o x i c T l ym p h o c yt e ( C T L ), o r T C cell. ( 1 ) T H c e ll s c a n b e d i v ide d in t o t wo f u nc ti o na l g ro u ps : T H 1 an d T H 2 . Th e s e c el ls ha v e di f f e ren t f un c t i on s i n t he im m un e r es po ns e a n d r e g ul a te im m u ne r es po ns es t h ro ug h th e p r od uc t io n of in t e rl e uk in s ( I L ; a ls o c al l ed l ym p ho k in e s ), wh i c h a re p ro t ei ns t h a t a ct on c e ll s i n a n au t oc r in e , p ar a c r i ne , o r e nd oc r in e m an n e r. P.197
Figure 10-2. Helper T cell (TH cell) antigen recognition. MHC, major histocompatibility complex; APC, antigen-presenting cell.
( a ) T H 1 c el l s a c t i v a te oth e r c e ll s , in cl u di ng so m e T H c e ll s , T C c e ll s , a n d m ac r op h ag es . I n a dd i t io n , t he y c an de c re as e a nt i bo d y ( A b) p r o du c ti on b y in hi b it i ng th e fo r m a t io n o f T H 2 c e ll s. ( b ) T H 2 c el l s a c t i v a te B c e ll s t o d i vid e a n d p r od uc e Ab . Th e y c a n a l so in hi b it t he fo r m a t io n o f T H 1 c e ll s. ( 2 ) T C c e ll s a r e a b le to k i l l c el ls th a t a r e i nf ec t ed b y v i r u s e s . Th e y d o th is t hr o ug h d i re c t b in d in g wi t h t h e i nf ec t ed ce l l o r th r ou g h t he r e l ea se o f c y t ot o xi n s . ( 3 ) T r ce l ls , or T r e g ul ato r y c el ls , h a ve re c e n tl y b e e n d es c r ib e d . +
+
Mo s t o f th e s e c e ll s a re CD 4 , a lt h ou gh t he r e i s a C D 8 s ub s e t as we l l . A ll o f t he s e c e ll s s u p p re s s im m u ne r es po nse s th r ou g h t he s ec r e ti o n o f I L -1 0 a n d t ra n s f o rm i ng gr o wt h f ac t or β ( TG F - β ) ; i n +
+
a d di t io n , c el ls de s i g na t ed C D 4 C D 2 5 a r e a ls o ab l e t o i n hi bi t ot h er T c e l ls th r ou g h d i re c t c on t ac t . ( 4 ) I nt e rl e uk in s a r e p a rt o f a l a rg e r n e t wo r k o f r eg u la t o r y c yt o k i n e s . Th is ne t wo r k i nc l ud es s e cr e ti o ns o f ot h e r c el l t y p es in a d di t io n to th os e o f l ym ph o c y te s . Ta b l e 1 0 -1 li s t s t h e s ou r c e s a nd a c ti o ns o f im po r ta n t c y t ok i ne s t ha t re g ul a te t he im m u n e s y st em a nd i n f la m m at i on . 4 . N a tu r a l k i l le r ( N K ) c el l s ar e l a r ge , g r an u la r l ym p ho c y t es wi t ho u t a sp ec i fi c T o r B c e ll an ti g en r ec ep t o r. Th e i r c y t ot o xi c i t y is s im i la r t o t ha t o f C TL ( T C ) c e l ls . N K c el ls re c og ni z e an d d e s t r o y t um or s , a n d a r e i m p o rt a nt f o r c on t r ol l in g v i ra l i n fe ct i on s p r i o r t o t h e d e ve l op m e n t o f a da p ti v e i m m un i t y . 5 . AP C s a r e e s s en t ia l f or m os t i m m un e re s p on s es an d a r e f o un d i n t h e s i te s a t wh i c h t h es e r e s po ns es o ri gi n at e . a . Th e be s t un d e rs to o d A P C s a re th e m a c r op h ag e s a n d d e nd r i t ic c e l ls o f t he l ym p h n o d es , s pl e en , a n d o t he r l ym p h o id t is s ue . Mo s t i m m u ne r es po ns es wi t h i n th es e o r g an s b eg in wh e n t he s e c e ll s p r e se n t e pi t op es bo u nd to t he i r s u rf ac e MH C c l as s I I m o l ec ul es t o T H c e l ls an d s ec r et e c y t ok i ne s as ac ce s s o r y s i gna l s ( F ig u re 10 - 2 ) .
A P C s , es pe c i al l y m a c ro ph a g es , a r e a bl e t o c on t ro l th e t y p e of i m m u ne r es po ns e g e ne ra t e d. Th e y d o t hi s b y s ec r e ti n g d if f e re n t c yt o ki ne s i n re s p on s e t o d i f fe r e nt t ype s o f p a th o ge n s ( e .g . , e xt r a c e l lu la r ba c t e r ia , i nt r a c e ll u la r ba c t e r ia , vi rus es ) . P.198
Table 10-1. Major Cytokines and Their Actions Cytokine
Sources of Secretiona
Major Actions
IL-1
Macrophages, APCs, others
T and B cell activation, pyrogenic, proinflammatory
TNF-α, TNF-β
Macrophages, TH1 cells, TC cells
Similar to IL-1, but including cytotoxicity
IL-2
TH0 cells, TH1 cells
T cell, B cell, and NK cell activation
IFN-γ
TH1 cells
Induction of MHC, activation of macrophages and NK cells, formation of memory B cells, antiviral
IFN-α, IFN-β
Leukocytes, fibroblasts
Induction of MHC, antiviral, and growth inhibition
IL-3
Macrophages, TH cells
Proliferation of multilineage marrow stem cells
IL-4
TH2 cells
B cell activation and memory B cell formation, increased mast cell precursors, activation of mast cells
IL-5
TH2 cells
Memory B cell formation, eosinophil production
IL-6
TH2 cell, other types
Plasma cell maturation, others similar to IL-1
IL-7
Bone marrow stroma
Lymphocyte maturation
IL-8 (CXCL8)
Monocytes, macrophages, endothelial, fibroblasts cells
Chemokine, attraction and activation of neutrophils, attraction of T cells
IL-9
TH1 cells
Proliferation and differentiation of bone marrow cells and thymocytes
IL-10
Macrophages, TH2 cells CD8+ T cells, B cells
Increased humoral (antibody) immunity, decreased cellmediated immunity, mast cell growth
IL-11
Bone marrow stroma
Proliferation and differentiation of bone marrow cells and thrombocytes
IL-12
Macrophages, B cells
Promotion of cell-mediated immunity, activation of TC and NK cells, suppression of humoral immunity
IL-13
TH cells
IL-4-like effects on B cells, inhibition of production of inflammatory cytokines by monocytes
IL-14
TH cells
Important for the generation of B memory cells
IL-15
Endothelial cells, epithelial monocytes, muscle cells
IL-2-like effects
GM-CSF
TH1 cells, macrophages
Marrow proliferation of myeloid precursors
G-CSF
Fibroblasts, endothelial cells
Proliferation and survival of neutrophil precursors
M-CSF
Fibroblasts, endothelial cells
Survival of monocyte macrophages
APC, antigen-presenting cell; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; M-CSF, macrophage colony-stimulating factor; MHC, major histocompatibility complex; NK cell, natural killer cell; TCcell, T cytotoxic cell; THcell, T helper cell; TNF, tumor necrosis factor. a
Not all sources are listed.
b . A n y c e ll in th e b o d y c a n ac t a s a n A P C f or im m u ne r es po ns es i n vo l vin g C TL c e ll s . N uc le a t ed c e ll s c a n p r es e nt fr a g m e n ts o f +
a n t ig en s b o un d t o t h ei r s u r f ac e MH C c l as s I m ol ec u l e s t o T c ( C D 8 ) l ym p ho c y t es . c . B ot h T an d B c el ls c on t i nu al l y ci r c u la t e f r om th e bl oo d th r ou g h t h e l ym ph no d es , s pl e en, a nd o th e r s ec on da r y l y m p ho i d t is s u e a nd t h e n b ac k in t o t h e b lo o d. I f th e r e is an t ig e n p re s en t in th e s ec o nd a r y l ym p ho i d t is s u e th a t b in ds s p ec i fi ca ll y t o th e re ce p to r on t h e T o r B c e ll , th e n a n im m u n e r es p on se c a n b eg i n . P.199
6 . N e ut r o p h il s , m ac r o ph a g es , eo s in o p hi l s, b as o p h il s , p l a te l et s , a n d m a st ce l l s as s i s t i n e l im in a ti n g a nt i ge ns f rom t he bo d y. Th ei r f u nc t io ns m a y b e p ha g oc y t i c , p r oi n fl am m a t o r y , c y t o t o xi c , r e g ul a to r y , o r a c om b in at i o n o f t h es e. C . H u m o ra l im m un i t y: p r i m a r y a n d m em o r y r e s p o n se s th a t p r o d u ce an t i b od i es 1 . O ve r vi ew . I n m os t h um o r al i m m u ne re s p o ns es, a n ti ge ns a re r e c og ni z e d b y a n ti g en -s p e c i f ic B c el ls a n d T H c el l s ( no n - an t ig e ns p ec if ic B an d T H c e ll s do n ot r es po n d ). In i ti a ll y , B a n d T H 2 c el ls d i vi de t o i nc r ea s e th e ir c e l l n um be r s . R es p on d in g B c el ls p r o du c e b o t h m e m o r y B c e ll s a n d p l as m a c el ls , ai de d b y c yt o k in es s e c re t ed b y T H 2 c e ll s . T -i n d ep e nd e n t re s p on s es to c e r tai n ba c t e r ia l p o l ysa cc ha r i de an t ig en s d o no t re q ui r e T H c e ll s . D u r i ng Ti n de p en d en t re s p o ns es , a s u bc l as s o f B ce ll s ( B 1 B c el ls ) re sp o nd s a l on e a n d p r od uc es pl as m a c el ls t ha t s ec r et e IgM a n t i b o di es , b u t n o m em o r y B c el ls a re pr o d uc ed .
2 . P r i ma r y i m m u n e re sp o n se . Th e f i rs t ti m e a sp e c i f ic a n ti g en is e n co u nt e re d , o nl y vi r g i n B c e ll s a n d vi r g i n T H ce l l s a r e p r es en t to r e s po nd t o t he an t ig e n. In i t ia ll y , t he T H c el ls be c o m e T H e f f ec t or c e ll s, an d th e B c e ll s p r od u c e pl as m a ce ll s t h at s e c r et e I g M a n t ib od y . L at e r i n t h e im m u ne r es po ns e , p la s m a c e ll s p r od uc in g o t h e r cl as s e s o f a n ti b ody d e v e l op . Th e p r im a r y im m u n e r es p on s e is d e t ec te d i n th e s e ru m a fte r 4 d a ys a nd pe ak s i n 7- 1 1 da y s . I n a p r i m a r y im m u ne r es po ns e , I g M i s p r od uc e d f i rs t a n d i s f ol l o we d b y I g G . Me m o r y B an d T H 2 c e ll s a r e a ls o p ro d uc ed . Me m o r y B c el ls c a n a ls o b e a c t i v a te d t o p r o du c e t he ot h e r c l as ses o f a nt i bo d y in s u bs eq u en t i m m un e re s po n s e s . 3 . M e m o r y i m m u n e r esp o n se s . Th e s e co n d o r s u bs eq u en t e n co u nt e r wi t h t he s a m e a n ti g en o r a c lo s e l y r el at e d a n ti g en p r o du c e s re s p on s es b y m em o r y B c el ls an d m em o r y T H 2 c el ls . Th e s e re s p o ns es ar e m or e r ap i d b ec au s e m e m o ry c e ll s r e qu i re le s s a n t ig en f o r s t im u la t io n an d a re of g re a te r m a gn i tu d e b ec a us e t he r e a r e m o re an t ig e n -s pe c i f ic B an d T c e ll s t o r es p ond . Mo s t s e r um a n t ib od y p r od u c e d i s I gG , wi t h s m a ll e r am o un t s o f I gA an d Ig E . S i g ni f ic an t am ou n ts o f an t i bo di es a re p ro d uc ed as r ap i dl y as 2 -3 d a ys a f t e r t he r ee nc o un te r wi t h an t ig e n, an d th e a b s o l ut e a m o u nt o f an t ib o d y (m ea s u r e d i n m il li g r am s pe r de c i l it e r o f se r um ) i s g r e a te r th an in p ri m a r y im m u n e r es p on s e s . Th e d u r a ti on o f m e m o r y va r i e s am o ng an t ig e ns an d p ro ba b l y a m o n g i nd i vi d ua l s . S om e, bu t n o t a l l, m e m o r y is li f el ong . 4 . M a j o r ro l es o f a n t ib od i e s a . Th e fi r s t fu nc t io n o f an a nt i bo d y is to ac t a s an a n ti g e n r e ce p t o r f o r B c el ls s o th a t t he B c e ll s c a n re c o g ni z e an d r e s po nd t o a n t ig en s . b . Th e s ec o nd f un c t i on of a n a n ti bo d y is to ai d i n t h e e l i mi n a ti o n o f a n ti g en . E li m i na t io n o c c u rs t hr o ug h n o ns pe cif i c f u nc ti o ns , s uc h a s p h ag oc y t o s i s o r c om pl e m e n t ac t i v a ti on . Th e m e c ha n ism of e l im in a ti o n d ep e nd s o n th e c l as s o f a nt i bo d y in v ol v e d . c . Th e t h i rd fu nc t io n o f an a nt i bo d y is ne u t r al iz a ti o n o f t o xi n s. N e u t r al i z a ti on oc c u r s wh e n an an t ib o d y b i nd s t o th e to xi n a n d p r e ve n ts i t f ro m r ea c hi ng t h e t a rg e t c el l o r re c e p to r . D . I m mu n o gl o bu l i ns : a n t i g en b in d i ng a nd cl a ss - s p ec i f ic f u n c t io n s. Th e te r m s a nt i b od y a nd i m m u no g lo bu li n ar e us ed i n t er c ha ng e ab l y . 1 . S t r uc t u r e . Th e s t a nda r d i m m u no gl o bu li n u n it h a s f ou r p o l yp ep ti d e c ha in s : t wo id e n ti c a l l ig h t ( L ) p o l y pe p t i d e c h a in s a nd t wo i d e nt ic a l h ea v y ( H ) po l y p e pt id e c h ai ns . Th e s t r u c t u r e is r e p r es en t ed as H 2 L 2 . Eac h c ha i n c an be di vi de d in t o a C - t e rm i n al c o n s ta n t re g i on an d a n N - t e r m i na l va r i ab l e r e gi o n of am in o a c i ds ( F i gu r e 1 0 - 3) . Th e N -t e rm i na l v a ri ab l e r eg i on fo rm e d f r om th e H a n d L v a r ia bl e d om a in s is r es po ns i bl e f o r a n ti g en b i nd in g b y t h e
i m m u no gl o bu l in . Th e C - te r m in al c o ns t an t re gi o ns o f th e H c ha in d e t e rm in e t h e c l as s o f t he im m u n og l ob ul i n. 2 . C l as s . Th e r e a r e f i v e g e n er a l h ea v y - c h ai n , c on s ta n t - re gi o n a m in o a c i d s eq u en c e s . Th e s e de t e rm in e t h e f i ve g e n e ra l cl a ss e s o f i mm u n og l o bu l in s : I gM , Ig G , I g E, I g A, an d IgD . W ith in s o m e c l as s e s, v a r ia n ts o f th e h e a v y - c ha i n s e q ue nc e yie l d s ub c l as se s : I g M1 - 2 , I g G 1 -4 , a n d I g A1 - 2 . Th e c l as s o f a n i m m u n o gl ob u li n d e f in es it s n on s p e c i fi c an t i ge n e li m i n at i on o r i nf l a m m a to r y f u nc ti o n. Th e s e fu nc t io ns a re ac tiv a t e d o n l y a f t e r a nt i ge n -a n t ib od y c om p le xe s a r e f o rm ed , no t b y un bo u nd an t ib o di es . a . I gM i s t h e f i rs t im m u no g lo b ul i n s e c re t ed du r ing p ri m ar y i m m un e r e s po ns es . It pl a y s a m in o r ro l e i n m e m o r y r es po n s e s. I t d oe s n o t l e a ve t h e b lo o d i n s i g ni fic a nt am ou n ts be c a us e o f i t s p en t am er ic s t r uc t ur e a n d l a rg e s i z e ( m o l wt 9 0 0 ,0 00 da l to ns ). I t a cc o un ts fo r a p p ro xi m a t el y 2 0% o f t he a du l t s e r um im m u no g lo b ul i n . I g M i s t h e m os t po t en t a c t i va t o r o f t h e c o mp l em e n t s ys t e m ( se e I . E . 2) . It s s e r um h a lf - li f e i s 9 -1 1 da y s . P.200
Figure 10-3. Immunoglobulin molecule. Fc, fragment, crystallizable.
b . I g G i s t h e p re d om in a nt s er um im m u n og lo b ul in s ec r e te d a t th e e n d o f t he p r i m a r y im m u ne r es po ns e s a n d d u ri ng m e m o r y r es p on se s . I t c an di f fu se f r o m b lo o d i nt o o t he r e xt r a c el lu l ar f lu id s , p a rt ic ula r l y in in f la m e d m ic r o v as c u l at u r e, an d i t c r os s e s t h e p la ce n ta to e n t e r t he fe t al c i r cu la t ion . I t ac co u nt s f o r a pp r o xi m a t e l y 7 0 % o f a du l t s er u m i m m un o gl o bu li n . I t o p s o ni z e s a n t i ge n s f o r p h a g oc yt o s i s a nd ac t i va t e s t h e c o mp l em e n t s ys t e m . I ts s e r um ha l f- l if e is 25 - 35 da y s . c . Ig E is s ec r e te d d u ri n g m em o r y re sp o ns es an d m a y al so be se c re t ed la te d u r in g a p ri m a r y r es p on s e . I t n o rm al l y ac c o un ts fo r < 1 % o f s e ru m i m m u no gl o bu l in . I t bi n d s t o I g E r e ce p t o rs l oc a ted o n th e c e l l s u r fa c es o f
b l o o d b as o p hi l s a n d o n m u co s al a nd co n n ec t ive t i s s ue ma s t c e ll s t o t r i gg e r th e s ec r et i on of in f l am m a to r y m ed ia t o rs fro m th es e c el ls in th e p r e se nc e o f s pe c i f ic an t ig e ns . Ig E m e di a te s a ll e rg i c r e ac ti o ns . I ts s e r um h a l f- l if e i s 2 - 3 d a y s , bu t i t s m as t c el l -b ou n d h al f - li f e i s s e v er a l m o n th s t o ye a r s . d . I g A i s s e c re t ed du r in g m em o r y re sp o ns es an d m a y al so be se c re t ed la te d u r in g a p ri m a r y r es p on s e . I t ac c ou n ts f o r 1 0 % o f s e ru m im m u n og l ob ul i n. H o we ve r , i t is s e c re t e d in l a r ge q ua n t it i es a c ros s mu c os a l s u r fa c es i nt o g a s t r oi n t es t i na l , re s p i ra t o r y, l a c h r ym a l , m amm a r y, a n d g en i t o u ri n a ry s e c r e ti o ns , w h e re i t p ro t e c ts m uc o sa f r om co lo n i z a t i on b y ba ct e r ia and o t h e r m i c ro o rg a ni s m s . Its s e r um ha l f- l if e i s a pp r oxi m a t e l y 5 d a ys . e . I g D a c c ou n ts fo r < 1 % o f s e ru m i m m un o gl ob u lin a nd ha s n o k no wn f u nc t io n a s a s ec r e te d im m u n og l ob ul i n. 3 . S pe c i fi c i t y. Th e s pe c if i c i t y o f e ac h im m u n og l ob u li n fo r a n ti g en bi n di ng r e s id es in th e t wo i d en t ic a l a nt i ge n -b i nd in g s i te s, e ac h f o rm e d b y th e c om b in a ti o n o f t he v a r iab l e r e gi o ns o f he a v y a nd l i gh t c ha i ns . I g G , I g E , an d I g D as we l l a s s er um I g A h a v e t wo an t ig e n- b in di ng s i t es . I g M a n t ib o di es h a ve 10 id e nt ic a l a nt i gen - b in d in g s it es t hr o ug h th e c om b in a ti o n o f P.201
f i ve H 2 L 2 un i ts wi t h a jo in i ng po l y p ep t id e c ha i n to f o rm a pe n ta m er . L i ke wi s e , s ec re t e d I g A ty p i c al l y e xi s ts as a di m er wi t h f ou r bi n di ng si t es . 4 . Q u a nt i t a ti o n o f im m un o g l ob u l in : a n t i ge n bi nd i n g a n d c r o ss 8
r e a c t i vi t y. B e t we e n 1 0 a n d 1 0
11
un i qu e i m m un og l ob u li ns wi t h di f fe r en t
a n t ig en - b in di n g s pe c i fi c it i es a re fo r m e d b y t h e im m u ne s ys t em . a . E ac h i m m un og l ob ul i n s p ec if ic i t y c a n b in d t o s ev e r a l di f fe r en t , b u t c l o s el y s t r uc t ur a ll y r el a te d , a n tig e ns . Th is ab il i t y i l lu s t r at e s t h e p he no m en on o f c r os s - re ac t i v it y o f a s i ngl e an t ib od y f o r m ul t ip le an t i ge ns . Ea c h i m m u no gl o bu l in - an t ig e n i n t er a c t i on i s q u an t it a te d b y i ts as s oc i a ti o n c o n s ta n t ( K a ) . b . C r os s -r e ac t i v it y m a y a l s o oc c u r th r ou g h t he sh a r in g o f s om e , b u t n ot a l l , a n t ig en s b y t wo s t ra i ns of b ac t er i a, v i r us es , o r oth e r m ic r oo r g an is m s . c . B ec au s e ea c h m ic r o o rg a ni s m ha s s e v er a l a nt i ge n s, ea c h el ic i ts th e p r o du c ti on o f m u l ti pl e ant i b od ie s wi t h u ni q ue s p ec i fi c i t ie s b y t he im m u ne s ys t em . Th is re s p o ns e is k no wn a s a p ol yc l o n a l r e s p o ns e a nd r es ul t s i n a c om b in a ti o n o f a nt i bo di es k n o wn as a p o l yc l o n a l a n t is e r um a nd de fi n es t h e s e ro t y p e o f t h e im m un i z i ng o rg a ni sm . 5 . F r ag m en t s o f im m uno g l o bu l i n f o r cl i n ic a l us e . Im m u no gl o bu li n s c a n b e en zy m a ti c al l y c l ea v ed i nt o f r a gm en ts — f o r e x a m pl e , F ab a nd F (a b ' ) 2 ( a n ti g en - bi n di n g f r ag m en t s ), F c ( c r ys t al l i zab le f ra g m e n t ), an d F v ( va r i a ble r e g io n fr a gm en t ) . F ab a nd F ( ab ' ) 2 f ra gm en t s a r e c l in ic al l y us e fu l b ec a us e t h e y r et a in an t ig e n s p ec if i c i t y , bu t n o t c la s s -s p ec i f ic ( e. g . , in f la m m a to r y ) f u nc t io ns , an d a r e r e ad ily e xc r e t e d re n al l y. C on ve r s el y , th is c h a ra c te r is tic l i m i ts th e i r e ff e c t i v e ne s s i n c e rt a in s i tu a ti o ns .
E . An t i g e n e l i mi n a ti o n a n d a c u te i n fl a mm a to r y m e ch a ni s ms o f h u mo ra l i m m un i t y 1 . O p s on iz a t io n i s t h e pr e p a ra t io n o f a n y e xt r a c e l lu l a r a nt i ge n f o r p h a go c y to s i s t h ro u gh bin d in g o f an t ib o d y. N e u tro p hi ls an d m ac r op h ag es h a ve a v a r i et y o f re c e p tor s fo r th e c o ns ta n t r e gi on o f I g G an t ib od i es (F C γ R ) , wh i c h bi n d a nt i ge n -a n ti bo d y c o m pl e xe s . W hen the a nt i ge n i s so l ub l e, th e i m m u ne c om p le xe s m us t b e s u ff ic i en t l y l a rg e to in d uc e t h is re ac t io n . Thi s b i nd i ng t ri g ge r s p ha go c yt o s i s o f t h e a n ti ge n - an ti bo d y c o m pl e x a n d a c t i v a te s t h e m e ta bo l is m o f t he pha g oc y t e , s hi f ti n g i t t o wa rd t he p ro d uc ti o n o f b a ct e r ic id al o xy g e n r ad ic a l s ( e .g . , s up e ro xi d e a nio n , h y d r o ge n p e ro xi d e ) . 2 . C o mp l em e n t is a g r ou p of ap p r o xi m at e l y 2 0 s e r u m p ro t ei ns t ha t , wh e n a c ti va t ed , fo r m a p r o te o ly t i c c as c a d e s i m i l a r t o t he c l o t ti ng an d fi b ri no l yt ic s e qu e nc e. W it hi n th is c om p le x o f p r ot e in s, t he r e a r e s om e th a t in h ib i t c om p le m e n t a c t i v a ti o n. C o m pl em e nt is re s p o ns ib l e f o r i nc r ea s i n g t he i n f la m m at o r y r es po ns e , p h a go c yto si s o f a n ti g en , l y s is of c e ll s ( us u al l y p a t ho g en s ) , an d c le a ra nc e o f im m u ne c om p le xe s . a . I n t he cl a ss i c a c ti va t i o n pa t hw a y, i m m u ne c om p le xe s o f I g M o r I g G a n t ib od i es bo un d to an t ig e n b in d s u bu ni t s o f c om p le m e n t c o m p o ne n t 1 (C 1 ) a n d t r i gg e r a n i ni t ia l s er ie s o f pr o te o l y ti c c le a va ge s . b . I n t he a lt e r n at i ve ac ti va t i o n pa t hw a y, t h e c ell wa l l s o f c er t ai n m ic r o or g an is m s (e . g ., g ra m - ne ga t i v e b ac t e ri a ) a re a bl e t o b i nd C 3b an d o t h e r co m p l em en t p r o te in s th a t i ni ti a te a d i ff e r ent s eq ue n ce of p ro t eo l yt ic c l ea va g es , l ea d in g t o t he s a m e en d po in t a s t h e c l ass ic ac t i v at i on pa t h way . c . In th e m a n no s e- b i nd in g p at hw a y, m a n n o s e - bin d in g p r o te i n ( MB P ) i s p r o du c e d b y t h e l i v e r d uri n g t h e ac u te - p ha s e r es po n s e . MB P b i nd s t o m a nn os e o n th e s ur f ac e o f ba c te r ia an d , i n c on jun c ti o n wi t h as s o ci a te d s e r um p r o te as es , t ri gg e rs p ro t eo l y t ic c le a va ge s id e n ti ca l t o th os e s ee n i n t h e c la ss ic pa t h wa y o f c o m pl em e nt . d . C 3 b, C 4b , an d a s s oc ia t e d d eg r ad a ti o n p r od uct s pr o v i de op s o n i z at i on , v i a c om p le m e n t r ec e pt o rs on c e l ls s uc h a s m a c ro p ha g es an d n e ut r o ph il s , in a d di t io n to th a t p r o v id e d b y I g G in im m u ne c om p le xe s . e . P r o in f l am m at o r y f r a g m e n ts of c e r ta i n c o m ple m en t p r o te i ns a c t b ot h b y d i r e c t a c ti vi t y o n t h e mi c r o va s cu l a t u re , p r om o ti n g a r t er i ol e d il a ti o n a nd i n c re as ed v a s c ul a r p e rm e a bi l it y , a nd b y tr i gg e ri ng t he r el e as e o f h is t am i ne a n d o t he r pr o in f la m m at or y m e di a to r s f r om m as t ce l ls an d b as o ph il s . f . A c o m p le x o f c om pl em e n t p r o te i ns k no wn a s t he m em b r an e a t t a ck c o m pl e x ( M AC ) c an in s er t i nt o a n y li p id bi la y e r m e m b ra ne , fo r m i ng a l a rge c h an n el th r ou g h wh i c h i on s a n d wa t e r di f f us e. Ma n y b ac t e ri a , e n vel o pe d vi r u s es , a nd s o m e hu m an o r m am m a li a n c e l ls a re s u b j e ct t o t hi s o s m ot ic l ys is . P.202
3 . C i r cu l a ti n g b a so p h ils a nd c on n ec t i ve t is s ue m as t ce l ls a re m a in l y p r o in f la m m a to r y c e ll s t ha t r ap i dl y in i ti a te ac u te i n f l am m a ti o n. Tr i g ge r s o f
s ec r e ti o n i nc lu de m e c h an i c a l a nd t he r m a l t r au m a a n d im m u n ol o gi c t r ig ge rs , c om p le m e n t, an d Ig E . a . I g E a n ti b o di e s, r eg a rd l es s o f a n ti ge n s p ec if ic it y , e q ui li b ra t e b e t we e n s e r um a n d b in di n g n on c o v a l e nt l y to hi g h -a f fi ni t y I g E r ec ep t o rs o n m as t c e l l a n d b as o ph il s u r fa c es . Th i s ac t i v i t y a r m s th e m as t c el ls an d b as op h il s, but t h e tr i gg e ri n g o f s ec r et i on b y t he se c e ll s r e qu i re s t h a t a nt i ge n b in d to an d c r os s -l in k a n ti g en -s p ec ifi c Ig E m ol e c u le s a l re a d y a f fi xe d t o th e i r r ec e pt o rs . b . Ma s t c e ll s a nd b as oph i ls , wh e n t r ig g er e d, im m e di a te l y s ec r e te t he c o nt e nt s o f th ei r s t o ra g e g r a nu le s , i nc lu di n g h is ta m in e , t um o r n ec r os is f a c to r α ( TN F - α ) , pr o te as es , an d c he m o t ac ti c p ro t e in s f o r n eu t r op hi ls and e o si n op hi ls . In ad d it io n , a c ti v a t io n o f ph os p ho li pa s e A 2 re l ea se s a r a ch id o ni c ac i d f r om m e m b ra ne ph o s p ho l ip id s an d r e s ul ts in th e s y n t he s i s o f va r io us le uk o t ri en e s , p r o s t a gl an d in s, an d th r om b o xa n es . Th e p r im a r y e f f ec ts o f t he s e m e di a to rs a re ( 1 ) V as c u la r di l at io n ( 2 ) I nc r ea s e d v as c u la r pe r m ea bi l it y ( 3 ) C o nt r ac t io n o f re s p i ra t o r y an d g as t r oi n te s t i nal s m oo t h m us c l e ( 4 ) N e ut r op h il an d e os i no p hi l c he m ot a xi s 4 . An t i b o d y- d e p e n d e n t c e l l -m e di a t ed c yt o t o x i c i t y i s m ed i at e d b y ce ll s wi t h c yt o to xi c p o te n ti al as we l l a s re c e p to r s f o r I gG . Th e s e c el ls , N K c el ls , m ac r o ph a ge s , an d s om e T C c e l ls , b i nd to an d l y s e t a rg e t c e l ls c o at e d wi t h IgG. 5 . Ac u t e in f l am ma t i o n a l lo ws i nc r ea s ed ea s e of m o v em en t of c r u c i al c om p on e nt s o f t h e b lo o d i n to th e ti s s ue s , in c l u din g ph a go c yte s ( e s p ec ia l ly n e u t ro ph i ls ) , I g G a n ti b odi e s , c o m p le m e n t , c l o t ti ng p r o te i ns , a nd ki ni ns . The a d a pt i ve re s u l t is th e i s ol a t io n a nd r em o v al o f i n va d in g m ic r oo r g an is m s a nd n e c ro t ic t is s ue s , fo l lo we d b y t is s u e r e pa i r a nd r eg e n er a ti o n. F . C e ll - m ed i a te d i m mu ne r es p on s e s ( c el l - me d iat e d im m un i t y) a r e t ho se i n wh i c h an t i b od y i s n o t i n vo l ve d i n t h e e l im i nat i o n o f a n ti g en . 1 . N o n vi r a l i n t ra c el l u lar p a r a si t e s o f m a c ro p hag e s , su c h as My c ob ac t e ri a , L i st e ri a , a n d c e r t ai n p r o to z o a , a r e p r im a ri l y el im in a t ed b y T c e l l+
m ac r o ph a ge i m m u ni t y . CD 4 T H 1 c el ls r ec og n i z e in f ec t ed m a c ro ph a ge s a nd s ec r e te l y m p ho k i n es , p ar t i c u la r l y in t e rf e r on γ ( I FN - γ ) . Th es e l y m ph ok i ne s a c ti va t e m ac r op ha g es to p r o du c e m o r e b ac te r ic ida l o xy g e n r ad ic al s (e . g. , s u pe r o xi d e a n io n , h y d r og e n p e ro xi d e ) a nd al s o to i n c r ea s e th e s ec r e to r y f u nc t io n o f th e m ac r op h ag e s a nd in h ib it p ha go c y to s i s , e na b li n g t he m ac r o ph a ge s t o k i l l t he p a r as i te s i n t he ex t r a ce ll u l a r e n vi r on m e n t. 2 . V i r us e s m u s t b e e li m in a t ed f ro m b ot h e xt r a ce llu l a r s i t es an d i n fe c t e d c e ll s. a . An t i b o d ie s o ps o ni z e v i r u s p a r ti c l es in bl oo d an d ti s s ue f lu id s f o r p h a go c y to s i s , b ut an t ib od i es a re ge ne r a ll y i ne f fec t i v e a ga i ns t i n fe ct e d ce ll s . b . C T L c e ll s re c o g ni z e in f ec t ed ce ll s a nd di r ec t ly k i ll th e m in an a nt ig e n s p ec if ic m a nn e r , s ec r et in g l ym p ho k i n es , s uc h as TN F - β a s we l l a s g r a n zy m es a n d g r an ul y s in s . I n a d di t io n , C TL c an i n du c e a po p to s i s v i a F AS l i ga n d b in di n g t o F A S on t h e t a rg e t c el ls . O f te n , th e c e ll s a r e ki ll e d b e fo r e
i n f ec ti o us v i ru s p a rt ic l es a r e a s s em bl e d. W he n k il l ed ce ll s r e le as e i n f ec ti o us v i ra l p a r ti c l es , t h e y m a y be op s o n i z ed b y a n a n ti b od y . C e ll m e di a te d i m m un i t y a n d hu m o ra l i m m un it y m us t f un c ti o n i n co nc e r t t o p r o vi de op t im al an t i v i ra l d e f en s e s . c . N K c e l ls k i ll in f ec te d ( a n d t um o r ) c el ls i n a n on - a n ti ge n -s p ec if ic m a nne r , b i nd i ng to MH C - l i k e m ole c ul es us in g a va r ie t y o f r e ce p to r s . N K c e ll s ki l l t h e ir t a rg e t c e l ls u s i n g m e c ha n is m s s im i l a r t o t h os e u se d b y C TL s. d . I F N - γ (s ec r e te d b y C TL , N K , a n d T H 1 c el ls ) a nd I F N - α a n d I F N -β ( s ec r e te d b y f ib r o bl as ts a n d o t he r c e ll s) p ro v i d e a d di t io n al an t i vi ra l i m m u ni t y b y bi nd i ng to re c ep t o rs o n o t he r c e ll s an d in du ci n g s y n th es is o f k i na se s a nd en d on uc l eas es ( i. e . , a nt i v i ra l p r o te in s ) , wh i c h i nh i bi t vi ra l an d c e ll ul a r g r o wt h . In t e rf e ron s a ls o u p r eg ul a te c l as s I MH C p r o t e i ns , wh ic h m ak e i n fe c te d c el ls m o r e v i s ib l e t o C TL c el ls . 3 . T um o r s a r e m o d if i ed h o s t c e ll s a nd m u s t be eli m in a te d b y t he im m u ne s ys t em , u s u al l y b y c e ll -m e di a te d i m m un i t y . a . N K ce l ls a re p ri m a r il y r e s p o ns ib le f or ki ll i ng tum o r c el ls . Th e y ac t b y r e c og ni z i n g c h a ng es in c e l l -s u rf ac e p r o te i ns o r by a n t i b od y- d e p e n d en t c e l l -m e di a t ed c yt o t o x i c i t y. P.203
b . C T L c e ll s re c o g ni z e tu m o r c e l ls i n a n a n ti g en -s p ec if ic m a nn e r a n d k i l l t h em b y s ec r e ti n g l y m p ho k in es , s uc h a s TN F - β , a n d b y i nd uc i ng ap op t os is t h r o ug h t h e b in di n g o f FA S a n d F A S -l i ga n d. c . M a c ro p h ag e s al s o k i ll t u m o r c el ls in a n on s pec i fi c m an ne r , th r ou g h t he r e l ea se o f TN F - α . 4 . G r a f t re j ec t i o n ( s e e V )
II. Hypersensitivity Reactions are exaggerated, inappropriate, or prolonged immune responses that cause damage to otherwise normal tissue. F o u r t yp e s o f h y p e rs en s it i v i t y r ea c ti on s a r e r ec o gn i z e d , p r im ar i l y o n th e b a si s o f t h e m e c h a ni s m s o f pa t ho ge n es is ( Fi gu r e 1 0 - 4) . Ma n y d i f fe r en t d i se as es a re in c l u de d wit h i n e ac h t yp e . Al l e r g e ns a r e b ro a dl y d ef i ne d a s a n t ig en s o r ha p te ns th a t i n du c e h y pe r s e ns i ti v i t y r e a c t i on s, an d th e y ar e u s ua ll y n o np a th og e ni c , no n t o xi c a g en t s.
Figure 10-4. The four main types of hypersensitivity reactions. RBC, red blood cell.
P.204
A. I g E - m e d ia t e d t yp e I h yp e r s e n s i t i vi t y r e a c t io n ( im m ed i a te h yp e r s e n s i t i vi t y) 1 . A t ype I h y p e rs en s i t i v it y r e a c t io n i s c au se d b y i n a p p ro p r i a te p r od u c tio n a n d h yp e r s e c r e t i on o f Ig E t o s pe c i f ic a l le r ge ns p l us au xi l i a r y f ac to r s , s uc h a s i nc r e as ed m uc o s a l p er m e ab il i t y to ir r i ta n ts (e .g . , S O 2 , N O 2 , di es el f u m e s ). Th e t en d en c y t o h yp e r s e c r e te I g E i s in h e r i ta b l e ; a c hi ld ' s p r o ba b il i t y o f be in g a h yp e r s e c re t or is 50 % i f o ne p a re n t is a h yp e rs ec r eto r a n d 7 5 % i f b ot h p a r en ts a r e h y pe r se c r e t or s . Th es e i n di v i du a ls ar e c o ns id e re d to be at o pi c . a . I gE is p ro du c e d l oc a lly a f t e r n on s ys te m i c e xp o s u r e t o a n a n ti ge n . ( 1 ) I n n or m os ec r et o rs (1- 1 0 µ g/ d L o f I g E ) , a rm ing o f l oc al m a s t ce ll s o c c u r s ( s e e I . B .6 ) . ( 2 ) I n h y p e rs ec r et o rs ( t yp i c a ll y 1 00 µ g - 1 m g / dL of I g E ), I g E sp i ll o ve r o cc u rs , ar m i n g b as op h il s a n d n on l oc al m as t c el ls a n d c au s i n g i nc r ea se d o cc u pa nc y o f m as t c el l an d ba s o p hi l I g E r e c e p to rs b y Ig E . b . B ec a us e t he r e i s a l ag p e ri od f or I g E s y nt h es is an d c el l a r m i n g, a t y p e I r e a ct i on us ua ll y d oe s n ot o c c u r o n t he fi r s t ( o r f i rs t s e as on a l) e xp o s ur e to a s p ec if ic al l e rg en . 2 . C o mm o n a l le r g en s a . R es p i r a to r y a l l e r g e ns i nc lu de p ol le ns o f v a r io u s p la n ts (e . g ., r ag we e d , g r a ss es , t r ee s ) , f un g i, an i m a l f u r , c a r p et m i te s , a n d o t he r s h ed al le r g en s . b . G a s t r oi n t es t i na l a l ler g e n s i nc lu d e d ai r y p r odu c ts , s he l lf is h , t r ee nu t s, a n d p e an u ts . c . S ki n a n d m o u th al l e rg e n s i nc lu d e t op ic a ll y ap p li e d d r ug s ( e .g . , p r o ca in e ) . d . I n t ra ve n o us a ll e r ge ns i nc lu de in s ec t v e n om s a n d d r ug s t h at ac t a s c ell o r pl a sm a p ro t ei n - bo u nd h a pt e ns (e . g ., pe n ic il li n , c ep h al os p or i ns ,
va c ci n es ) . Th es e d r ug s m a y c a us e t y p e II o r I I I h y p e r s e ns i ti vi t y r ea ct i ons in p e o pl e wh o d o n o t h y p e rs ec r e te I gE in r es po ns e t o t he s e dr u gs . 3 . Ac t i va t i o n o f ma s t ce l l an d b a so p h il se c r e t io n b y an al le r g en r eq ui re s t wo o r m or e re c e p to r - bou n d I g E m ol ec u le s t o b e c r os s -l in k ed b y a sp ec i fic a l le r g en . Ha p te n -s i z e d ru g s t ha t pr o vo k e th is r eac t io n b o th s e ns i ti z e th e i m m u ne s y s t em a n d t r ig ge r m a s t c e ll s wh e n t he dr u g i s b o un d t o a la r ge r m o le cu l e ( e .g . , a p r o te i n) . A c ti v a ti o n l ea ds t o a t ra n si e nt in c re as e i n t h e c yc li c a de n os in e m on o ph o s p h at e (c A MP ) l e v e l , fo l lo we d b y a n i nc r ea s e in t h e l e ve l o f c y c l ic gu a nos i ne m o no p ho sp h at e (c GMP ) r e l a t i v e to c A MP . T h i s i s fo ll o we d b y p h os ph o lip a s e C pr o du c i n g s e c o nd m e s s e ng e rs , wh ic h l e ad t o a r a pi d i nc r ea s e in c y to p la s m ic c a lc iu m i on s ( Ca c yt o pl as m i c Ca
++
++
) . W ith t h e i nc r ea s e in
, th e r e is im m e di a te f us io n o f v es ic l es c on t ai n in g
i n f la m m at o r y m e di a to r s wi t h t h e c el l m em b ra ne a n d re le as e o f th es e m e di a to r s i nt o t h e e xt r a c e l lu l a r m i li e u. I n a dd i ti o n, a f te r de g ra n ul a ti on , m as t c e ll s p r od uc e a dd i tio n al c yto ki n es , l eu k ot r ien e s, an d p r os t ag l an di n s. Th e s e a c ti v a t e t he la t e -ph a s e r es po ns e , wh i c h f ur t h e r a ct i va te s t h e l oc al i n f la m m at o r y r es po ns e . P r o l on g ed in c r e as es in cA MP l e ve l s in hi b it m a s t c e ll ac ti v a t io n . 4 . E f f ec t s o f m e d ia t o r s s e c r e te d f ro m m a s t c el ls a nd b as o ph i l s a . V as od i la t io n a nd in c rea s ed c a pi ll a r y pe r m e a bi lit y a r e c a us ed b y h i st am i ne ; th e l eu k o t r ie ne s C 4, D 4 , a nd E4 ; an d p r o st a gl an d in D 2 (P G D 2 ) s ec r e te d b y m as t c el ls . b . G a s t r oi n te s ti na l a n d re s pi r a to r y sm oo t h m u s c le co ns t r ic ti o n is c a us e d p r i m a r il y b y hi s ta m i ne , th e le uk o t ri en es C 4 , D 4 , a n d E4 ; P G D 2 ; a nd p l a te le t - ac ti v a t i ng fa c t o r s ec r e te d b y m a s t ce l ls an d ot h e r l eu k o c y te s . c . E os in op h il an d n eu t r op h il in f il t r at i on is c au s e d b y c he m o t ac ti c f ac t o rs s ec r e te d b y m as t c el ls . 5 . L oc a l s ym p t o m s o f pa t h o ge n es i s i nc lu d e i nf la m m a ti o n o f t h e u pp e r ( r h i ni t is ) a n d lo we r r e s p ir a t o r y t ra c t ( as t hm a) , gas t r oi n te s t i na l t r ac t , a n d s ki n . a . C om m o n c li ni c al s y m pt o m s in c l ud e u r t ic a ri a , p ru r i tu s (i tc h in g ), na s al c o ng es t io n , b r on c h oc o ns t r i c t i on , m uc us an d l ac h rym a l h y p e rs ec r e ti o n, l a r yn ge a l e de m a , v om i tin g , a n d d ia r r he a . b . S ym pt om s m a y b e c on f i ne d t o th e p o rt a l o f a lle r g en en t r y ( e .g . , r e s pi r at o r y al l er g en : re s p i r at o r y s ym p to m s ) or m a y b e m o re wi d es p r ea d a s a r es u lt of al l e rg en s p il l ov e r i n to th e c i rc ul a ti o n (e . g . , f oo d a ll e r ge n : g a st r o in t es ti n al , s k i n, r es p i ra t or y s y m p t om s ). c . At o p i c d e r ma t i t is t y pi c al l y in c l ud es s e ve r e p ru r i ti c d e rm a ti ti s , a nd m ay a l so in cl ud e rh i ni t is o r as t hm a , f oo d a l le r gi es , a n d c h a ng es in th e c e ll m e di a te d i m m un e s y s tem . d . Th e lo c a l i n tr o du c ti on o f al le r ge n s om e ti m e s le a ds to an a ph y l a xi s . e . A pp r o xi m a te l y 50 % o f p a ti e nt s wi t h as t hm a h yp e r se c re t e I g E. Th i s t e n de nc y i s p ro b ab l y c o nt r i bu t o r y, b u t a nc il l ar y, to t he un d e rl yi ng b ro nc h ia l h yp e r r ea c ti v i t y p re s e n t in t he s e pa t ie n ts (s e e C ha p t e r 4 8) . P.205
6 . S ys t e m i c a n ap h yl a c t i c ma n i fe s t at i o ns o f p at h o g en e si s . I n s en s i t i zed i n di vi d ua ls , i n t ra v e n ou s in j ec t io n o f a n a l le r ge n (e . g . , b ee v e no m ) o r a b so r p ti on ac r os s t he m u c ou s m em br a ne s ( e .g . , p e a nu ts ) c a n c a u s e s ys t em ic e d em a a nd h y po v o l em ic s h oc k , wi t h c a rd i ac a rr h y t hm ia , a s ph yxi a t i o n a s a re s u l t o f b ro nc h oc on st r ic t io n an d m uc o us h ype r s e cr e ti on , a n d u r t ic ar i a. D e at h u s ua l l y oc c u rs be ca u s e of as p h yxi a t i on . W hil e o t he r s e ns it i z e d i nd i v i du al s m a y h a v e on l y m il d l oc a l s ym p t om s u po n e n co u nt e ri n g t he al l e rg en , t he s e re s ul ts de m o ns tr a t e d i ff e r in g h os t r e s po ns es to id e nt ic a l p ro t e in s . 7 . T im e c o u rs e . I m m ed ia t e h y p e rs e ns it i v i t y re a ct i o ns h a ve t wo ph as es . Th e e a r l y r e a c t i o n, r es ul t in g f r om m e di a to r s e cr e ti o n b y m as t c el ls , b e gi ns wi t h i n 1 -2 m i n a ft e r a l le rg e n c on t ac t a n d p ea ks wi t h in 1- 2 h r . Th e l a t ep h a se r ea c t i on be gi n s 6- 1 2 hr a ft e r c on t ac t wi t h t h e a l le r ge n a n d l as ts for s e ve r al ho u rs . Th e l at e -p h as e re ac t io ns a re in i tia t e d b y ne wl y s yn t h es i ze d l e uk o t ri en es an d p r os t agl a nd i ns a l on g wi t h c y t ok in e s , ch em ok i ne s, an d o t h e r i nf la m m a to r y m e d ia t o rs . Th e l a te - ph as e rea c ti o n is ch a ra c te r i z ed by i n c re as ed nu m be rs o f e os i no p hi ls a n d i s m a i nt ai ne d b y th e p r od uc t s o f t h es e c el ls . 8 . D i ag n os i s . I n s c r a tc h t e s t s , a va ri e t y o f al le r ge n s a r e i nj ec t ed i n t ra d e rm al l y to s c r ee n fo r t he p re s e nc e o f a wh e a l an d f l ar e (i . e. , ed em a a n d e r yt h em a ) r es p on s e i n th e s k i n . R a d io a ll e r go s o r b en t ( R AS T ) a nd r a d i o im m un o so r b e n t ( RI S T ) as s a ys u s e r ad io l ab e le d re a ge n ts to de t ec t s e r um I g E c o nc en t ra t io ns . Th e re s u l ts o f th es e as s a ys do no t a l wa y s a g re e wi t h e ac h ot h er o r wi t h c l i ni c a l m an i fe s ta t io ns of t y p e I h y p e rs e ns it i vi t y. 9 . P r o ph yl a x i s a . I de n ti f y i ng an d a v o id in g al le r g en s is t he m os t i m po r t an t f o rm of p r o ph y l a xi s . b . H yp o s e n s i ti z at i o n ( de s e ns i t iz a ti o n ) is p er f o rm e d b y in j ec ti n g we e k l y, i n c re as in g d os e s o f a ll e rg e n i n t ra m u sc ul a rl y t o e li c it an al l er g en - s p ec i fi c I g G r es p on s e an d d ec r ea s e t he al l e rg en - s p ec i fi c I g E . On c e d es en si t i z at io n h a s b ee n a c h i e v ed , m on th l y i nj ec t io ns a re us ed to m a i nt a in th e Ig G le ve ls . I g G is ab l e t o b in d to th e a l le r ge n a n d i nh ib i t i ts bi n di n g t o t h e m a s t- c el l b o u nd Ig E . 1 0 . Th e r ap y a . C o mp e t it i ve H 1 - an t ago n is ts o f h is ta m i n e a r e us e fu l i n l oc a l f o rm s bu t do n o t c om pl e te l y r e v e rs e th e in f la m m at i on be ca us e h is t am in e i s n o t t he on ly i n f la m m at o r y m e di a to r in t h e r e ac ti o n. C om p et i ti v e H 1 - an t ag o ni s t s h a v e l i t tl e e f fe c t o n a na p h y la x i s . b . E p in e p h ri n e r e v e rs es a n ap h yl a xi s t h r ou g h i ts α - a g o ni s t an d β -a g on is t e f f ec ts . Pa t ie n ts wi t h s y s t em ic al le r gi e s a re gi v en e pi ne p h ri ne se l f a d m i ni s t ra ti o n k it s . β 2 - ag o ni s ts (e . g. , al bu t e ro l ) a r e ab le t o p ro m o t e b r o nc ho d il a ti on , an d α 1 -a g o ni s t s ( e .g . , p h en yl p rop a n ol am in e ) d ec r ea s e n a sa l c on g es ti o n.
c . C r om o l yn s o d i u m (c ro m og l y ca t e ) is a l oc al l y a d m i ni s te r ed in h ib i to r o f m as t c e ll de g ra n ul a ti on . G l u c o co r t i c oi d s a r e a ble t o b lo c k th e l a te ph as e o f t he re ac t io n b u t a r e l es s e f fe c ti v e du r in g t h e ea r l y p ha s e . An t i l e u k o t r ie n e t h e ra p ie s a re al so ab le t o b lo c k t h e l at e ph as e o f t h e r e a ct i on . d . T op i ca l s te r o id s i n hib i t i n fl am m a t io n a n d im m u ne r es po ns es . To pi c al a p pl ic a ti o n v i a s p ra y o r in h al e r l im i ts th e s id e e f fe c ts s e en wh e n g l uc oc o r ti c o id s a r e a dm in i s t e r ed s y s t em ic al l y. I n a d di t io n to us in g t o pi c a l s t e ro i ds a l on e , t he y a r e a l s o c om b in e d wi t h lo n g -a c ti n g β 2 - ag o ni st s a s t h e r ap y f o r as t hm a . e . An t i - I g E th e r ap y i s c o m po s e d o f a hi g h -a f fi n ity m o no cl o na l a n ti b od y t o t h e Fc re gi o n o f I g E . I t is ab l e t o b in d Ig E an d p re ve n t s e ns it i za ti on o f m as t c e ll s a nd ba s o p hi ls . Th is t h e ra p y is u s ef u l in hi g h l y a t op ic in d i v id ua ls a nd i s u se d fo r i n di v i d ua ls wi t h s e v e r e a st hm a fo r wh o m o t he r th e r ap ie s h a v e p r o ve n i ne f f ec ti v e . B . N o n - I gE - m ed i a te d t yp e I h yp e r s e n s i t i vi t y r e a c t i on s a r e p r ob a bl y t h e r e s ul t o f s e v e ra l p o o rl y un d e rs t oo d c au se s a nd a re s o m e t im es c a ll ed a n a ph yl a c t o i d r ea c t io ns . Th e fo ll o wi n g fa c t o rs m a y c o n t ri bu t e t o a n d e xa c e r b a te no n - Ig E -m e di a t ed t ype I re ac t io ns . 1 . R es pi r a to r y β 2 - r ec ep to r u nr es p on s i v e n es s , wh i c h l ea ds to a d im in i s h ed b r o nc ho d il a to r y e ff e c t of t h e s y m p a th e ti c n e r v ous s ys t em . 2 . H yp e r re ac t i v it y o f m as t c el ls th r ou g h H 2 - r ec ep to r u nr es p on s i v e n es s . Thi s d e c re as es th e n e ga t i v e fe e d ba c k o f hi s t am i ne on t h e a c t i v a ti o n o f m a s t c e ll s. P.206
C . T yp e I I h yp e r s e n s i t ivi t y r e a c t i o ns 1 . P a th o ge n es i s . A n ti b od y - m e di a te d c y t o to xi c i t y o cc u rs t hr o ug h t h e p r o du c ti on o f I g M a n d I gG . Th e s e a n ti bo d ie s a r e a b le t o b in d t o s pe ci f ic a l le r g en s l oc at e d o n c e l l s u rf a c e s . a . Th e s e al le r g en s m a y b e in t ri n s i c t o t he ce ll ( i.e . , na t ur a l ce l l -s ur f ac e c om p on e nt s ) o r e xt r i n s ic c om po u nd s ( i .e . , d r ug s ) a ds o r be d t o th e c el l s u r fa ce . b . C yt o t o xi c it y m a y r e s u lt f r om ac ti v a t io n o f c om pl e m e n t, ph a go c y t os is o f t h e Ig G op s o n i z ed c e ll , or b o th . c . A t h ir d c y t o to xi c m ec ha n is m , k n o wn as an t ib o dy- d e p en d en t , c el l m e di a te d c y t o to xi c i t y , inv o l v e s th e d i re c t k i ll i ng o f an t ib o d y -c o at e d ce l ls b y N K c el ls , m ac r o ph ag es , o r e os in op h il s . d . Typ e I I re ac t io ns m a y e xh i b i t an a ph y l ac t ic s ig ns an d s ym pt om s i f e n ou gh c om p le m e n t is ac t i v at e d; h o we v e r , t he y us u al l y do n ot p ro g re ss to t hi s s t ag e . 2 . C o mm o n a l le r g en s . Ty p e I I a ll e r ge ns a re di ver s e . I t i s t h e p at h og en ic m ec h an is m t h at is c om m o n to al l t h e r e ac ti o ns .
a . F or e ig n b lo o d s ur f ac e a n ti g en s m a y a c t as al ler g e ns to p ro d uc e t r a n s f us i on m is ma t c hes o r Rh d is e as e . b . D r ug al l e rg en s (o r d r ug m e t ab o li t e a ll e rg e ns ) ac t i n g a s h ap t en s a r e t h e l e a d in g c a us e o f he m o lyt i c a n e m i a. ( 1 ) Th e s e al le r g en s m a y d i r ec tl y a ds o r b t o c e l l s ur f a c e s a nd be sp ec i fi c a lly b o u nd b y a n ti b od ie s ( e . g. , p en ic il li n s , c e ph a lo s p or i n s , qu i ni di n e) . ( 2 ) A lt e r na t el y , t he y m a y f o rm s e r um - ph as e i m m un e c om p le xe s , wh i c h a d so r b n on s pe c i f ic al l y to b l oo d c el l s u rf ac es . Th is m a ke s t he c e ll s us c ep ti b le to l y s i s o wi ng t o t h e “ in n oc en t b ys t and e r ” e f f ec t ( e .g . , ri f am pin , s u lf o na m i d es , c hl o rp r om a z i n e ) . c . S el f - an t i ge n s a r e t he a l le r g en in c e r ta in a ut oim m u n e d is ea se s ( e .g . m ya s th e ni a g r a v is , a u to im m u n e h em ol y t ic a ne m ia ; se e I I I ) A u to im m u n e h e m o l yt ic a n em ia is s om e t im es as s o ci a te d wi t h ad m in is t r at io n of α m e th y l d op a , wh i c h i nd uc e s a u to a nt i bo d ie s a ga in s t t h e r ed bl o od c e ll s u r fa ce . d . H yp e r a c u t e re j ec t i o n o f t ra ns pl a nt e d t is s u e (se e V ) 3 . C h em i ca l m e di a t o rs . C o m pl em e nt p ro t ei ns p ro d uc e c y t o to xi c i t y a nd i n f la m m at i on , wh ic h s t im u l a te ma c r op h a ge s a n d g r a n u lo c yt e s t o s ec r e te c yt o ki ne s a n d e n z y m e s , wh i c h in tu r n e n ha nc e i nf l am m a t io n . 4 . C l in i ca l s ym p t o m s de p e nd on th e t y p e of an ti g en o r a ll e rg e n i n vol v e d ( s e e I I . D. 2 ) . H e m o l y t ic an e m i a a n d t h ro m b oc yt o pe n ia a re t he m a jo r c li n ica l s i gn s o f t y p e II h y pe r s e ns i ti v i t y r ea c ti on s . I n h ype r a cu t e g r af t re j ec ti o n, th e t r a ns p la n te d t is s u e d o es n o t s ucc es s fu ll y p e r fu s e b ec a us e o f a n ti b od y m e di a te d c y t o to xi c i t y t o t h e tr a ns pl a nt e d v a sc ul at u r e . 5 . T im e c o u rs e a . I n t he fi r s t s e ns i ti z a t io n to a d r ug al l er g en , the b lo od c e ll l y s i s a nd i n f la m m at i on be gi n 7 - 1 0 d a y s a f t e r in i ti a ti o n o f d ru g th e r ap y. Th e s ec o nd e xp o s u r e t o th e d r ug c a us es s ym p to m s wi t h in 3 da y s . b . T r an s f us i o n m is m at ch . H em o l ys is be g in s 1 - 2 h r a ft e r t r a ns fu si o n. P eak e f f ec ts oc c u r af t e r a pp r oxi m a t e l y 12 h r. +
c . R h d i se a se do es no t o c c u r i n t h e f i rs t Rh D p re g n an c y o f an R h D
-
m o th e r . Ma t e r n a l I g G i s p r o du c e d i n th e s ec on d a n d s ub s e q ue n t +
p r e gn a nc ie s a f te r t ra ns pla c en t al m a te r n al s e ns it i za t i on to t he R h D f e ta l r e d bl oo d c el ls . Th is s e ns i ti z a t io n u s u a ll y t ak es pl a ce in th e th i rd t ri m e s t er . Ma t e r n a l an t i- R h D Ig G c r o s s es t he pl ac en t a , b ind s to th e f e t al re d b l oo d c e ll s, an d a c ti v a t es th e fe t a l c o m p l em en t s y s te m p r e na t al l y, wh i c h le ad s to p e r in a ta l h em o l y ti c a nem i a. 6 . P r o ph yl a x i s a nd t he ra p y. I n d r ug - i nd uc ed h yp e r s e ns i ti v i t y r ea c t i on s, wi t h d r a wi n g th e d r ug us u a ll y r e ve rs e s t he l ys is . P r e ve n ti n g r ec o nt a ct is th e b e st p ro p h y la xi s . I n R h di s ea s e , a n ti - R h D i s a dm in i s t e r ed du r in g p r eg n an c y +
a n d wi t hi n 7 2 h r po s t p a rtu m fo r e a c h R h p r eg n anc y. Th e s i m p le s t e xp l a n a ti o n f o r t h e e ff ic ac y o f a n ti - R h D i s t h at th is pa s s i v e i m m un i z a ti o n ( s e e V I . B. 2 . d) bi n ds to fe t a l r e d bl o od ce ll s i n t he m a t e rn a l c i r c u la t io n a nd p r e ve n ts s en s i t i z a ti on o f t h e m at e rn a l im m u n e s ys t em .
D . T yp e I I I h yp e r s e n s i t ivi t y r e a c t i o ns in vo l ve the p e rs is te nc e o f im m u ne c om p le xe s i n t h e c i r c u la ti o n o r at lo c a l t is su e s i tes wh e n th e y a re no t r e m o ved af t e r p r od uc t ion o f s pe c i f ic a n ti b od ie s a n d a n ti g en - an t ib o d y c om p le xe s . Th e s u bt y p es o f t y p e I I I h y p e rs en s i t iv i t y r e a ct io n s h a ve d i v e rs e c a us es , a n d o nl y t he pa th o g en ic m ec h an is m is co m m o n t o t h em a l l. P.207
1 . P a th o ge n es i s . Im m une c o m p l e xe s ac ti v a t e c om p le m e n t, ca us e i n f la m m at i on , a n d i nd uc e p os it i v e c he m ot a xi s in n e u t ro ph i ls . P e rs is t en ce o f i m m u ne c om p le xe s m a y b e c a us ed b y th e f o ll o wi n g : a . A hi g h c o nc e n t ra t i on o f a nt i g en o r a n t ib o d y, wh i c h l e ad s t o a di s p a rit y i n th e m ol a r ra ti o of an t ig e n t o a n ti b od y a nd t he p r o du c ti on o f sm al l i m m u n e c om p le xe s . b . C h r o ni c fo r m a ti o n o f i m mu n e c o mp l ex e s i n th e c i rc u la t io n a s a re s u l t o f p e rs i s te n ce o f a n ti ge n as wi t h s om e c h ro ni c i n f ec ti o ns . c . O t he r fa c t o rs t ha t c aus e i ns o lu bl e i m m u ne c om p le xe s t o f o rm an d p r e ci pi t a te i n t ra v a s c ul a r ly o r o n b as em en t m em b ra n e s . 2 . C o mm o n a l le r g en s a . S el f - a n ti g en s in mo st n o n -o r g a n -s p ec i f ic ( rhe u m a t ol o gi c ) a ut o i mm un e d i s o r de r s (e . g. , s y s t em ic lu p us e r yt h em a to su s , rh e um a to i d a r th r it is ) b . B a ct e r i al o r p r o t oz oa n an t i g en s i n pe r s is t en t o r ch r o n ic i nf e c ti o ns a n d i n t h e i ni t ia l s ta g es o f v i r em ia fo r c e r ta i n v i ra l in f ec ti o ns (e . g. , p r o d ro m e of h ep a ti ti s B v i r u s i n fe c t i on ) . c . D r u gs ( e. g ., pe n ic il li n, s ul f on am id es , th i ou r ac il ) . d . An t i s e r a f r om an o th er s pe c i es ( e. g . , h or s e) , c a n c a us e s er um s i ck ne ss wh e n u s e d fo r p a s s i v e im m u n i z at i on . e . F un g al a nd ba c t e ri a l s p o r es in th e l oc a l r es pi r a to r y f o rm of t he re ac t io n 3 . C h em i ca l m e di a t o rs . C o m p l em e nt p r o te i ns c a u s e in f la m m at i on an d s t i m ul a t e m as t c e l l a nd b a so p h il se c r e t io n s, wh i ch en h an c e i n f la m m at i on . Th e i nc r eas e d v a sc u la r p e rm e ab il i ty a l l o ws i m m un e c om p le xe s t o l e a v e t he c i r c ul at i on an d a t t ac h t o ba s em en t m em b ra n es , wh i c h un d e rl a y th e e n dot h e li al li n in g o f b l oo d v es s e ls . Th e k id n e y g l om e ru l us a n d s m al l a r te r i es ar e p a r ti c u l ar l y s u sc e pt i bl e . C om p le m e n t a nd m as t c e ll pr o te i ns a t t r ac t n e ut r o ph il s ; t he s e c e ll s c a n p ha g oc yt i z e i m m un e c om p le xe s a nd r el e as e en z y m e s t h at da m a g e l oc a l ti s s ue , th us in t en si f yin g i n f la m m at i on . I n a d di t io n, p la t el e t a gg r e ga ti o n a nd m i c ro t h ro m b us fo r m a t io n m a y oc c u r . 4 . C l in i ca l s ym p t o m s de p e nd on th e s e ve ri t y and s y s t em ic o r l oc al na t u re o f im m u ne c o m p le x d e p os i ti o n a nd pe r s i s t e nc e. a . Th e fi r s t s y m p to m s of s y s t em ic re ac t io ns a re l ym p ha d en op a th y , s p le n om eg al y , f e v e r, and r as h . Th e s e a re c o m m o n in d ru g -i n du ce d a nd vi r e m ia - in d uc ed t y pe I II h y p e r s e ns i ti v i t y r ea c t i ons . b . Mo r e s e ri ou s s y m p t om s i nc lu d e va s c u li ti s a nd g lo m e r ul o ne p hr i ti s , b oth o f wh i c h m a y b ec om e n ec ro t i z i ng . Th es e s y m p t om s o f t en oc c u r wi t h s y st e m ic
l u pu s e r y t h em at os u s ( S LE ) . A r t hr a lg i a a nd ar t h ri ti s o cc u r i n b ot h s y s t em ic a n d l oc al r ea c ti on s . c . Th e m os t c om m o n t y pe s o f lo c a l t yp e II I h y p e rs e ns it i v i t y re a ct io n s a re p n e um on i ti s f r om i n ha led f un g i a nd ba c t e r ia to wh i c h th e p a ti e nt is o cc u pa t io n al l y e xp o s e d (e . g . , m o l d y h a y in f a rm er ' s l un g ) a n d r e ac ti o ns to s p o re s b o rn e i n a e ro s o l m ic r o dr o pl e ts f ro m d ir t y u l t ra s on ic hu m i di f ie r s ( e . g ., h um i d if i e r l u n g) . Th e c au se o f t he s e di s ea s es i s n o t c o m p l et e l y u n d er s to od , bu t b o th I g E a n d I g G a r e i n v o l v ed . IgE c au s e s t h e i ni t ia l i n f la m m at i on an d t r a pp ing o f a n ti ge n , a nd I g G i s r e s po ns ib l e f o r t he lo n g t e r m e f fe c t s . S y m pt om s in c lu d e ( 1 ) N as a l c o n ge s t i on and b r on c h oc o ns t ri c t i on ( 2 ) Jo in t pa in an d i n fl am m a ti o n o f r h eu m a t oi d a r th r i ti s c au s e d b y j oi n t l o ca li ze d i m m u ne c om p le xe s i n vo l vin g rh e um at o id f ac t or an d ne u tr o ph il p h a go c y to s i s ( s ee C ha p te r 4 9) 5 . T im e c o u rs e a . S ys t e m i c . I n p a ti en t s wi t h n o p r i or e xp o s ur e to t h e a ll e rg e n , t he s ym p to m s a p pe a r i n 1 - 2 we e k s (p o s s ib l y l o ng e r ) a f t e r e xp o s u re . In pa t ie nt s wi t h p r e e xi s ti n g a nt i bo die s , s y m p t om s a pp e ar wi t h i n s e ve ra l h ou r s t o 1 day a f t e r e xp o s u re . Se v e r e s y m p t om s , s u ch as g l om er u l on e ph r it is , us ua ll y r e q ui r e 2 we e k s o r m o r e t o ap p ea r . b . L oc a l. I n p at i en ts wi t h p r ee xi s t i ng an t ib od i es , h y p e rs e ns it i vi t y p n e um on i ti s s y m p t om s ap p e ar 6 -8 h r a f te r e xp o s u r e to th e a n ti g en . 6 . P r o ph yl a x i s a nd t he ra p y. I n d r ug - i nd uc ed r eac t io ns , w i t hd r aw i n g t h e d r u g us ua l l y re v e r s e s t he r e ac ti o n. Tr e a tm en t i nc l ud es an t ih is t am in es o r c o r ti co s te r oi ds . Tr a ns ie nt i nf e c t io u s f o rm s r es ol v e sp o nt a ne o us l y a s i m m u ne c om p le xe s a r e re m o v ed b y ph ag oc y t e s. E . T yp e I V h yp e r s e n s i t ivi t y r e a c t i o ns 1 . P a th o ge n es i s . Ty p e IV r e ac t io ns in cl u de pr o lon g e d in a pp r o pr i at e a n d a p p ro p r ia t e im m u n e r es po n s e s m ed ia t ed b y an t ige n - s p ec i fi c T H 1 c el ls i n c o nc e rt wi t h ac ti v a t ed m a c r op ha g es . P.208
Th e T H 1 c e ll s i nf il t r at e tis s u e s in wh i c h t he an t ige n is p r es e nt e d a nd r ec ru i t a n d a ct i v a te m a c ro ph a ge s . Th e r el e as e o f e n z ym es an d c yt o k i ne s b y t he s e c e ll s r es u lt s i n i nf l am m a ti o n a nd di s ru p ti o n o f t is s u e s t r uc t ur e i n th e a b se nc e o f an ti b od y . a . R ea c t i on s to in f e c ti on s in v o l ve a T H 1 r es p ons e a g ai ns t s p ec if ic i n t ra c el lu l ar ba c te r ia l (e .g . , My c ob ac t e ri a ) a nd p ro t o z o an pa r as i te s . W hen t h e re sp o ns e is p ro l on ged a nd in e ff ec t i v e , g r an ulo m a f o rm at i on wi l l o c c u r. b . C o n ta c t d e r ma t i t is is a n i n ap p ro p r ia t e s k in r ea c ti o n t o h ap t en s (e . g. , p e n ta d ec ac at ec h ol s o f po i s o n i v y) , wh i c h b in d to e p id e rm a l c e l l su r f ac es a n d e li c i t a C TL a nd T H 1 c el l re sp o ns e. c . Tu b e r cu l in r e ac t i on is ob s e r ve d i n th e d e rm is a n d is an ap p r op r ia t e r e a ct i on to m y c o ba c t e ri al a nt i ge ns . Th is re ac t io n i n di c a t es a s ta t e o f a c t i ve T H 1 i m m u ni t y ( o wi n g t o an ac t i v e i n fe c t i on ) o r T c e l l m em o r y t o th e
o r g an is m . ( I n p at i en ts wh o ha d a po s i t i ve t ub e rcu l i n r ea c ti on , a s u bs e que n t n e g at i ve re ac t io n wo u ld in d ic a te im m u no l og ic an er g y o r un r es po n si ve ne s s . ) 2 . C o mm o n a n ti g e ns a . I n fe c ti o u s a ge n t s i nc l u de My c o ba c te r iu m t ub er c u lo si s, M. l e p ra e , L i st e ri a m o no c y to g en es , t r yp a no so m e s , a nd v i r us es . b . H a p te n a l le r g e ns , s uc h a s p e nt a de c a ca t ec ho ls f ro m p oi s on i vy , p o is on o a k, ch r om a te s , ni c k el ion s (l e ac he d f r om wa t c h b a c k s a nd ot h er je we l r y ) , a c r yl at es , ha i r d y es t ha t c o nt a in p -p he n y l en e d i am i ne , p a r a- am i no b en zo ic a c id , a n d c e r t ai n a n ti b io ti c o i nt m e n ts (e . g ., t op ic al n eo m yc i n ), m a y i nd uc e c o n t ac t de r m a ti t i s. c . A nt ig e ns th a t i nd uc e a t u be r c u l in re ac t io n i nc l ud e pu r i fi ed p ro t ei n d e r i v a ti v e ( P P D ), t ub e rc u l in ( Ma n t o u x r e a c t io n ) , C a n d id a , m u m p s , a nd oth e r a n t ig en s f r om m i c r o o rg an i s m s . 3 . C h em i ca l m e di a t o rs a r e i m po r ta n t i n t yp e I V r e a c t i on s . Th e s e m e di a to r s a r e c yt o k i ne s p r od uc e d b y a c ti v a t ed T H 1 c e ll s . Th e c y t o ki n es a t t ra c t a nd a c ti va t e m ac r op ha g es to t h e s it e (s ) wh e r e t h e p at h o ge n /a ll e r ge n i s l oc at ed . I n t ur n , t h e ac t i v a te d m ac r o ph ag e s s e c re t e c y t ok in e s , wh i c h a re r es po ns i bl e f o r in f la m m at i on an d c y to t o xi c i t y (e . g ., TN F - α ) . 4 . C l in i ca l s ym p t o m s de p e nd on th e s ub t y p e o f r e a ct i on . a . G r a nu lo m a s a r e l oc al a g g re g at i on s o f T H 1 c el ls , m ac r o ph ag es , an d g ian t e p i th el i oi d c el ls ( de r i v ed f r om f us io n o f a c ti va t ed m ac r o ph a ge s ) . Th e y oc cu r a t si t es o f c h ro n ic i n fe c tio n an d s e r v e t o r e s t r ic t th e s p r ea d o f th e i n fe c t i on . b . I n co n ta c t s e ns i ti v i t y , c e ll ul a r i n fi l tr a ti o n o f t h e e p id e rm is b y C TL , T H 1 c e ll s, an d m ac r op h ag es p r o du c e s m ic r o ves ic le for m a ti o n wi t h sp on g io s i s . c . Tu b er c ul in te s ts c au s e e r y t he m a an d i n du r a ti on as a r e su lt o f ce l lu la r i n f il t ra t io n o f th e d e rm is , b u t n o e pi d e rm al s p on gi o s is i s o bs e r v ed . 5 . T im e c o u rs e a . G r a nu lo m a s f o rm at v a r i ou s t im es af t e r t h e o ns e t o f a c h r on ic im m u ne r e s po ns e b u t g en e ra l l y re q ui r e a m i ni m u m o f 2 we e ks . b . C o nt ac t s e ns it i v i t y m ay n o t occ u r wi t h t h e f i rs t t r a ns i en t e xp o s u r e. H o we ve r , i n a s e ns i ti z e d i n di v i du a l, sk in in f la m m a t i on wi l l a pp e a r 1 2 -2 4 hr a f t e r co n ta c t wi t h t he an ti g en an d pe ak s b et we e n 4 8 an d 7 2 h r af t e r e xp o s u r e . c . Tu b er c ul in r ea c t i on s fo l lo w t h e s am e ti m e c o u rs e a s c on t ac t s en s i t i vit y . Th i s r ea c t i on is o f t en c a ll e d d e la ye d c u t a ne o us h yp e r s e n s i t i vi t y, o r d e la ye d - t y pe h y p er s en s it i v i t y . 6 . P r o ph yl a x i s a nd t he ra p y. Tr e a t m e n t o f g r an ulo m as d e pe n ds o n th e o r g an is m i n v ol v e d . Pr o pe r t r ea tm e nt t o r es ol ve th e in f ec ti o n wi l l al so ai d i n r e s ol vi ng t he c h r on ic i m m u ne r es po ns e . F o r c on ta c t s en s i t i vit y , i t is n e ce ss a r y to id en t i f y t h e a n ti g en / al le r g en in v o l v ed . R em o va l a nd a v oi da nc e o f t he al le r g en i s i m p o r ta n t fo r p r o ph y l a xi s . Fo r tr e a tm e nt , to pi ca l c o r ti co s te r oi ds s u pp r es s T c e ll an d m ac r op h ag e fu n c t i on . In s e v e r e c a se s , o r a l c or t ic os t e ro id t he r ap y m a y be r eq ui r e d.
III. Autoimmunity
i s a ti ss u e- d am ag i ng im m u ne r es po ns e d i re c te d s p ec i f ic a ll y a nd i n ap p r op r ia t el y a ga i ns t on e o r m o r e s el f - an ti g en s . A. Th e o r i g i n of au t o re ac t i v e i m m un e r e s p on s e s i s n o t g en e r al l y k n o wn , bu t i t r eq ui r es lo s s of s e l f- t ol e r an c e an d d e r eg ul a ti o n o f th e c on t r ol ne t wo r ks t h a t n o rm al l y p re v e n t d ev e l o pm e nt of au t oi m m u ne d is ea s e . Su c h d e r eg u la t io n m a y i nc l ude l ac k o f r eg u la t io n o f T H a n d T C c e ll s , P.209
c r os s - re ac t i v it y wi t h a nt ig e ns f ro m m i c ro o r ga ni s m s , l os s o f se l f -t o le r an ce o r f a i lu r e t o d e v e lo p t ol e r an c e, an d a b e r ra n t p re s en t a ti o n o f s el f -a n ti g en on s p ec if ic H L A m ol ec ul e s . B . E p i de m io l o g y 1 . F am i li a l c l us t e r in g i s e v i d en t fo r m an y , i f n o t m os t , a u to im m u n e r e a ct i on s r e pr es e nt i ng a c om p le x i n h e ri t ed p re d is p o si t io n t o wa r d a u t oi m m un i t y . I n m os t c a s es , t h is p r e di s p os i ti on i s a s s oc ia t ed wi t h s p ec if i c MH C t yp e s , u s u a ll y c l as s I I m o l ec ul es ( e. g . , r heu m at o id a rt h ri t is wi t h t h e MH C c l as s I I m ol ec u le HL A - D R 4 ) . 2 . Th e se re a c t io n s a re m o r e c om m o n i n wo m e n . Th e fe m a l e -t o -m al e ra t io in m ya s th e ni a g r a v is i s a ppr o xi m a t e l y 2 : 1 a nd in S LE i s a pp r o xi m a te l y 10 : 1. I n c o nt r as t , Sj ög r e n 's di s e as e a n d G o o dp as t u re s y nd r o m e ar e m o re c o m m on i n m e n t ha n i n wo m en . C . P a t h og e ne s is 1 . O ve r vi ew .
In a specific autoimmune disorder, the primary pathogenic
mechanism may be humoral (mediated by antibodies with or without a contribution by complement), T cell mediated, or involve both humoral and cell-mediated components. These diseases are commonly associated with exacerbation and remission of the disease. 2 . E n vi r o nm e n ta l fa c t o rs a r e t ho u gh t t o c o nt r ib ut e t o p at h og en e s i s . H o we ve r , s p ec if ic as s o c ia t i on s h a v e b ee n fo un d in o nl y a fe w c as e s; th es e i n cl ud e S tr e pt o c o c c us g ro u p A p ha r y n gi t is , rh eum a ti c f e ve r , e xp o s u re to o r g an ic s o l v en t s , G o od pa s tu r e s y n d ro m e , ul t ra v io l e t i r ra d ia t io n , a nd S LE. I t i s l ik e l y t h a t e n v ir o nm ent a l f a c t o rs ac t i n c on ce r t wi t h g en e ti c p r e di sp os i ti o n t o i nd uc e d i s e as e . 3 . O r g a n -s pe c i f ic an d sys t e m i c ( n o n -o r g an - s pe c i f ic ) di s o r de r s a . O r g a n -s pe c i f ic di s o rd e r s (e . g ., an t it h yr o id au t o im m u ni t y ) a re li m i t ed t o a n d d i re c te d s pe c i f ic al l y a g ai n s t s e lf - a nt i ge n i n a s i ng le o rg a n. Le si o ns a nd c l in ic al s ym p to m s a re lim i te d p r im a ri l y t o t ha t o rg a n . C e ll ul a r d am a ge m ay b e m e di a te d t h r ou gh an t ib o d y- m e di a te d a n d c om pl e m e n t -m ed ia t ed c yt o t o xi c it y ( t y p e I I h y per s e ns it i v i t y ) a n d/ o r t h r oug h c e ll - m e di a te d c yt o t o xi c it y ( t y p e I V h y pe r s en s i t i v it y) . b . S ys t e m i c d i s o rd e r s (e . g . , S L E ) ( 1 ) Th e s e di s o r de r s a r e a l s o k n o wn as c o nn ec t i ve t is su e , co l la ge n vas c u la r , o r r he um a to l og ic di s o r d er s . Au t oa n ti b od ie s a r e f or m e d a ga in s t a nt i ge ns
f o u nd in m os t or al l ti s s ue s , e s p ec i al l y th os e l oc at e d i n t h e n uc le i o f c e ll s a n d c on t ai n in g D N A, R NA , o r n uc l ea r - as so c i a te d p r o te i ns (a n t in u cl e a r a n t i bo d i es ) . Pa t ho lo g ic c h an g es o c c u r s y s te m a t ic a ll y , p ri m a r i l y i n t he c o nn ec t i v e t is s u e a n d a re a t l ea s t p ar t ia l l y c au s ed b y t y p e I I I h yp e r se ns i ti v i t y r ea c t i ons . S y m p t om s m a y b e s een i n t he bl o od v es s el s , k i dn e y gl om e ru l i, s k in , j oi n ts , an d s er o us m em b r an e s . ( 2 ) N o n- o r ga n -s pe c i f ic dis o r de r s a re so m e t im es di f f ic ul t to di st i ng ui s h f rom o n e a n ot h er be c au s e of th e s im i la r it i es i n a u to a nti g en s a n d p at h og en e s i s . F o r e xa m pl e , m o s t p at i en t s wi t h S L E h a v e c i rc ula t i ng an t in uc le a r a n t ib od i es ; h o we v e r , th es e a ls o o c c u r i n 5 0 -6 5 % o f pa t ie n ts wi t h Sj ö gr e n 's s yn d r om e a nd r he um a to id a r th r i ti s as we l l a s i n a s m a ll pe r c e n ta g e o f c l in ic al l y no r m a l i n di v i dua l s . B y co n t ra s t , rh e um at o i d f ac t or ( an t i -I g G ) i s s e en in 75 - 90 % o f pa t ie nt s wi t h rh e um at o id ar t h rit i s o r Sj ö gr e n 's s ynd r om e a s we l l as in 35 % o f pa t ie n ts wi t h S L E. Th e s y n ov i t i s o f rh eu m a t oi d a r t h rit i s i s o f t en a c l i ni c a l f in d in g i n SL E , a n d t he v a sc ul i ti s o f SL E is fo u nd in r h e um a to id a rt h r it is (s e e C h a pt e r 4 9 ) . D . O r g a n - sp e ci f i c a u to im m u ni t i es 1 . R h eu m at i c f e ve r is no t t ec hn ic al l y an au t oi m m u ne r es po ns e b ec a us e a n t ib od i es ar e p r o du c e d a g ai n s t g ro up A s t r ep t oco c c i a n d c ro ss - r ea c t wi t h c a r di ac m us c l e fi be r s t ha t a re da m a g ed b y c om pl e m e n t. I nc re a se d r is k i s r e l at e d t o a s t r on g i m m un e r es po ns e t o s t r ep t oc oc c a l M a n t ig en . 2 . An t i t h yr o i d a u t o im mu n i t i es (s ee C h ap t er 5 2). A s pe c t s o f s e v e ra l s u bt yp e s m a y o c c ur in t he s a m e pa t ie n t . I nc r ea s ed r is k is as so c i a te d wi t h MH C c l as s I I t y pe s D R 3 a n d D R5 . a . P r i ma r y a u t o i m mu n e m yx e d e m a . A n ti b od ie s a g ai n s t th e th yr o id s t im ul a ti n g h o rm on e ( TS H ) r e c e p to r on th y r o i d f ol l i c le ce ll s a c t as a n t ag o ni s t s t o t h e s ti m u la t i on of g ro wt h o f t h e f oll i c l e c el ls no rm a ll y p r o vo k e d b y TS H . Th e r es u lt is th yr o id a tr o ph y wi t h h y po t h y r oi d is m . P.210
b . H a sh i mo t o 's t h yr o i d i t i s . An t ib o di es ag ai n s t th yr o i d p e ro xi d a s e o n f o l li cl e c el ls c a us e c y t oto xi c i t y a nd in f la m m a ti on t h r o ug h t h e ac t i v a ti on o f c om p le m e n t. A n ti bo d ie s a g ai n s t th y r o g lo bu l in (c ol l o i d ) a ls o m a y be pr es en t . C e l l -m ed i at e d im m u n it y m a y c a us e s om e c y t o to x i c d am a ge . Th e r e su lt i ng h yp o t h yr oi di s m is tr e at ed wi t h s ynt h et ic t h y r oi d h o r m o ne . c . G r a ve ' s d is e as e . A n tib o di e s ac t a s a g on is ts of TS H , b i n di ng to t he TS H r e c ep t or a nd s t im ul a ti ng h y p e r s e c re t io n o f t h y r o id h o rm o ne ( th y r o id s t im ul a ti n g im m u n og lo b ul i ns ) . Th e r es u lt is h yp e rt h y r o i di sm , wh i c h i s t r e a te d b y a n ti th y r o i d d ru g s ( e .g . , p r op y l t hi o u ra c i l ) o r th yr o i d a bl a ti on wi t h s u r ge r y o r r a di a ti o n. 3 . M ya s t h e n i a g r a vi s a . P a th o ge n es i s . A n ti b od i es ag ai n s t th e n ic o ti n ic a ce t y l c h ol i ne r ec ep t o r on s ke l et a l m u s c le pl a s m a m em b r an e a t n e u ro m u s cu l a r j u n c ti on s a ct as c om p et i ti v e an t ag o ni s t s o f ac e t yl c h o l i n e bi n di ng. Th i s a c t i v i t y c a us es
we a k n es s a n d f at i gu e i n s k e l et a l m u s c le s . I n a dd it i o n t o t hi s d i re c t b l oc ka g e o f n eu r om us c u la r t r an sm is s i on , d o wn r eg u la t io n o f r ec ep t or s a nd c om p le m e n t d am ag e to m us c l e fi be r s o c c u r. Ma n y p a ti e nt s h a v e s wa l l o wi n g a n d re sp i ra t o r y m us c l e dy s f u nc t io n t h at m a y b e ca u s e d b y p en ic i ll am in e t h e r ap y. In c re as e d r is k is as s o c i a te d wi t h MH C c l a s s I t yp e B 8 . b . T he r a p y. A n t i c h ol in es t e r as e t h e ra p y ( e. g ., n eos t ig m i n e ) in c re as e s a c et yl ch o li n e s y na p ti c c o n c e n t ra t io ns ( pr es e r va tio n of en d og e no us a c et yl ch o li n e) . Im m u no s u p p re s s io n wi t h c o rt ic os te r o id s i s us e d i n s e v e r e c as e s; pl as m a p he r es is to r em o ve a u to r e ac ti v e an t i bo di es f r om t h e b lo o d i s a l so he lp f ul . Th y m ec t om y h e l ps m an y p a ti e nt s. 4 . Au t o i m mu n e p e r ni c io u s a n em i a a . P a th o ge n es i s . A n ti b od i es ag ai n s t in t r in s i c f ac t o r a re s ec r e te d i n to th e s t om ac h l um e n, wh e r e t he y i n hi bi t th e a s s oc ia t io n o f i n t ri ns ic f ac to r wi t h vi t a m i n B 1 2 . Th us th e a bs o r pt i on of v i ta m i n B 1 2 is d ec r e as ed . Th is c o nd i tio n a l so c a n r es u lt f ro m a n tib o di e s a ga in s t g as t ri n rec e pt o rs on pa r i et al ce ll s o f t h e s t om ac h m u c o s a t ha t b l oc k st im u la t io n o f t h e c e ll s b y ga s t ri n a nd d e c re as e t h ei r s ec r e ti on o f in t r in s i c f ac t or . b . T he r a p y i s i n t ra m u s c u l a r i nj ec t io n o f c ya n oc ob a la m i n o r o ra l a d m i ni s t ra ti o n o f c on c e nt r a t ed in t r in si c f ac t or p rep a r a ti on s . 5 . G o o dp a st u r e 's s yn d r o m e a . P a th o ge n es i s . A n ti b od i es ag ai n s t g lo m e ru l a r c a p i ll a r y b a s e m e n t m e m b ra n e ( G B M ) a c ti v at e c o m p le m e n t a n d n eu t ro p hi l -m e di a te d d am a ge . Th i s ac t i v at i on l e ad s t o g l om e ru l on e ph r it is , wi t h r a p id de t e ri o ra t io n o f re na l f u nc t io n . Th es e a nt i bo die s c r os s - r e ac t wi t h p ul m o n a r y c a pi ll a r y ba se m e nt m em b r an e , p r od uc in g p ul m on a r y he m o r r ha g e i n s m ok e rs . In c re as e d r is k is a ss o ci at e d wi t h MH C c l as s I I t y pe D R 2 . b . T he r a p y. I m m u no s u pp r e s s i v e t he r a p y i nc l ud es co r ti c os te r oi ds , wi t h p l as m a p he r es is to r em o ve a ut o r ea ct i v e a n ti b od ies . 6 . Au t o i m mu n e h em o l yt i c a ne m ia ( r ed b lo o d c el l ) , t h ro m bo c yt o p e n i a ( p l a t el e t ), n eu t r o pe n i a ( n e u t r op h i l ), an d l ym p h o p e n ia ( l ym p h o c yt e ) a . P a th o ge n es i s . A n ti b od i es ag ai n s t m em b r an e a n t ig en s o f o n e o r m o re o f t h e i n di c a t ed c e ll t y pe s m a y ac t i v at e c om pl em e nt a nd op so n i ze t h e c e ll s f o r r a p id sp le n ic p h ag oc y t o s i s . I t m a y al s o oc c u r a s p a r t o f th e s pe c t r um o f a u t oi m m un i t y i n n o n -o r ga n - s p ec i fi c d is o rd e rs , p ar t i c u la r l y S L E. Th e s e a u t oi m m un e v a ri e ti es m us t be di s t i ng ui s h e d f r om t h os e p r ec i pi t at e d b y r e s po ns es to e xt e r n al ant i g en s ( e .g . , d r ug s ) b ut th e c l in ic al e ff ec t s a re s im i la r . b . T he r a p y. Th e s e d is o rd e r s a re o ft e n ac u te an d s el f - li m i t in g , b ut th e r apy i s re q ui r ed wh e n th e y are c h r o ni c. In a du lt s , t r eat m en t be gi ns wi t h c o r ti co s te r oi ds . Ad d it i ona l op t io ns a re c y c lo p ho s p h am i de , c hl o ra m b u ci l, a n d i n t ra ve n ou s i m m un e g lo bu l in ( I V I G ). 7 . I ns u l in - d ep e nd e n t d ia b e t es me l li t u s ( I D D M; s e e C h ap t e r 5 1 ). P r o g r ess i v e a n d u lt im a tel y c om pl e te de s t ru c t i on o f pa nc r e at ic B - is le t c el ls o cc u rs in di a be t es . Al th ou g h t h e y a r e p r e di ct i v e l y u s e f ul , an t ib od i es a g ai ns t i n su li n a n d s ur f ac e c y t opl a s m ic a n ti g en s o f t h e B -i s le t c el l a r e p r es en t
b e f o re c l in ic al on s e t . The m a i n c y t ot o xi c m e ch a ni s m s a pp e a r t o b e m e di a te d b y T c e ll s a nd m ac r o ph a ge s . Th is vi e w i s s up p o rt e d b y t he b e n ef ic ia l e f f ec ts of c yc lo s po r in e th e ra p y in pa t ien t s wi t h e a rl y - s ta ge I D DM a t le ve ls t ha t h a v e l i tt l e e f f ec t o n a n ti b od y p r od uc t io n . I nc r ea s ed ri s k is a ss o ci at e d wi t h MH C c l as s I I t y pe s D R 3 an d D R4, a nd D Q 2 an d D Q 8. 8 . M u l t ip l e s c le r o si s (M S ) a . P a th o ge n es i s . T c el ls a n d m a c ro p ha g es , wh i ch a r e t ho u gh t t o be c yt o ci da l fo r o l ig o de nd r oc y t e s , in f il t r at e t h e c en t ra l ne r v o us s ys t em ( C N S ) a n d a t t ac k th e b a si c p ro t e i n o f P.211 m ye l i n a s a n a u to a nt i gen . Th e i m m u no lo g ic c om p o n en t m a y be s ec o nd a ry t o o th e r, un k no wn i ni t ia t in g ag e nt s. C N S de m ye l i n a t i on w i t h s c le r o t ic p l a q ue s l ea d s t o s p a s t ic i t y . I nc r ea se d ri sk i s a s so c ia t ed wi t h MH C c l as s II t yp e D R 2 . Gu i ll ai n - Ba r r é s y n d ro m e is a r el a te d co n di t io n th a t i n v ol v e s p e r ip h e ra l n e r v ou s s y s tem ( P N S ) d em y e l in a ti on th a t , u nl ik e MS , c an be a c ut e . b . T he r a p y. S p a s t ic i t y i s t r e at e d wi t h b ac l o fe n wi t h va ri a bl e e f fe ct i v e ne ss . Th e p e ri p he r al s k el e ta l m us c l e re l a xa n t da n t r ole n e i s e f fe ct i ve i n s om e p a t ie n ts . Ad r e n oc o r t ic ot r o p i c h o r m on e ( AC T H ), r a th e r t h an c o r ti co s te r oi ds , i s t h e f av o r e d im m u no s u p pr es s i ve t he r a p y . R e c o m b i na n t I F N - β - 1 b ( B e ta s e r o n) , IFN - β - 1 a , a n d g la t ir am e r ac e ta t e a r e a pp r o ve d b y th e U . S . F oo d a n d D r u g A dm i n is t ra t io n (F D A ) as a t r ea t m e n t f o r MS . E . N o n - o rg a n -s p ec i f ic au t o i mm u n it i es . Th e s im il a r it i es a n d d if f e re nc es in t h is cl as s o f d is o rd e rs a re s h o wn b y a c om pa r is on o f S j ög r en ' s s y n d r om e a n d SL E . Rh e um at o id a rt h r i ti s is di sc us s e d i n Cha p t e r 4 8. 1 . S j ög r e n 's s yn d r o m e a . D i ag n os i s i s us u al l y b a s e d o n l y m ph oc yt i c i nfi l t ra t io n a n d t he p re s e nc e o f au t oa n ti b od i es a g ai ns t s al i v a r y g l an d a n ti g en s a n d e xo c r i ne gl an d s o f t h e e ye s , g as t ro i nt es t in al a nd r es pi r at o r y s ys t em s , an d v ag in a . H yp e r g am m a g lo bu l in em ia ( 5 0% ) a s a r es ul t o f h y p e r ac t i v e B c e ll s , a n t in uc le a r a n ti b od ie s (50 - 6 5% ) , a n d r h eu m a t oi d f a c to r s ( an t i -I g G ; 7 5 - 90% ) a r e pr es e n t in t he in di c at e d p e rc e nt a ge s o f p a ti en t s . b . P a th o g en e si s . P r im a ry s y m p to m s in c l ud e in h ib i t i o n o f e x oc r i n e g la nd s e c r e ti o n , wi t h d r y ne s s o f t he e y es , m ou t h, an d g a st r o in t es ti n al , r e s pi r at o r y , an d v ag in a l m uc o us m em b ra n es ; a n d p a in an d e d em a i n t he s a li va r y g la nd s . P a ti e nt s wi t h h yp e rg am m a g lo b ul in e m i a o f te n h a ve t y pe I II h yp e r se ns i ti v i t y r ea c t i ons ( e. g . , va s c ul i ti s wi t h CN S i n v o l v em en t a n d k id ne y d i se as e ; s ee II . D ) . c . Th e r a p y. Mi l d c as es ar e t r ea t ed wi t h a r t i f ic i a l t e a r s a n d f r eq ue n t d r i nk in g o f wa t e r . F o r m o r e s e ri o us c as es ( e. g . , v a s c ul it is ) , tr e a tm en t i s s im i la r to th a t f o r S L E (sys t e m i c c o r t ic o s te r o i ds ) . 2 . S L E ( S ys t e m i c Lu p us E r yt h e m a t o s us ) a . D i ag n os i s i s c o m p l ic a t e d a nd de p en ds on th e p r es e nc e o f 4 or m o r e of 1 1 c r i te r ia . Th e m os t u s ef u l c r it e ri o n i s a h ig h c o nc e nt r a ti o n o f a nt i nu c l e ar
a n t ib od i es di r ec te d a g ain s t d ou b le - s t r a nd ed D NA a n d t he Sm i th ( Sm ) n u cl e ar an t ig e n, bo t h o f wh i c h a re c o ns id e re d s pe c i f ic f or S L E. O t he r d i ag n os ti c c r it e ri a i nc l ude t he p re se nc e o f th e l up u s e r y t he m a t os us c e ll (a n e u t ro ph i l t ha t ha s p ha go c y t os e d n uc le i ); a d is c oi d er yt h em a to us f ac ia l r a s h; ph o to s e ns i ti v i t y ; o ra l ul c e r s ; a rt h ri t is ; p e rs is t en t pr o te i nu r ia ; an d a n t ic a rd io l ip in , an t ie r y t hr o c y t e , o r a n ti le uk oc y t e a n t ib od i es . b . P a th o g en e si s i s t ha t o f t yp e I I I h yp e r s e n s i t i vi t y. P a t i e n ts ha ve h yp e r a c t i vi t y o f B c e l l s o f un k n o wn o ri g in . Th is h yp e r r ea c ti vi t y c a us es h yp e r ga m m a gl ob u li ne m ia , wi t h c i rc ul a ti n g im m u ne c o m p l e xe s of D N A an d o t h e r n uc le a r a nt i ge ns th a t p r ec i pi t at e o n to v a sc u l a r b as em en t m em b r ane s a n d a ct i v a te c o m p l em en t. ( 1 ) Mi l d a rt h r it is , fe v e r , ra s h, an d fa t ig ue oc c u r . ( 2 ) P r og r es s i v e ne c ro t i z in g v as c ul it is wi t h C N S i nv o l v e m en t a n d g l om e ru l on e ph r it is a re the m o s t s e r i ou s c o ns e qu en c e s , o cc u r ri ng in a p p ro xi m a t el y 5 0% o f p at i e nt s . ( 3 ) H yp e r te ns io n m a y dev e l o p s ec on d a r y t o k id n ey d i se a s e . ( 4 ) H em o l y ti c a ne m i a a nd t h ro m b oc y t o pe n ia a re c om m o n . ( 5 ) B eh a vi o ra l c ha ng e s o c c u r i n a p p ro xi m a t el y 25 % of p a t ie n ts . ( 6 ) S e ve ra l d r ug s (e . g. , p r o c a in a mi d e, h yd r a l a z i n e , q u i ni d i ne , m e t h yl d o p a , i s on i az i d , p h e n yt o i n , c h l o r p r om az i n e) p ro vo k e a l up us - l ik e s yn d r om e t ha t us ua ll y r es o l v es wh e n t h e d r ug i s wi t h d r a wn . Th e ba si s f o r t h is s ynd r om e i s n ot un de r s to o d. N o r e na l d is o rde r oc cu r s i n d r ug - in d uc ed SLE. c . Th e r a p y. Mi l d d is ea s e ( e . g. , lo w- g r a d e f e v e r, ar t h r i ti s) is m a na ge d wi t h n o ns t e ro id a l a nt i -i n fl am m a to r y d r ug s ( N S A I D s) . Th e r a p y f o r p at i en ts wi t h s e ve r e s y m p t om s is us ua l l y or a l m e t h y l pr e dn is o lo n e . C yc l op ho s p h am id e m a y al s o be us e d, an d pl a s m ap h er e si s t o r em o ve c i rc ul a ti n g im m u n e c om p le xe s m a y b e h e lp fu l . F . P r o sp e c ts f o r m o r e sp e c i fi c im mu n o lo g i c t he r a p ie s . Cu r r en t th e ra p ie s i n vo l ve a p pr o ac he s t h at s u pp r es s a ll im m u ne r es p o ns es ; ho we v e r , cu r r ent c l in ic al t ri a ls s ee k t o s upp r e s s o n l y l ym ph oc yt e s th a t a r e a c t i v a t ed — fo r e xa m p l e : 1 . F ee d in g a u t oa n t i ge ns t o p a ti en t s t o i nd uc e im m u n ol o gi c su p pr e s s io n 2 . V ac c in a t io n w i t h a u to r e a c ti ve T c e l ls to in du c e im m u n ol o gi c s u pp r es s i o n P.212
3 . A dm in is t r at i on of an t i- T H m o n oc lo n al an t ib od ie s (p a r ti cu la r l y an t i - C D4) t o e l im in a te au t o re ac t i v e T c e ll s 4 . A dm in is t r at i on of co n ju g a t es o f I L -2 a nd t ox in s f ro m p la n ts or b ac te r ia t o el im i na t e a ut o re a c t i v e T c e ll s wi t ho u t g en e r al iz e d T c e ll s u pp r es s i on
IV. Immunodeficiency
i s e i th e r p r im a r y o r s e c on d a r y . P r im a r y i m m u n od e f i ci e nc i es a re ei t he r h e r e d it a r y o r c o n ge n i tal , a nd at le as t o n e e le m en t ba s i c t o t h e im m un e s ys t em d o es no t f u nc ti o n p r o pe r l y o r is a b se n t. Se c o nd a r y i m m un o d ef i c ie n ci e s a re t he r e su l t o f an o t he r s ys t e m i c di so r d er o r a r e i a t r o ge n i c i n p a t ie n t s gi ve n i mm u n os u p p re s sive t h e r a p y. Th e y u s ua l ly d e ve l op i n pa ti e n ts wh o p r e v i ou s l y s ho we d n o rm a l im m u ne fu nc t io n . Th e e xp e c t e d c li ni c a l o u tc om e o f a n i m m un od e fi c i e ncy i s go v e r ne d b y t h e s p ec if ic po r t io n o f th e i m m u ne s y s t em th a t is a ff ec t ed ( e. g . , B an d T c e ll s , p h a go c y ti c c el ls , a n d c om p le m e n t ). A. P r i m a r y i m m u n o d e fic i e nc i es a re , wi t h o n e exc e p t i o n, r a re . E xa m pl es a r e th e f o ll o wi n g : 1 . X - li n ke d ag a mm a gl ob u l i ne m ia ( h ypo g am m a gl o bu l in em i a) is an in he r i te d d e f ic ie nc y i n a nt i bo d y p ro d uc t io n (h um o ra l i m m un i t y ) in wh i c h T c el l f u nc t io n i s r e la t i v el y n o rm a l, bu t B c el ls do no t fu l l y m a tu r e b ec a us e o f a f a i lu r e o f B c e l l s i g na li n g. S e r um i m m un o gl o bu li n l e v e ls a re lo w. B e c a us e t h is di so r d er is li nk ed t o t h e X c hr om o so m e , i t o cc u rs p ri m a r il y i n m e n . a . P a th o ge n es i s o c c u rs 6 - 9 m o nt hs a ft e r b i rt h a nd r e pr es e n ts s it u at i on s in wh i c h an t ib o d y fu nc t io n is de f ic ie n t b u t T- c e ll fu nc t io n i s i n ta ct , s uc h a s r e c ur r e nt in f ec ti o ns wi t h e xt r a c e l lu la r p y og e ni c ba c te r i a ( e .g . , s t re p to c o cc i , p n e um oc oc c i , Ha e m o ph ilu s ) . I m m un i t y to fu n gi and m o s t vi r us es is g e n er a ll y f un c ti on a l. b . C l i ni c al s ym p t o m s i nc l ud e p n eu m o ni a , s in us i ti s , o ti t is , m en i ng i ti s , an d s e pt ic em i a. c . Th e r a p y i s p a ss i ve im m u ni z a t i o n w i t h h u man i n t r a ve no u s i m m un o g lo b u li n ( IV I G ; s e e V I . B .1 .c ) . 2 . C o mm o n va r i a b le imm u n o de f ic i e nc y i s a n ac q ui r ed de f ic ie nc y o f B c e l l m a tu r a ti o n t o p la s m a c ell s . I t c an oc c u r at an y a ge a nd in ei t he r s e x. S ym p t om s a nd t re a tm en t a r e s im il a r t o t h os e f o r X- l i n k ed a g am m a g lo bu l in em ia ; the p at h og e ne s i s a nd o ri gin v a r y s ig ni f ic an t l y. 3 . S el e c ti ve I g A d e f ic i en c y i s t h e m o s t c o m m on p r im a r y im m u no de f ic ie nc y , a f f ec t in g a pp r o xi m a te l y 0 . 5 % o f t h e U . S . p op u la ti o n . I t a p pe a rs to be i n he r i te d . Th e lo w s e c re to r y I g A (s Ig A ) co nc en t r at i o n p r ed is po s e s p a ti en ts t o e xt r a c el lu l ar ba c te r ia l i n fe c ti on s o f t h e m u c os a l s u r fa c e s , le a di n g t o r e s pi r at o r y , ur o ge n it al , an d ga s t r o in t es ti n al in f ec ti o ns . So m e a ff ec t ed i n di vi d ua ls a re as y m p t om a ti c f o r u nk n o wn r ea s on s . Ce r t ai n a u to im m u ni t ie s m a y be m o r e p r e v al e nt . Th e r e is no s p ec if ic im m u n ol o gi c t h er a p y. 4 . D i G e o rg e s yn d r o m e re s ul ts f ro m d e v e lo pm en ta l fa i lu r e o f t h e t h ym u s a n d p a ra t h y r oi d g l an ds , a c c o m p an i ed b y c a rd i o va s c u l a r an d o t he r d e ve l op m e n ta l a no m a l ies . P at ie n ts ha ve a d ec r ea s e i n t o ta l T c e ll nu m b er s b u t re l at i v el y n o rm al im m u no g lo bu l in le v e ls . a . P a th o ge n es i s i n s e v er e c a s e s ( i .e . , l i tt l e f un c ti o na l th y m ic ti s s ue ) r e p r es en t s c o n di t io ns inv o l v i n g T c e ll de f ic ie nc y, s uc h a s r ec u r re n t i n f ec ti o ns o f th e s k i n , lun g s , ge n it o u ri na r y t r ac t , a n d b lo o d wi t h o p p or t un is t ic pa t ho ge n s , p a r ti c u l ar l y v i r us es (e . g. , h er p es v i ru s e s ) , f un gi ( e . g ., C a nd id a ) , a nd p ro to z o a ( e. g ., P ne u m o c y s t is c a r in ii ) ; i n cr e as ed
i n ci de n c e of c e r ta i n c a nc e r s ; g r af t - v e rs us - h os t ( G V H ) d is e as e ( se e V. C ) a f t e r t r an s fu s i on o f wh o le b lo od ; an d d e at h i n i n fa n c y o r ea r l y c h il d ho od . b . T he r a p y f o r s e v e r e T c e ll de f ic ie nc ie s i s b on e m a r ro w t r a n sp la n ta t io n , a l t ho ug h th y m us gr a f ts m a y be a tt em p te d i n Di G e o r ge s y nd r om e ( s ee V .C ) . 5 . N ez e lo f s yn d r o m e i s p r o ba b l y i n he r i te d a nd c a u s e s l ym ph op e ni a a n d t h ym ic ab no r m a l it i es b u t n o rm a l o r e le va t ed se r um i m m u no g lo b ul in le ve ls . G r a m - ne g at i v e s ep s i s m a y o c c u r i n a dd i ti o n t o t he o pp o r tu ni s ti c i nf ec t io ns a ss o ci at e d wi t h T c el l d ef i c i e nc y . 6 . S e ve r e c om b i ne d imm u n o de f ic i e nc y d i s o r de r s ( S C I D s) a re a h e t e ro ge n eo us g ro u p o f i n he r i te d d is o r de rs wi t h d e f ic ie nc ie s i n T c e ll s , B c e ll s ( va r ia b le ) , a n d s e r um im m u no g lo b ul in . In f ec t i o ns wi t h o pp o r tu n is ti c o r g an is m s oc c u r i n t h e f ir s t fe w m o nt h s p os tn a ta ll y , a nd su r v i v a l f o r l on g er t h a n 1 y ea r is ra r e wi t hou t s u c c es s f ul bo n e m ar ro w t r a n s p l an t at i on . Th r ee f o r m s i n v o l v e f ai l u re of D N A b i os y n t he si s o r re pa i r , a n d a f o u rt h d e fe c t is t h e re su l t o f d e fi c i en c y of t h e γ c ha in o f t he IL - 2 re c ep t o r. P.213
7 . C h r o ni c g r a n ul o ma t ou s d is e as e ( C G D ) is a de f ec t in th e a b il it y o f p h a go c y te s t o k il l b ac t e ri a . Th e d is ea s e is c a us ed b y a g en e ti c d e fe c t in th e p r o du c ti on o f o xy g e n r a di c al s t ha t ar e i m p o r ta n t fo r in t r ac el l ul a r a nd e xt r a c e l lu la r k i ll in g o f bac t e ri a . Th e de f ec t c an oc c u r i n a n y of t he fo u r p r o t ei ns es s e nt i al fo r p ro d uc i ng o xy g e n r ad ic al s , b u t t h e m o s t co m m on d e f ec t i s X- l i nk e d. C G D is c h a ra c te r i zed b y c h ro ni c i n fe c ti on wi t h or g an ism s s uc h a s St a ph y l oc oc c u s a u r eu s a nd is us ua ll y f a ta l . 8 . L eu k oc yt e a d h e si o n d e f i ci e nc y ( L A D ) i s as so c ia t ed wi t h a de f ec t i n th e p h a go c y ti c c el ls . Th es e c e ll s l ack in t e rc el l ul a r ad h es i on m o le c u le s , t he p r o t ei ns ne c e s s a r y fo r b in d in g to th e e n do t he li a l c e ll s o f t h e b lo od ve s s els a n d o t he r c e ll m em b r an es . Th is de f ec t l ea d s t o an i na bi l it y o f p h ag oc yt ic c e ll s t o e xi t t h e b lo o d a nd e nt e r t h e t is su es . In ad d i ti on , th e p h ag oc yt e s h a ve a d ec r ea s e d a b il it y t o bi nd t o ac t i vat e d c om p o n en ts of co m p l em en t o n a b ac te r i al s u r fa c e , l e ad in g to a d ec r ea s e in ph a go c y t os is . Pa t ie n ts ha v e s e ve r e b ac te r i al i n fe c ti on s , e s p ec i al l y i n th e m out h an d g as t r oi n te s ti na l t r a ct . 9 . C h éd i ak - H i ga s h i s yn d r o m e i s a d e fi c i e nc y in t h e fu s i on o f l y s o so m e s wi t h p h ag oc y t i c v e s i c l es . Th e c au s e is u nk n o wn , b u t th is s yn d r om e l ea ds t o b a ct e r ia l s ur v i v a l i n th e p h a go c y te , wi t h a n i nc r ea s e i n b ac te r i al in f ec ti o ns . 1 0 . De f e c ts in c om p le me n t m a y be t he r es ul t o f d e f ec ts in th e a c ti v a t io n p a t h wa y s , m em b ra n e a tta c k c o m p l e x, o r re g ul at or y p r o t ei ns . De f ec ts in t he a c ti va t io n p a th wa y s a n d i n th e m em b ra n e a tt a c k c om p le x a r e as so c i a t ed wi t h i nc r e as ed in f ec ti o ns o wi n g to p y o ge ni c b ac t er i a a n d wi t h i nc re a se d r a t es of im m u n e c o m p l e x d is e as es , s uc h a s S L E . D e f e c t s i n r e gu la t io n c an b e ob se r v e d a s a ng i on eu r o ti c e d em a a nd no c t u rn a l p a ro xs ys m a l h e m o g lo bi n u ri a.
B . S e c on d a r y i m m u n o de f i c ie n ci e s i n v ol ve de c re a se d i m m un o lo gi c r e s po ns i v e ne s s . 1 . C yt o t o x i c d ru g s p r e ve n t th e d i vis io n o f re s pon d in g l ym p ho c yte s , s u pp r es s t he p ro d uc ti o n o f bl o od c e ll s i n b on e m a r r o w, a n d m a y d i re c t l y k i ll c e ll s. P at i en ts wh o r ec e iv e c he m ot h er a p y an d e xh i bi t a s i g ni f ic an t l os s o f n e u t ro ph i ls m a y be t re a te d wi t h fi lg r as t im o r r ec om b in a nt g ra nu l oc y t e c o lo n y - s t im u la t in g f ac t o r ( G - C S F ; N eu p og e n) , to r e s to r e t h e wh i t e b l oo d c e ll c o un t to no rm a l l e v el s . Tr ea t m e n t t o i nc r ea s e n e ut r o ph il le v e ls in th e s e p a t ie n ts re s u l ts i n d e c r ea s ed m o r bi di t y r a te s f r om ba c te r ia l i n fe c t i on . C o r t ic os t e ro i ds b r o ad l y s u p p re s s im m u ne s ys t em c e ll s, in c l u di ng de c re as ed d i vi si on , c y t o k i ne s e c re t io n , a n d c h e m o t a xi s (e m ig r a ti o n f r om th e b l oo d i nt o t i ss ue s ) . 2 . L eu k em i as , l ym p h o ma s , a n d m ye l o m a s a r e as so c i a te d wi t h d ec r e as ed i m m u ne r es po ns i v e ne s s , a t l e as t s om e o f wh ic h re s ul ts f ro m d es t r uc ti o n of t h e a r ch i te c t u r e o f l y m pho i d o r ga ns ( e. g . , sp l ee n , l y m ph no d es ) . Ma l i g n a nc y - r e la t ed im m un o d ef ic ie n c y a ls o o cc u rs i n o t he r c a nc e rs . 3 . P r o te i n -c a l o ri e m a l nu t r i t i o n s i g ni f ic an t l y d ec r e a s e s im m u n e c om p et e nc e , p ar t ic ul a r l y i n c hi l dr e n. 4 . Ag i n g is a s s oc ia t ed wi t h d ec r e as ed im m u no lo gi c c om pe t en c e. 5 . Ac u t e in f e ct i o ns p rod u c e a t r an s i e nt im m u nod e f ic ie nc y. 6 . AI D S i s a s ec o nd a r y im m u n od e fi c i e nc y t ha t i s u s ua ll y p e rs is t en t a n d is a n in di r ec t c o ns eq u en c e o f i n fe c ti o n b y H I V -1 o r H I V - 2 . H I V -1 i s t h e m o r e c om m o n s u bt y p e i n t h e U n i t ed S ta t es an d we s ter n E u ro p e. a . P a th o ge n es i s . Th e v ir a l e n v e lo p e g l yc o p ro t ein 1 20 ( gp 12 0 ) h as a s t ron g a f f in i t y fo r C D 4 ( s e e I. B .3 . c ), al l o wi n g t he vi r us to d ir e c t l y in f ec t TH c e ll s . I n ad d it i on , t h es e p r ot e in s u s e o ne of t wo c h em ok i ne r ec ep t o rs : C C R 5 to g a in en t r y t o m a c ro p ha ge s a n d d en d ri t ic c e ll s a nd C XC R 4 t o ga i n e nt r y i nt o +
C D 4 T c e ll s . B ec a us e i t i s a re t r o vi ru s , vi r al en t ry a n d u n c o a ti ng r el ea s e t h e vi ra l R N A g en om e a nd t he as so c i a te d re v e r se t r a ns c r i pt as e e n z ym e , wh i c h s y nt h es i z es a do ub l e -s t ra n de d D N A c op y of t h e g en om e ( p r o vi ru s) . Th e p r o v i ra l c op y i s i nt eg r a t ed in t o t he ge n om e o f t he i n f ec te d c el l , a nd t h e vi r u s e n te r s a p e r io d o f la t e nc y , du r in g wh ic h i t is e s s en t ia l l y h i dd e n f r om t h e i m m un e s y s te m . ( 1 ) D u ri n g i n i ti a l i n fe c t io n , th e r e m a y b e a n a cut e il l ne ss th a t la s ts a n a ve r a ge o f 3 we e k s a n d r e s em bl es m o no n uc le os is ; s om e i n di v i du a ls h a ve n o s ym p to m s . ( 2 ) S e r oc o n ve r si o n (i . e., t h e a pp ea r a nc e o f a n tiv i r a l a n ti b od i es ) o c c u rs 3 we e k s to 6 m on t hs a f te r t h e i n it i al e xp o su r e t o H IV - 1 . A p e ri o d o f a s ym p t o m a t ic i n fe c ti o n t y p i c a ll y f o ll o ws s e r oc on v e r s io n . P.214
( 3 ) I nf ec t ed T H c el ls a re k i ll ed wh e n vi r a l g e ne s a r e r ea c t i va t ed f r om l a t e nc y a n d v i r us es bu d f r o m t he ce ll . In ad d it i on, i nf e c t e d T H c el ls m a y f u se t o f o rm s y n c y ti a . Thi s fu s i on m a y h as te n th e s p re a d o f v i r us t o
u n in f ec t ed T H c el ls an d c o n t ri b u te to c e ll k i ll in g . A p r o g r es s i ve de p le t i on 3
o f T H c e ll s oc c u r s ( n o rm a l c o un t : 8 00 - 1 00 0 /m m ). H o we v e r , e v e n b ef o r e a n +
+
o b vi o us l os s o f C D4 T c e l ls oc c u rs , th e re is e v ide n c e of a d e fe ct in C D 4 T c e ll fu nc t io n . Th e f un c t i on a l d e fe c t is a f ai l ur e o f t h es e c el ls t o r es p on d t o a n t ig en s t o wh i c h th e y we r e pr e vi ou s l y s en s i t i zed ( e . g. , te t an us t o xo i d ). +
Th e d e fe c t i n r es p on s i v en e s s m a y be a f un c ti o n o f t he C D 4 T c e ll s, t he A P C s , or bo t h . ( 4 ) Ma c r o ph a ge s m a y p ro d uc e n e w v i r u s wi t ho u t b e in g k i l l ed an d m a y +
s p r ea d t h e v i r us to un i nfe c te d T H c e l ls a n d o th e r c e ll t ype s . C D 4 c e ll li nes t h a t a r e s u s c e pt i bl e t o HI V i nf ec t io n i nc l ud e n e uro n s , li v e r , a n d f ib r o bl as ts . I n di r ec t c el l - to - c e ll t ra ns f e r o f t h e vi r us , m in im a l e xp o s u r e t o t h e e xt r a c e l lu la r im m u ne s y s t e m ( e .g . , a n ti b od y ) m a y o c c u r . ( 5 ) AP C s a r e a ls o a f fe c te d b y th e i n fe ct i on . Th e re is a l os s o f f ol l ic ul a r d e n dr i ti c c el ls an d i n te r di g i ta t in g c el ls in th e l y m p h oi d ti s s ue . Th is lo s s +
l e ad s t o d ec r e as ed an t ige n p re s e n ta t io n t o th e CD 4 T c e ll s . I n a dd i ti on , +
t h e c yt ok i ne s p r od uc e d b y t h e AP C s m a y pr o du ce C D 4 T c el ls th a t i n c re as e B c e l l ac t i v at i on b ut do no t pr o du ce t he a p p ro p ri a te c y t o k i n es f or T c e ll pr o li f e ra t io n . Th i s ac t i v i t y c h a ng es th e T H c e l l r a t io s . b . C l i ni c al s ym p t o m s ( 1 ) P e rs i s te n t ge n e ra l iz e d l ym p h a d e n o pa t h y ( e xt r a i n g u in a l) is an i n di ca t o r o f i m p e nd in g p ro g r es s i on t o f ul l d is e as e. U n e xp l a in e d f e ve r, ni gh t s we a t s , d ia r r he a , a nd o th e r s y m p to m s k no wn a s AI D S - r e l a t e d co m pl e x ( AR C ) m a y o c c u r . ( 2 ) P r og r es s i on t o f ul l -b lo wn A I D S m a y o c c u r 8 ye a r s o r l on g e r a f te r th e 3
i n i ti al in f ec ti o n. D e pl e ti on o f t h e T H c el l l e v e l t o < 2 0 0/ m m a n d o ra l +
c a nd i di as is s u gg es t i m m i n en t di s e as e . B ec a us e C D 8 T c e ll s a r e n ot +
+
s i gn i fi ca n tl y a f fe c t e d, the r a ti o o f c i rc ul a ti n g C D4 t o C D8 c e l ls i s i n v e rte d . I n ad d it i on , t h e n um be r o f v i r gi n T H c e ll s r e la t i v e t o m em o r y T H c el ls i n c re as es . TH c e l ls a r e lo s t , a nd m em o r y T H c el ls a r e l os t i n re l at i vel y l a r ge r nu m b e rs . Th e re is a ls o a sh i ft in th e t y pe of T H c e ll he lp be i ng g e n er a te d . ( 3 ) A di ag n os is o f A I D S in v o l v e s t h e oc c u r r en c e o f o pp o r t u ni s t ic i n f e c ti o ns o r n e op l as ms a s a r es u l t o f th e p r og r e s si ve i m m un o d ef i c ie n c y c a u s e d b y s e v e re de p le t io n of T H c e ll ( C D 4 ) f un c ti on . A l s o i nc lu de d i n th is di ag n os is a re th e H I V wa s t in g s y n d r om e a nd e n ce p ha lo p at h y . ( a ) O p po r t un is t ic i n fe c ti on s a r e t h e m aj o r c o ns e qu e nc e o f A I D S, pa r t ic ul ar l y b y P . ca r in i i ( as m a n y as 8 0 % o f p a ti en t s ) , C an d id a al bi c a n s, My c o b a c t e ri u m av iu m - i n tr a c el lu l ar e , h e rp es s i m p le x v i r u s ( H S V ) , c yt o m e g al o v i ru s ( C MV ) , a n d o t he r s. Tu b e rc ul os is o c c u rs as a r ea c t i va ti o n o f a l at e n t in f ec t io n i n c ar r i e rs . C um ul a ti v e l y , th es e op p o r t un i s ti c i n f e c ti o ns a r e t h e p r ima r y c a u s e o f d e at h . ( b ) K a po s i s a r co m a, an o t he r wi s e ra r e c an c e r , oc c u r s i n f e we r t ha n o n e h a l f o f p a ti en t s wi t h A I DS . N o n - Ho d gk in l ym p hom a i s a ls o m or e c om m o n i n t h es e i n di v i d ua ls th a n i n t h e g en e r al po pu l at i on .
( 4 ) H I V -a s so c i at e d d eme n t i a c om p le x ( H AD C ) a f f ec ts m o r e t ha n o n e h al f o f pa t ie n ts wi t h AI D S . In H A D C , m a c ro p ha g es i n fi l t ra t e t h e b r ai n a nd a re t h e m os t p r o du c t i v e l y i n fe c te d c el l i n c om pa r is o n t o ne u r on s o r g li a . So m e p a t ie n ts s ho w d e m y e li nat i o n. ( 5 ) O t he r im m u ne s ys t em ab n o rm al i ti es i n c l ud e p o l y c l o n a l B c e ll ac t i v at io n a n d h yp e rg a m m ag lo b ul ine m ia wi t h a co nc om i ta n t d e c re as e d a bi li t y t o m o un t h u m o r al im m u ne r es po ns e s to s p ec if ic an t ig e ns . C h e m o t a xi s , c yt ok i ne s ec r e ti o n, an d c y t o to xi c a b il i t y of m o no c yt e- m ac ro p h ag es ar e al l d i m i ni s h e d. Th e s e p ro ble m s a re c o ns eq u en ce s of im p a i r ed T c el l r e g ul a ti o n. c . Th e r a p y ( 1 ) C u r re n t t he r a p y i nc l ud e s p r op h y la c ti c us e o f a n t ib io t ic s a nd an t if u ng al a g e nt s. O p ti m a l a n ti - H I V t h e ra p y is c om b in a ti on th e r ap y wi t h t h re e a n t ir e t ro v i r a l d ru gs . A t pr e s en t , t he r e a r e f o u r cl as s e s o f a n ti r e t ro v i r al d r u gs ap p ro v e d b y t h e FD A . Th e s e a r e n uc le os ide r e v e rs e - tr a ns cr i pt as e i n hi b it o rs ( N R TI s ; e . g. , zi d o v u di ne - A Z T, la m i v u d in e , s t a v ud in e , zal c i t ab ine d d C , d i da n os in e -d d I , a nd a ba c a v i r ) , n o nn uc le os id e r e v er s e- t r an s c r ip t as e i n hi b it o rs ( N N R TI s ; e . g. , n e v i r ap in e , d el a vi r di ne , e f a v i r en z ) , p ro t ea se i n hi b it o rs ( e. g . , s a q ui na v i r , in di n a vi r, r it o na vi r , n el f i na v i r ) a n d i nt e g ra s e i n hi b it o rs ( e. g . , r al t eg r a vi r ) . IF N - α is r ec om m e nd ed f o r t he t re a tm e nt of K a p os i s a rc om a. O t he r dr u g s a nd im m u no m o d ul a to r s a r e c u rr e nt l y un d e r d e ve l op m e n t a nd te s ti ng. P.215
( 2 ) A n e f fe c t i v e a c ti v e va c c i ne is n e ce s s a r y t o l im i t t h e sp r ea d o f H I V i n f ec ti o n. B ec au s e o f v i ra l an t ig en ic v a r ia t io n , c el l - to - c e l l t r an s m is s i on , an d t h e u nc e r ta i n r ol e o f an t ib o di e s in p ro t ec t io n , t he p r o c e s s o f v ac ci n e d e ve l op m e n t is di f fi c u l t . A l i v e , a t te nu a te d vac ci ne ( se e VI . C . 2 ) is c o ns id e re d to o g r ea t a r is k . Tr i a ls of su bu n it v a c c i ne s a r e u nd e r wa y .
V. GRAFT REJECTION A. O ve r vi e w . In d i v id u al d i f fe r e nc es i n t h e m ol ec u l a r s t ru ct u r es o f c el ls an d t i ss ue s o c c u r, e xc e p t i n id e n ti c a l t wi n s , b ec a us e o f t he ge ne t ic v a ri a ti o n i n he r e nt in hu m a ns . B ec a u s e of t he se m o le c u l ar d i f fe r e nc es , t r an sp l an t ed t i ss ue s o r or g an s ( i .e . , gr a f ts ) a re li k e l y to be an ti g en ic a ll y d if f e re n t f r om t h e re ci p ie n t a nd th e re f or e m a y s ti m u la t e a n i m m u n e re sp on s e. 1 . A lt h ou g h MH C c l a s s I a n d I I gl y c op r o te in s p la y a n e ss e nt ia l ro l e i n al l T c e ll im m u ne r es po ns es (s e e I . B .3 . a ), th e se m o lec u le s a r e p a rt ic ul a r l y a n t ig en ic a nd v a ri a nt in s t r uc t ur e a m o n g d if f e re nt h um an s (p ol ym o rp h ic ) . 2 . E ac h p e rs on ' s s e t o f MH C g l yc o p ro t ei ns is c all e d h is o r h er h um a n l e u ko c yt e a n t i ge n ( H L A) , o r h i s to c om p a ti b i li t y t yp e . C l a s s I g l yc op r o te in s a r e k no wn a s H LA - A , - B, an d - C a n ti g en s . C l as s I I g l yc op r o te in s a r e k no wn a s H LA - D R , - D P , a nd - DQ a n t ig e ns . E ac h p e rs o n
r e c ei ve s o ne s e t o f g e nes ( a h ap l ot y p e ) e nc o di ng t h es e p r ot e in an t ig e ns f r o m e ac h p a re n t. 3 . I de n ti c a l t wi n s h a v e th e s am e h is t oc om p at i bi lit y t y p e . Fo r ot h er s i bl i ngs , t h e p r o ba bi l it y i s a pp r o xi m a te l y 25 % (0 . 25 ) th a t two s i b li n gs wi t h t h e s a m e p a r en t s a r e H L A i d en ti c al , o r m a t ch ed , an d a p pr oxi m a t e l y 50 % th a t t he y ar e o n e h al f H L A m a t c h e d, or h a pl oi d en t ic al . Pa r en t s a n d c h i ld r en a re al m o s t a l wa ys h ap l oi de n ti c a l . So m e t r an sp l an t ed ti s s ues a re r ej ec t ed be c a us e of H L A i nc om pa t ib il i t y . I n ot h e r c as es , t h e r e as on for r e je c ti on is th e re s u l t of m i no r hi s t oc om p at i bi li t y a n t ig en s o r is u nk n o wn . H L A m a t c h in g i s n o t a l wa ys a fa c t o r i n re je c tio n . B . C o m mo n s o l id - o r g an t r a n sp l a n ts ar e k id n e y , h e a rt , l i ve r , h ea r t -l u ng , a n d p a nc re a s . O r ga n s a re o bt a in e d f r om c ad a v e rs o r l i v in g d o no rs . Th e p r o ba b il i t y o f an e xa c t HL A m a t ch in a ca d a v e r gr a f t i s a pp r o xi m a te l y 1 i n 1 0 m i ll io n . 1 . H L A m a t ch i n g a . Th e pr im a r y p ro bl e m wi t h o r g an do n at io n i s rej e ct i on of t he t ra ns pl a nt ed o r g an b y th e h os t ' s i m m u n e re s p on s e. D on a ti o n o f an o rg a n b y an H L A m a tc he d s ib l in g i s t he bes t wa y t o a v oi d t h is p r o bl e m . b . A l th ou g h H L A - D R an d H L A - B m a tc hi n g d ec r eas es t he r ej ec ti o n r e ac ti on i n re n al an d c a rd i ac g r a ft s , re je c ti on do e s oc cu r i n H L A -m a tc he d s i tu a ti ons . H L A m a t c h in g i s n o t im po r t a nt in li v e r t ra ns pl a nta t i on . 2 . T yp e s o f r e j ec t i o n o f o r g a n g r a f ts a . H yp e r a c u t e re j ec t i on i s m ed ia t ed b y pr e e xi s t in g an t ib o d y i n t h e r e c ip ie n t , us u al l y ag ai ns t A B O m i sm a tc he s . C om p l em e nt is a c ti v a t ed , c l ot t in g o c c u rs , a n d t he v a s c ul at u r e o f t h e t r an s pl a n te d o r ga n i s o c c lu de d. R e j ec t io n o c c u rs wi t h in 2 d a ys a ft e r t r a ns pl an t a ti o n . A n A B O -m is m a tc h ed g r a f t is r a re l y at t em p te d . R e j ec ti o n is es s e n ti al l y u n t r ea t ab le . b . Ac u t e r ej e c ti o n i s a T c e l l -m ac r op ha g e -m ed ia t e d a t ta c k o n th e g r af t b a se d o n HL A an d o t he r t i s s ue an t ig e n m i sm a tc he s . T c e ll s a nd m ac r o ph a ge s i nf il t r at e the g r af t a n d, in 10 - 1 4 d a ys , c a us e c e l lu la r ne c ro sis a n d i n fl am m a t io n p e ri v as c u l a rl y . Th e e n ti r e g r a ft b e gi ns to ne c ro s e i f u n t r ea t ed . c . C h r on i c r e j ec t i on oc c u rs s e v e r al m o n th s t o se v e r a l yea r s a ft e r t r a ns p la n ta t io n . I t c au s es f ib r os is a n d o cc lu s i on o f s m al l a r te r i es a n d a r t e ri o le s i n t he k i dn e y s a n d a t he r os c l e ro s i s i n t h e h ea r t . I t i s c on t ro l le d by i m m u no lo g ic i n ju r y a nd m e di a te d p r im a ri l y b y a nt i b o d y a nd in c l u de s t he r e l ea se o f i nf l am m a to r y c y t o k i ne s b y m ac ro p ha ge s . De sp i te th e h i gh s uc c ess r at e o f MH C - m at c he d , p ha r m a c o l og ic a ll y t r e at e d g r af t s i n t he fi r s t ye a r a ft e r tr a ns pl a nt a ti on ( 8 5- 9 0% k i dn e y g ra f ts ), t h e r ej ec t io n ra t e a f te r 5 ye a r s i s n ea r l y 50 % . Th is f or m o f re je c ti o n is r ela t i v e l y re si st a nt t o t he r ap y, a l t ho ug h t re a tm en t wi t h c o r ti c o s te r oi ds c a n b e he l p fu l . C . B o n e m a r r ow t ra n sp la n t a t io n i s s om et im es at t e m p t ed in pa t ie n ts wi t h i m m u no d ef ic i en c y d is e as e s , a pl as t ic an em ia s , som e l e uk em ia s , an d c e r tai n g e n et ic di s e as es . Th e g ra f t c o nt a in s a P.216
h i gh p ro p o rt i on of do n or l y m p ho c yt es t h at r es po nd t o t h e h os t HL A an d o t h e r a nt i ge ns . Th is re s po n s e c a us es g ra f t - v er s us - h os t ( G V H ) d is ea s e . 1 . G r a ft T c el l re c o gn i ti on o f t h e h os t i s im po r t ant i n G V H d is ea se , as s h o wn b y th e d ec r e as ed i n c i de n c e of G V H di se ase a f te r p r oc e du r es th a t p u r ge m a t ur e T c e l ls fr om t he do no r m a r r o w. 2 . C l in i ca l s ym p t o m s o f G V H d is e as e a r e s e e n in t he s k in (e . g ., r as h, d e sq u am at i on ) , g as t r oi n te s ti n al t ra c t ( e. g . , p ai n , vo m i ti n g, in t es ti n al b l ee d in g ) , a nd li v e r (e . g ., n ec r os is i n di c a t ed b y i n c r ea s e d s e ru m b il i ru bi n l e ve ls ) . De a th c o m m on l y o c c u rs . 3 . H L A m at c h i ng is i m p or t a n t i n b on e m a rr o w t r an s pl a nt a ti o n, bu t th e f a ilu r e r a t e e ve n o f m a tc he d g ra f t s as a r es u lt o f G V H di s ea se is h i gh . 4 . B ec au s e t he r ec ip ie n t o f t he m a r ro w ( h o s t) is im m u n os up p r ess e d, o wi ng t o p ri m a r y im m u n od e fi c ie n c y o r b y dr u gs or r ad ia t i on , h os t re j ec ti o n o f t r a ns p la n te d b on e m a r row i s l es s im p o rt a nt . D . P r o p h yl a x i s a n d t r e at m e n t o f g ra f t r ej e c ti o n 1 . I mm u no s up p r e ss i on o f t h e g r a f t r e c ip i en t a . C o r t ic o s te r o i ds (e . g ., m et h y l pr e dn is o lo ne , pre d ni s on e ) a r e a dm in is t e re d j u st be f o re t ra ns p la n ta t io n an d ra pi d l y ta pe r e d be c au s e o f t he i r s id e e f f ec ts . C or t ic os t e ro id s a r e us ed in c om b in a ti on wi t h a z a t hi o p ri ne , c yc lo s po r in e , o r a n t il ym p h o c yt e g l o b u l i ns / an t i th ym o c yt e g l o b u li n s ( AL G s / AT G s ) . b . Az a t h io p r i ne is gi v e n b e fo r e t r a ns pl an t a ti on . Ma i n t e n a nc e d os es a r e g i ve n a f te r wa r d . c . M e t ho t r e xa t e is us e d p r i m a r il y f o r b on e m a r row t r a n s pl a nt a ti o n i n c om b in a ti o n wi t h A L G / ATG . I t i s a dm in is t e re d e i th e r a f e w d a ys b ef o r e o r a t t h e ti m e of t ra ns p la n ta t io n . 2 . S pe c i fi c su p p re s si o n o f T c e ll s a . C yc l o s p o r i n e A ( c y c lo s po r in ) bi n ds t o a n i n t ra c el lu l a r p ro t ei n k n o wn a s c yc lo p hi li n a n d b lo c k s t he t r an s c r ip t io n o f c y t ok i ne g en es in a T c e ll th a t h a s r ec o gn i z e d a nt i ge ns . I n t h is wa y , i t i nh i bi ts T H c el l s ec r e ti on of I L -2 an d p r o du c ti on o f t he hi g h- a ff i n it y I L -2 r ec ep t o r a nd pr e ve n ts c o m p le t e T c e ll a c ti va t io n . I t i s a dm in is te r e d p r op h yl ac ti c a l l y b ec a u s e it is m o re e ff ec t i ve i f i t is p r es e nt be f o re r ej ec t i o n b eg in s . C y c l os po r ine A is c om m o n l y c om bi ne d wi t h o t he r ag e nt s . Th e m a j o r s i d e e f fe ct is ne p hr ot o xi c i t y . b . T ac r o l im u s ( F K - 50 6 ) i s a n i m m un os u pp r es s i v e a ge n t t ha t in hi b it s TH c e ll fu nc t io n i n t h e s am e wa y a s c y cl os p o ri ne A . B o t h d r u gs f u nc ti o n t h r o ug h t h e s a m e pa t h wa y a n d a r e n ot us ed t og et h e r . c . R ap a m yc i n ( s i r ol im us ) i nh i bi ts T H c el l re sp o ns e t o I L -2 an d p r e v e nt s T H c e ll ac ti v a t io n . I t wo r k s th r o ug h a di f f er e nt pa t h wa y t h an ei t he r c yc l os po r in e o r t ac r ol im us an d i s es pe c ia ll y e f fe c ti v e in c om b in a t io n wi t h t he o th e r d r u gs . d . AL G a n d AT G a r e a nti s e ra de r i ved f ro m a ni m al s . Th e y c on t ai n a v a r ie ty o f an t ib o d y s pe c i f ic i ti es a g ai n s t T c el l a n ti ge ns . Th e y a r e us ed bo t h
p r o ph y l ac t ic al l y an d th e ra p e ut ic al l y in bo n e m ar ro w a n d o rg a n t r a ns p la n ta t io n . e . M u r o mo n a b- C D 3 ( O KT3 ) i s a m o us e m on oc l on a l a n ti bo d y s p ec i fi c f o r t h e C D 3 a n ti ge n , wh ic h i s p re s en t o n a l l p e ri ph e r al T c el ls . O K T3 is us ed t h e r ap eu t ic al l y t o h al t a nd r e v e rs e a cu t e r e je c t i on a s s oo n a s i t i s d i ag n os ed . ( 1 ) I ts m ai n a c ti o n is th e o ps o ni za t io n o f T c e l ls fo r e nh an c e d ph ag oc yt o s is . I t is ad m i ni s te r ed da i l y fo r 1 0- 1 4 d a y s. O n l y o n e c o u rs e is t y p ic al l y us ed b e ca us e i t c a us es a n i m m u ne r es po ns e a g ai ns t th e fo r e ig n m ou s e an t ib od y . ( 2 ) A cu t e s i d e e ff e c t s a re c o m m on , p ro ba b l y b e ca u s e of no n s p ec i fi c T c ell a c ti va t io n th a t c a us es t he r el e as e o f c y t ok i ne s . Si d e e f fe c ts i nc l ud e h ig h f e ve r , c hi l ls , b lo o d p r es s u r e c h an ge s , v o m i t in g , di a r r he a , a nd r es pi r at o r y d i st r es s . O K T3 i s c o n t ra in d ic a te d i n p a ti e nt s wh o h a v e fl ui d o v e r l oa d b e ca us e i t m a y c a us e f a ta l pu lm on a r y ed em a . ( 3 ) O K T3 m a y a ls o b e u s e d in v i t ro to pu r g e d on or b o ne m a r ro w o f T c el ls t o r ed uc e t h e r is k o f G VH d is e as e . 3 . I n ve st i g at i o na l a g e nts b ei ng t es te d to p re v e nt o r re v e r s e g ra f t r e je c t io n i n cl ud e a n ti - T c el l i m m un o t o xi n s ( s e e VI I . C .1 ) , c o n ju g at e s o f I L -2 an d a t o xi n , a nd o th e r m on oc lon a ls th a t p r e v en t T c e l ls f r o m a dh e ri n g t o f o r ei gn g r a f t c e l ls . Th es e a ge n ts a r e a dm i ni st e re d to th e g r a f t r ec i pi en t . I n a d di t ion , m o no cl o na l a n ti bo d ie s ar e us e d t o m ask H L A a n ti g en s o n t h e g r af t ti s s ue b e f o re it is tr a ns pl a nt e d i n t o t he r ec ip i en t . P.217
VI. VACCINATION A. O ve r vi e w 1 . P as s i ve va cc i na t i o n i s th e i nt r am us c ul a r o r i nt r a v e n ou s i nj ec t io n o f a n t ib od y p r ep a r at i on s t o e n ha nc e a pa t ie n t 's im m u n e c om pe t en c e . P r o t ec t io n d e pe nd s o n th e s e r um h a lf - li f e o f t h e i n je c te d a n ti bo d y a nd is l i m i t ed to s e v e r al we e k s t o s e v e r al m o n th s f o r e ac h a dm i ni s t r a ti o n o f h um a n s e r a. 2 . Ac t i ve va c c i na t i on is t h e i nt r am us c ul a r, s u bc u t a ne o us , o r o r al i n t ro d uc t io n o f o n e o r m o r e an t ig en s d es ig n ed t o s t im ul a te th e i m m un e s ys t em to pr o du c e a s pec i fi c im m un e r es p on se . Th i s r es po ns e g e ne r a te s a n t ib od y , ac t i v a te d T c e ll s , a nd sp ec i fi c m e m o r y. P r o t ec t io n t h r ou gh m em o r y v a r ie s wi t h t he va c c i ne , b u t i m m un i t y i s lo n g l as t in g . B . P a ss i ve va c ci n a t io n ( Ta b l e 1 0 - 2 ) 1 . P r e pa r a t io n s. D os es o f in t r am us cu la r p re pa r at i o ns a r e s om e ti m e s g i v en i n un i ts p e r k il o gr am an d s om e ti m e s i n m i ll i li t e rs p e r k il o g ra m . Th e do s e va r i e s wi t h t he v ac c i n e an d pa t ie n t p op u la ti o n. I nt r a ve n ou s p r ep a ra t io ns ar e c om m o n l y u s ed in hi gh do s es .
a . S t an d a r d h um a n s e ru m im m u no g lo b u li n f o r i n t r am u sc u l a r va c c i n a ti o n i s a p o l yc l on a l a n ti s e r um pr e pa r e d fr o m p o ol ed pl a s m a o f d o n or s . I t c on t ai ns 16 5 m g /m L h um an im m u n og lo b ul i n, P.218
p r e do m i n an t l y th e f o ur s u b c l as s e s o f I g G . Si d e ef f e ct s a r e r a re , m i ni m a l , a n d u su a ll y c o n fi n ed to m i no r i n fl am m a t io n a n d p a in a t t he si t e o f i nj ec t io n . Th i s p re p ar a ti o n is un s u it a b le fo r in t r a ven ou s i nj e c t io n b ec a us e a n ti bo d y a g g re g at es f o rm a n d m ay a c t i v at e c om pl em e nt an d pl a te le t s.
Table 10-2. Passive Vaccines Illness
Vaccine
Rationale
Intramuscular Hepatitis B (HBV)
Hepatitis B immunoglobulin (HBIG)
Prophylaxis
Hepatitis A (HAV)
Immunoglobulin, intramuscular (IGIM)
Prophylaxis
Non-A, non-B hepatitis
IGIM
Prophylaxis, therapy
Measles
IGIM
Prophylaxis, therapy
Rabies
Rabies immunoglobulin (RIG)
Prophylaxis
Rubella
IGIM
Fetal prophylaxis in exposed mother
Varicella
Varicella zoster immunoglobulin (VZIG)
Prophylaxis and therapy in immunocompromised individual
Tetanus
Tetanus immunoglobulin
Prophylaxis
(TIG) Hypogammaglobulinemia
IGIM
Therapy for antibody deficiency
Rh disease
Rho (D) immunoglobulin (RhoGAM)
Prophylaxis during pregnancy and after delivery of Rh+ fetus by Rh- mother
Botulism
Botulism antiserum (equine)
Prophylaxis, therapy
Snakebite
Polyvalent antivenin (equine)
Prophylaxis, therapy
Black widow bite
Black widow antivenin (equine)
Prophylaxis, therapy
Hypogammaglobulinemia
Intravenous immunoglobulin (IVIG)
Therapy for antibody deficiency
Idiopathic thrombocytopenic purpura (ITP)
IVIg
Therapy
Chronic lymphocytic leukemia
IVIg
Therapy for antibody deficiency
Cytomegalovirus (CMV) infection
CMV IVIG
Therapy in renal transplant patients
Intravenousa
Acute renal rejection
Muromonab-CD3 (murine)
Reversal of acute rejection
a
U.S. Food and Drug Administration-approved uses; many others currently in trials result from vaccine preparation in cells of nonhuman origin. The valence of a vaccine indicates the number of strains of organism included (e.g., trivalent polio vaccine includes three strains of poliovirus).
b . S p ec i al i nt r a m us c ul ar i m m un o g lo b ul i n s ( I G IM s ) a r e i nd i v i du al s e r a p r e pa r e d f r om p l as m a l ot s of s u bj ec t s ac t i vel y im m u ni z e d a g ai ns t o r r e c o ve ri ng f ro m s pe c i f ic d i s e as es . Ea c h s e r um is e n ri c he d f o r a n ti bo d ie s o f t h e d es i r ed s p ec if ic i t y (e. g . , t e ta n us i m m u no gl o bu l in c o n ta in s m o re a n t ib od i es ag ai ns t te t anu s to xi n t h an wo u l d b e fo u n d in I G I M) . c . I VI G s a re pr e pa r e d f ro m p o ol e d h um an s e r um a n d m o d if i ed to m i ni m i z e a n t ib od y a g gr e ga t io n . C h i ll s , n au s e a , a nd ab d om i na l p ai n o c c u r i n a p p ro xi m a t el y 1 0% o f p at i e nt s . S id e e f f ec ts ar e di m in is he d b y r e du c i n g t he r a t e o f i n t ra v e n ou s i nf us io n . P re m e di c at i on wi t h c o r t ic os t e ro id s i s r e c om m e nd e d, an d i n t rav e n o us ep i ne ph r i ne is u s e d if an a ph yl a xi s oc c u rs . d . An i m a l a n t is e r a. E qui n e ( h o rs e ) a nt is e r a a re u s ed in c e r ta i n s i t ua t io ns ( Ta b l e 1 0 - 2 ). Mo u s e m on o c l o na l a n ti bo d y (m u r om o na b - C D 3 ) is us ed in a c ut e re n al re j ec ti o n ( s ee V . D . 2. e ) . Th e ha l f -l i v es o f a ni m a l a n ti bo d ie s a re s h o rt e r i n h um a ns . 2 . R a t io n al e s f o r pa s sive va c c i n a ti o n a . P r o ph yl a x i s o f i n f ec ti o u s d i se a se . An t ib o di es a re gi v e n p r o ph y l ac t ic al l y t o p re v e n t c l in ic a l s y m p t om s o f a v i r a l o r ba c t e ri a l i n f ec ti o us p r oc es s , p a rt ic u la r l y i n a p at i en t wi t hou t p re vi o us e xp o s u r e a nd t h e r ef o re wi t h o ut im m u no l og ic m e m o r y . Th e v ac c i n e p r o te ct s t h e r ec ip i en t d u r in g th e i nc ub a ti o n p er i o d f o r i n fe c t i on . F o r e x a m pl e : ( 1 ) C lo s t ri di u m t et a ni i n fe c ti o n h as a n i nc u ba t io n p e ri o d o f a p pr o xi m a te l y 5 d a ys b e f or e s ig n if ic a nt qu a n ti t ie s o f t e ta n us t o xi n a r e p r od u c e d . A p rim a r y i m m u ne r es po ns e o f 7 - 10 d a ys is to o s lo w. P a ss ive v a c c i n at i on wi t h t e ta nu s i m m u no gl o bu l in ( TI G ) bin d s t he t o xi n an d p r e v ent s di s e as e . ( 2 ) H e pa t i t is B im mu n og l o b ul i n ( H B I G ) is ad m in i st e r ed to in d i v id ua ls as s o on as po s s ib le a ft e r exp o s u r e to p re ve n t v ir a l in f ec t io n . b . P r o ph yl a x i s o r t he r ap y p r e v e n t s or a tt e nu a tes t he ef f ec ts of in f ec t io n i n s p ec ia l p o pu la t io ns . E xa m p le s a r e t he us e o f va ri c e l la z o s te r i m m un o g lo b u li n ( VZ I G ) i n i m m un oc om p r om is ed p a t ie n ts a n d t he us e o f I G I M i n p r e gn a nt wo m en wh o a r e e xp o s e d t o ru be l la an d h a ve no t b e en a c ti ve l y v a c c in a te d .
c . T re a t me n t o f an t i bo dy d e f i c i e n c y. I n d i v i d ua ls wh o a r e d e fi c i e nt in a n t ib od y p r od u c t io n , e i the r b ec au se of p ri m a r y im m u no d ef ic i en c y (s ee I V ) o r as a r es u lt o f c h r on ic l y m p ho c yti c l eu k em ia , rec e i ve i nt r a v e no us i m m u no gl o bu l in ( I VI G ) or I G I M e v e r y 2 - 4 we e k s to m a i nt a in hu m o r al i m m u ni t y . I VI G is p re f e rre d . d . O t h e r s i t ua t i on s . I V IG i s u s e d fo r i d io p at h ic (a u t oi m m un e ) t h r om b oc y t op e ni a p u rp u ra . I nt r am us cu l ar R h o ( D) im m u n og l ob ul i n ( R h o G AM) i s u se d p r o ph y l ac t ic al l y fo r R h d is e as e ( s e e II . C .5 . c ). Mu r o m on a b - C D3 (s e e V . D . 2 . e) is us ed fo r ac u te r e na l g r af t re j ec ti o n. C . Ac t i ve va c c i n a ti o n (Ta b l e 10 - 3 ) is us ed f o r pr o p h y la xi s . 1 . O ve r vi ew a . C o n te n ts . Ac t i v e v ac c i n es c o nt a in on e o r m o r e s ub u ni ts o f a p a th o ge n o r wh o l e p at h og en ic o rg a nis m s bu t m a y al so c o nt a in p r e s er v a t i v es , l o w d o se s o f an t ib i ot ic s , a nd ot h er c om p ou n ds th a t d o n ot af f e c t th e i m m un e r e s po ns e . b . Ad m i n i st r a t i on . Ac t i ve v a c c in e s a re ad m i n is ter e d s u bc ut a ne o us l y, i n t ra m us c u la r l y , i n tr a de rm a ll y , o ra ll y , o r i n t ra na s a l l y . So m e a re in t ro d uc ed a d so r be d to al um in um hy d r o xi d e o r al um in um pho s ph a te ad j u v an ts . A n a d ju va n t i nc r ea s es t h e an t i ge ni ci t y o f t h e v a c c in e. c . S e ro c on ve r s i o n. F or m os t ac ti v e va c c in es , the s u cc es s o f t h e se r i es of va c ci n at i on s i s in d ic at e d b y s e ro c o n v e rs io n o f the p at i en t . S e r oc on v e r si on i n di ca t es th a t a pe r s o n wh o p r e vi o us l y d i d n ot ha v e sp e c i fi c s e ru m a n t ib od i es (i . e ., s e r on ega t i v e ) n o w h as t he se an ti b od i es (i . e. , s e r op os i ti v e ) . S e r o co n v e rs io n d o es n o t i n di c a t e es t ab l is he d i m m u ni t y f or c e r t ai n vac c i ne s ( e . g ., ba c i l lu s C a lm et t e -G u é r i n va c c in e fo r tu b erc u lo si s ). d . A s c h ed u l e o f a c t i ve va c c i na t i o n is r ec om m e n d ed fo r in f an ts an d c h il d re n ( Ta bl e 1 0 -3 ) . The f i rs t v ac c i na t io n i s g i ve n af t e r t he in f an t is 6 we e k s ol d b ec au s e r es po n s e s a r e n o rm al l y in ade q u at e i n n e wb o r ns an d b e ca us e m a te r na l a n ti b od i es r em ai n i n t h e n e wbo r n c i rc ul a ti o n; s o m e va c ci n es (e . g ., he p at i ti s B v i r u s ; H B V ) , h o we v e r , m a y be gi v e n i m m e di at e ly a f t e r b i rt h . S om e v ac c i ne s a r e i n te n de d f o r u s e p r i m a r il y i n n on in f an t p o p ul at i on s . P.219
P.220
Table 10-3. Commonly Administered U.S. Food and Drug AdministrationApproved Active Vaccines
Vaccine
Target Populationa
Number of Vaccinations Schedule
Notes
Live, attenuate d viral Oral polio (OPV; trivalent)
Infants, children, healthcare and daycare workers
4
2, 4, 15-18 months; 1 at school entry
Approxim ately 1 in 2.6 million risk of vaccinein duced paralysis; no longer recomme nded because of risks; substitute killed vaccine
Measles, mumps, rubella (MMR)
Infants, children
2
15 months (< 12 months if high risk); 1 at school entry
Generally affords lifelong immunity
Rubella
Adolescent girls not previously vaccinated
1
Postpubert y
Protects future fetus from congenital rubella injury
Varicella
Children, other at-risk individuals
1 (if ≥ 13 years old, 2)
1 between 12 and 18 months or 2-3 years; after 13 years old,
Duration of immunity or effect on developm
Influenza (trivalent)
2-4 weeks apart
ent of shingles unknown
Individuals between 5 and 59 years old at risk for infection
1 per year
Annually for maximum protection
Administe red intranasall y
Individuals exposed to sputumpositive tuberculosis patients
Varies
Depends on success or initial vaccinatio n
Unpredict able effectiven ess; induces cellmediated immunity
Influenza (trivalent or polyvalent )
Geriatric patients, healthcare workers, individuals at risk for complications
1 per year
Annually for maximum protection
Variant strains may appear each year; vaccine must be updated annually
Hepatitis B (HBV)
All
3
Between 1 and 2 months, 2 and 3 months,
Recombin ant, subunit
Bacterial BCG tuberculos is
Killed, inactivate d viral or viral subunit
after 6 months Inactivate d polio (IPV; trivalent)
All children; as booster in healthcare and day-care workers
4
2, 4, 15-18 months; 1 at school entry
No slgA; thus reduced protection ; no paralysis risk
Killed, inactivate d viral or viral subunit Animal-care workers
4 or 5b, with boosters
7 days apart; boosters as required to maintain immunogl obulin
Two doses to exposed, already immune individual
Diphtheri a, tetanus, pertussis (DTP)
Infants, children
4, with boosters
2,4, 15-18 months; 1 at school entry
Tetanus toxoid (Td) booster every 10 years or on exposure through a wound
Tetanus and diphtheria
Children ≥ 7 years old; adults with no
3, with boosters
Second dose in 4-8 weeks;
Td booster every 10
Rabies (HDCV)
Bacterial, subunit
toxoids (Td)
vaccination
third dose 6 months later
years or on exposure through a wound if more than 10 years or vaccine history unavailabl e
Haemophi lus b (Hib)
Infants, children, HIVinfected adults
Depends on formulati on
Depends on formulatio n
Polysacch aride capsule is poor antigen; conjugate vaccines enhance potency
Pneumoco ccus (polyvale nt)
At-risk adults or children ≥ 2 years old (e.g., immunocompr omised patients, geriatric patients)
1 or 1 per year
As necessary in at-risk patients; not given during active infection; 1 per year in geriatric patients
Poor response to polysacch aride antigen in children < 5 years old
Meningoc occus (quadrival ent A, C Y, W135)
College freshmen living in dormitories; high-risk adults or children ≥ 2 years old, including individuals
1, subcutane ously
As necessary in at-risk individuals at 3- to 5year intervals
Polysacch aride vaccine give poor response in children < 2 years old; does not
with complement component deficiencies or anatomic or functional asplenia
protect against serotype B, which accounts for 46% of cases
BCG, bacille Calmette-Guérin; HDCV, human diploid cell vaccine; slgA, secretory immunoglobulin A. a
Entire target population is not listed in all cases.
b
Five doses to already exposed individuals.
P.221
e . Mo s t v a c c in es r eq ui r e a se r i e s o f va cc i na t i ons ; o t h e rs a re ef f ec ti v e wi t h a si ng l e v a c c i na ti o n. F o r t h os e t ha t re q ui r e a s e r i es , i nt e r v a ls b e t we e n va c ci n at i on s g r ea t e r t han t ho s e r ec om m e nd e d do n ot ge n e ra ll y d im in is h p r o t ec ti o n. Th e d u r at i on o f m e m o r y v a r ie s wi t h ea c h va c c i ne , a n d b o os t er va c c i n a ti o ns a re of t en n e c e s s a r y . f . S i de e f fe c ts in c l u de in f l am m a ti o n a t t h e s i t e of v a c c i na t io n , m a l ai s e , m i l d f e ve r , c hi l ls , h ea d ac he , m y a l gi a , a nd a rt h ra l gi a . Mo r e s e ve r e s id e e f fe c ts i n cl ud e fe b ri l e il l ne s s , s o m no l en ce , s ei z u r es , o r a n a ph y l ac t ic h yp e r se ns i ti v i t y t o v a c c in e an t ig e ns o r ac c es s ory c o m p o ne n ts (e . g. , a n t ib io t ic , c hi c k en p ro t ein ) . S e v e re re a c t io n s c o nt r a in d ic a te c o nt i nu a ti on o f a se r i es . A pe r s o n wi t h s e v e r e fe b ri l e i ll ne s s s h ou l d n o t b e ac t i v el y va c ci n at e d u n ti l t he il l nes s r e s o l v es . 2 . T yp e s o f a c t i ve vac ci n e s a . L i ve , a t te n u at e d vacc i n es c o ns is t o f wh o le or g a ni s m s ( us u al l y v i ru ses ) . Th e s e o r g an is m s m ul t ip ly a f t e r v ac c i na t io n , b ut ar e a tt e nu a te d t o re d uc e t h e ir p at h og en ic i t y . ( 1 ) A s m a ll d os e p ro d uc e s a s t r o ng i m m u ne re s po n s e be c a us e th e a n ti gen c o nc en t r at i on in c re as es wh e n t h e o r ga n is m m u lt ip l ie s . S om e vac c i ne s e lic i t l i f el on g i m m un i t y in t wo d o s e s —f o r e xa m p l e, t he m e as le s , m u m p s , r ub e ll a ( M M R ) v a c c i ne . Be c a us e o f th ei r r el a ti ve ge n et ic i n st a bi li t y , v i r us es c a n r e v e r t to v i r ul en c e a nd c a u s e th e d is e as e a ga i ns t wh i c h th e p a ti en t is va c ci n at e d . Th i s is a p a rt i c u l ar p ro b le m wi t h on e o f t he s e ro t y p es of t he o r a l p ol i o v a c c in e ( O P V ). ( 2 ) Li ve , at t en u at e d v i r a l v a c c i ne s a r e n o t r ec om m e nd e d f o r p r eg na n t wo m e n o r t ho s e in t en d ing t o b ec om e p r eg n an t wit h i n 3 m on t hs of
va c ci n at i on . L i v e , a t te n ua t e d v i r a l o r b ac t e ri al v ac c i n es a r e n o t g i v en t o i m m u no c o m p r om is e d i ndi v i d ua ls . b . K i l le d , i n ac t i va t ed va c c in e s m a y c on t ai n who l e k il le d c el ls ( e. g . , p h e no l -k il le d Bo r d et e ll a p e r t us s is ) o r a n y a n ti g eni c fr ac t io n i s o l at e d f r om t h e o r g an is m . Th e y a re u s ua ll y g i v e n a ds o rb ed to a dj u va nt . c . S om e is o la t ed an t ig ens ( su b u ni t va c ci n es ) m a y r e q ui r e i na ct i v a ti o n b e f o re th e y a re us ed in a v a c c in e — fo r e xa m p l e , f o rm a ld e h y de - m o di f ie d t o xi n o f C lo s t r id i u m te t an i , k no wn a s te t an u s t ox o i d (T d ) a f te r m o di f ic at i on . I n ac t i v at i on e li m i na t es pa t ho g en ic ity , b u t p r es e r ves s om e a n t ig en ic i t y . O th e r s ub un i t v ac c i ne s i nc lu d e p r ote i ns an d g l y co p r ot ei n s of a n o rg an is m t h at a re p rod u c e d b y r ec om b in a nt DN A t e c h no l og y i n b ac t er ia , ye a s t , o r m am m a li a n c e l ls an d a r e t h en us ed as th e an t ig e ns f o r va c ci n at i on . Th e H B V v ac c i n e c o n t ai ns pr o te i ns pr o d uc ed b y r ec om bi na n t g e n et ic te c h n ol o gi es an d i s a pp r o v e d b y t he F D A f o r us e i n h um an s . ( 1 ) B ec au s e n o li v e o rg an i s m s a re p re s e n t, r e v e rs i on to pa t ho g en ic i t y i s n o t a p r ob le m . H o we v e r , do s e s o f c e ll s o r a n ti ge n s m u s t b e h ig h e r t ha n i n l i v e, a t t en u at e d v a c c i ne s , and h y p e rs en s i t i v it y r e ac tio n s t o v ac c i ne c o m p on en t s a r e m o re c o m m on . Mi n im um e ff ec t i ve d os es a re u s u a ll y m e as u r ed in n u m b e rs of c e ll s o r m ic ro g r am s o f a n ti ge n . ( 2 ) V ac c i ne s i n wh ic h t he a nt i ge ni c f r a gm en t i s a p o l ys ac c ha r id e (e . g. , H a e m o p hi lu s b ) ar e u s u al l y p oo r at el ic i ti ng im m un e r es po ns es an d m em o r y, pr o ba b l y b ec a us e th e y do no t e vo k e T c e l l a ct i v a ti o n. Th e se va c ci n es ha v e be e n im p ro v e d b y c o nj ug a ti n g t he p o l y sa c c ha r i de to an o the r a n t ig en ic c o m p o un d (e . g. , Td ) . Th es e a r e k no wn a s c o n ju g a te va c ci n es . 4 . E xp e r i me n ta l va cc i ne s in c l ud e ot h er s u bu n it v a c c i n es ; p e pt i de s p r o du c e d b y c he m i c a l , c e l l -f r e e s y n th es is ; re c o m b i n a n t D N A vi r us es c o nt a in in g ge ne s f o r t h e a n t ig en s o f m ul t ip l e o r gan i sm s ; an d a n ti - id i ot yp e a n t ib od i es us ed fo r ac ti v e v a c c in a ti o n. 5 . S pe c i fi c va cc i n es i n c om m o n u s e a nd re c om m e nd e d a dm in is t ra t io n s ch e du l es a r e l is t ed in Ta b le 10 - 3 . D . S i m ul t a ne o us a dm i ni s t r a t io n o f a ct i ve a nd p a s si ve va c c in e s. S o m et im es ac t i v e a nd pa s s i v e v ac c i n es a g ai ns t a p at h og e ni c o rg a ni s m ar e a d m i ni s te r ed s i m u l ta ne ou s l y to m a xi m i ze p os t e xp o s u r e p r op h y l a xi s . Th e i m m u no gl o bu l in of f e rs im m e d ia t e p r ot ec t io n , a nd t he ac t i v e v a c c in e s t im ul a te s a n i m m un e res p on s e . Th es e v ac ci ne s a r e gi v e n a t s ep a r at e s ite s t o p re ve n t a n ti bo d y ( pa s s i v e ) a n d a nt i ge n ( a ct i v e) f r om r ea ct i ng an d i n ac t i vat i ng on e a n ot h er . 1 . I nf a nt s wi t h H B V wh o a r e bo r n t o m ot h e rs wh o h a ve th e h ep a ti t is B s u r fa ce an t ig e n ( H B s Ag ) a r e s ig n if ic a nt l y p ro t ec te d f ro m b ec om in g c h ro n ic c a r ri e rs b y th is c o m b in ed p r op h yla xi s . 2 . R a bi e s. P os t e xp o s u r e p r o ph y l a xi s t y pi c a l l y i ncl u de s t h e co m bi ne d u s e o f a c ti ve an d p a s s i v e v a c c in e s b ec au s e o f t he le t hal n at u r e o f t he un c he c k ed i n f ec ti o n. Th e e xc e pt i on i s p a ti e nt s wi t h a p r e v i ou s a c ti v e v ac c i n at i on wh o h a ve s u f fi c i en t e xi s ti n g s e r u m a nt i bo d y c o nc en t r at i o n. P.222
3 . T et a n us . Co m b i ne d pr o p h y la xi s i s s o m e t im es u s ed , d e pe n di ng on t he t yp e o f wo u n d a n d t he pa t i en t ' s h is to r y o f a c t i ve v a c c i n at i on . R ec om m e nde d g u id e li n es a r e a s f ol l o ws : a . A t e t a n us - p r on e w oun d is on e t h at p ro d uc es a n a er o bi c co n di t io ns ( e.g . , d e e p p un c t u r e) o r o ne in wh i c h e xp o s u r e t o Cl os tr i d iu m o r i t s s p o re s i s p r o ba b le ( e. g ., c o n ta m i na t e d wi t h an im a l f ec es ) . I f t he pa t ie n t 's hi s t o r y o f a c ti ve va c c in a ti o n is un c e r t ai n or in c l u de s f e we r th a n t h r ee do s e s, bo t h TIG a n d Td a r e a dm i ni s t e re d. Th e p at ie n t re t ur ns t o c o m pl e te th e to xo i d s e r ies . ( 1 ) I f t he wo u n d i s t et a nu s - pr o ne bu t th e p a ti e nt r e c ei v e d a fu l l s e r ie s o f a c ti ve va c c in a ti o n, no t re a tm e nt is ne c e s s a r y i f th e la s t Td d os e wa s r e c ei ve d wi t hi n t h e l as t 5 y e a rs . ( 2 ) I f t he la s t d os e wa s re c ei v e d m o re th a n 1 0 y ea r s a g o, Td , bu t n o t TI G , i s g i v e n t o b oo s t m e m o ry i m m u ni t y a nd an t ib od y p r o du c ti on . b . F o r a c l ea n , m i no r w o u n d , i f t h e p at i en t ' s h is t o r y o f a ct i v e vac ci n at ion i s u nc e r ta i n o r i nc lu d es fe we r t h a n t h re e d os es , Td is ad m i n is te r e d. ( 1 ) I f t he pa t ie n t r e c e i v ed a fu ll s e r ie s o f a c t i v e va cc i na t io ns , n o t re a tm ent i s n ec es s ar y i f t h e l as t Td d os e wa s r ec e i v ed wi th i n 1 0 yea r s . ( 2 ) I f t he la s t d os e wa s re c ei v e d m o re th a n 1 0 y ea r s a g o, Td , bu t n o t TI G , i s g i v e n t o b oo s t m e m o ry i m m u ni t y a nd an t ib od y p r o du c ti on .
VII. PROSPECTS FOR IMMUNOMODULATION A. F a b a n ti d i go x i n a n tib o d y p r e p a r at i on s o bt a in e d f r om s h ee p a r e a p p ro ve d fo r th e re v e r s al o f t o xi c i t y a s s oc i at e d wi t h t o xi c d ig o xi n se r um l e ve ls . Th e a n ti bo d y bi nd s d i go xi n a n d p re ve n ts i t f ro m b in d in g t o i t s n orm a l r e c ep t or s i t e. Th e Fa b -d ig o xi n c om pl e x i s e xc r e ted r e na ll y. B . M on o c lo n al a nt i b od ie s a re ge ne r a ll y p ro d uc ed t h ro u gh th e i n v it r o f u si o n o f a c a nc e ro us pla s m a c el l (m ye lo m a ) wi th a n ac t i v a te d m ou s e B c e ll . Th e r es u lt i ng h yb r i d o m a s ec re t es m u r in e (m o us e ) a nt i bo di es o f a s i ng le de f in e d s pe c i f ic it y a n d h as th e i m m o rt al i t y c h a ra c t e ri s ti c o f t h e m ye l om a. Te c hn iq u es for t h e p r od uc t io n o f h um an m o n oc lo n al an t ib od i es a n d a va r ie t y o f h y b ri d m o u s e - hu m an m o no c l on a l a n t i b od i es ar e a ls o a va i la b le . 1 . M o n oc l o na l a n t ib o d ie s — f or e xa m p le , wh o le a n t ib od i es or F ab or F (ab ' ) 2 f r a gm e nt s —a r e r o ut i ne l y u s e d fo r i n vi tr o di ag n os t i c t es ts ( e .g . , b lo o d g rou p a n d t is su e t y pi ng f o r H LA ) , s c r ee n in g f o r c an ce r -r e l at e d a n ti ge ns ( e. g . , c a rc i no em b r y on ic an t ig en ; C E A ) , u r in e t es t in g for d r ug s a n d m e t ab o li te s , a n d t es t in g fo r H I V i nf ec t i o n. In t he se an d m an y o t h e r d ia gn os t ic a p pl ic a ti o ns , m on oc l on al a n ti b od ie s a r e o f te n c onj u ga t ed t o e n z ym es , r a d io is o to p es , o r fl uo r es c e nt d y es . 2 . M u r o mo n a b- C D 3 is us e d t o t r ea t ac ut e g r a f t re j ec t io n . O t h e r m o n oc lon a l a n t ib od i es ar e u s e d fo r tr e a tm e nt of b re as t c a nc er a n d l eu ke m i a . 3 . I n cl in i c a l t r ia ls , th e us e o f mo n oc l o na l a n t i bo d i es a ga i ns t T c e ll s c a us es i m pr o v em e n t in c e r t ai n au t oi m m un e d is o rd e r s.
4 . M o n oc l o na l a n t ib o d ie s ag a i ns t ne o pl a s ti c ce l l s s ho w s o m e s uc c e ss , a n d a r e u s e f ul in t re a ti ng c e r t ai n l e uk em ia s a nd l y m p ho m a s , as we l l a s b r e as t a n d c o l on c a nc e rs . C . M on o c lo n al a nt i b od ie s a re c on j ug a t ed t o e nz ym e s , d r u gs , p ro d r u gs , r a d i o is o t op e s, o r pl a n t a n d ba c te r i a l t o xi n s t o p r o v i de s p ec i fi c d el i ve r y o f t he c o nj ug a te d a g en t t o on e o r m o r e f oc us e d in v i v o si t es o f ac ti o n. S e ve r a l p r ob le m s a re as s oc i at e d wi t h t he us e o f t h es e a g en t s. 1 . I mm u no t o xi n s a r e us u a ll y p r od uc e d b y t he c on j ug a ti o n o f a m o no c l o na l a n t ib od y t o a bi o lo gi c p ol y p e p ti de t o xi n ( e. g ., di p h t h e ri a t o xi n ) t ha t i s m o di f ie d t o re d uc e n on s p e c i f ic to xi c i t y . 2 . A lt h ou g h t he y a r e b ein g te s te d f o r g r a ft r ej ec t io n an d a u to im m u n it y , i m m u no t o xi n s a r e p ri m ari l y us e d as an t in e op l as tic a g e nt s . C l in ic al t ri a ls s h o w m od e ra t e s uc c es s i n t re a ti ng le u ke m i a a nd l y m p ho m a , wi t h l o we r s uc c ess r at es ag a in s t t um o rs s u c h as b r e as t c arc i no m a . 3 . M o n oc l o na l a n t ib o d ie s co n j ug a te d t o r a d io is o t o pe s (e . g. ,
90
Y) c a use
r e m iss i on s i n p at i en ts wi t h H od g ki n d is ea s e an d a c u t e T c e l l le u ke m i a . 4 . M o n oc l o na l a n t ib o d ie s co n j ug a te d t o e nz ym e s t h at ac t i vat e a p ro dr u g t o t he ac ti v e d ru g a t a s p e c i f ic ti ss ue s i te ( e. g . , n e o pl as ti c c el l s u rf ac e ) a r e i n hu m a n t r i al s . P.223
D . I m mu n os t i mu l a ti o n h a s b ee n a t te m pt e d wi t h a v a r ie t y o f c o m p o un ds , r a n gi n g f r om c y t ok i ne s to b ac te r i al pr o du c t s ( Tab l e 1 0 -1 ) . 1 . I F N - α h as m a n y s u bt y p e s . Two a r e c u r r en t l y FD A a p p ro ve d . B ec a us e i t i n hi b it s c el l g r o wt h , i t i s u s ed to t re a t h ai r y c el l le u k e m i a , K a po s i s a rc om a i n pa t ie n ts wi t h AI D S , a nd g en i ta l wa r ts . A t l o w do s es , i n te r fe r o ns s t im ul at e i m m u ne c e ll ul a r f u nc t io n ( e . g. , T c e l ls , N K ce l ls , m ac r o ph a ge s) , bu t a t hi gh d o se s, t he y a r e im m u n os u p p re s s i ve . Th e us e o f IF N - α a g ai ns t o t he r c a nc e rs p r o du c e s v a r i abl e re s ul ts . 2 . I F N -γ p r o v i de s g r ea t er i m m un os t im ul a ti o n in th e in t ac t i m m un e s y s te m , b u t i t s e ff ec t s d ep e nd on d os e a n d t im in g . Th e c om b in e d us e o f IF N - α a nd I F N - γ yie ld s b e tt e r re s u l ts . Th e m os t c om m o n s ide e f fe ct s o f i n te r f er o n t h e r ap y a r e in f lu e n z a -l ik e s y m p t om s . IF N - γ i s a pp r o ve d f o r u se as a m ac r o ph a ge - ac ti v a t in g fa c to r in c h r on ic g ra nu l om a to us di s e a se . 3 . S e ve ra l p r o to c o ls us ing I L -2 s h o w p r om is in g res u lt s , wi t h ap p a re n tl y c om p le t e r em is s i o ns i n s o m e p at i en ts wi t h m e la no m a. W it h t h is te c h ni q ue, k n o wn as ad op t i v e i m m un o t he r ap y , a p a ti e nt ' s p er i p h e r al bl o od l ym p ho c y t es , o r t u m o r - inf i l t ra t in g l ym ph oc y t es , a re r em o v e d. Th e y a re c u lt u r ed wi t h I L - 2 a nd r ei n f us ed wi t h a d di t io n al IL - 2 . Th es e I L -2 - r es po n s ive c e ll s a r e li k el y T c el ls and N K c e ll s . S e ve re c a pi l la r y l e ak ag e s y n d ro m e , o cc a si on a ll y l ea di n g t o de a t h, is a p ro b le m a t ic s id e ef f ec t . 4 . H o r mo n es o f t h e t h ym u s t h a t in d uc e T c e ll m a t u r at i on an d o t he r f u nc t io ns a re us ed t o i nc r e a s e c e r ta i n ce ll - m e d ia te d im m u ne fu nc t io n s, wi th va r i a bl e re s u l ts .
5 . S ul f u r- c on t ai ni n g c o m p o u nd s , su c h as le va m is o l e ( a p h en y l im i do t hi a zo l e a n t he lm in t ic ) an d d ie t h y ld i t hi oc a rb am a te ( Im u t h io l ) , ha v e i m m u no s t im u la t o r y a c ti v it y . Th e i r ef f ec t i s g r ea t er o n c el l -m e di a te d i m m u ni t y t ha n o n h um o ra l im m u ni t y . Le v a m i so le i s a p p ro v e d a s a n o r al a g e nt fo r us e i n c ol on c an c e r i n c o m b i na t io n wi t h f l u or o u ra c i l . 6 . I no s in e p ra n o be x i s li c en s e d f o r u s e in m a n y c o un t r ie s as an i m m u no s t im u la n t. I t i nd uc es T c el l d i ff e r en t ia t io n a n d a u gm en ts ce ll m e di a te d i m m un e f u nc ti on s , wi t h m i n im al to xi c i t y. 7 . A s a c om po n en t o f m y c o ba c t e r ia l c el l wa ll s , mu r a m yl d i p e p t i d e ( M D P ) s t im ul a te s m ac r op ha g e ac t i v a ti on an d m a y be us ed as an ad j u van t , g i ve n wi t h a n ti g en (s e e I ) , o r gi v e n al on e as a n i m m un os t im ul a nt . P.224
STUDY QUESTIONS D i r e c t i on s : E a c h qu es t io n , s t at em e nt , or i te m o r i nc om p le t e s ta t em en t i n t h is se ct i on c a n b e c o r r ec t l y an s we r ed o r c om pl e te d b y on e o f th e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r . 1 . A m a n h a s s ym p t o m s o f a vi r a l in f ec t i o n o f a b o u t 4 da ys ' d u r a t i o n . T o c on f i r m t h e d i ag n osi s , t he ph ys i c i a n d raw s a b lo o d s am p l e a nd r e q u es t s th e a n t i bo d y t i t e r ( le ve l ) f o r t h e s u spe c t e d a ge n t . T h e f i r s t b l o o d s am p le s how s a low ti t e r of a nt i b od y. A w e ek la t e r , a n ot h e r b l oo d s a m pl e is d raw n , a n d th e t i te r a ga i ns t t he vi r us i s m u ch hi g h e r. T hi s s i t u a ti o n i s a n e x am p le o f ( A ) a n i nf l am m a t or y r e s po n se to t he v i r al i n fe c ti on . ( B ) a pr im a r y im m u ne r es p on s e t o t he v i r al i n f ec ti o n . ( C ) a s ec o nd a r y im m u ne r e s p o ns e t o t h e vi r al in fe c ti o n. ( D ) a c e ll ul a r re s p o ns e to t he v i r al in f ec ti o n. V i e w A n s we r 1 . T h e a n sw e r i s B [ se ea n d] .2 . W h ic h c la ss o f a n t i bo d y h a s t h e l o ng es t s e ru m h a l f -l i f e a n d op s o n iz es an t i ge n s f o r p h a g oc yt o s i s t h r ou g h tw o d i f f e re n t pa t hw a ys ? ( A ) I m m un o gl ob u li n G (Ig G ) ( B ) I m m un o gl ob u li n M ( Ig M) ( C ) I m m un o gl o bu li n A ( Ig A ) ( D ) I m m un o gl o bu li n E ( Ig E ) V i e w A n s we r 2 . T h e a n sw e r i s A [ se e] . 3 . U r ti c a ri a t ha t ap p ea r s r a p i d l y a f t e r t h e i ng e st io n o f fo o d u s ua l l y i n d i c a t es w h i ch t yp e o f h yp e r s e n s i t i vi t y r e a c t io n ? ( A ) Ty p e I ( B ) Ty p e I I ( C ) Ty p e I I I ( D ) Ty p e I V
V i e w A n s we r 3 . T h e a n sw e r i s A [ se ea n d] .4 . I n w h ic h au t o im m un e d i s o r de r i s t h e m ec h ani s m o f p at h o ge n es i s c la s s i fi e d a s t yp e I I h yp e r s e n s i t i vi t y? ( A ) S y s t em ic l u pu s e r y t he m at os u s ( S L E ) ( B ) I ns u li n -d e pe nd e nt dia b e te s m e l li t us (I D D M) ( C ) G r a v e ' s di s e as e ( D ) H a s h im o to ' s th y r o id i ti s V i e w A n s we r 4 . T h e a n sw e r i s C [ se ea n d] .5 . A pa t i e n t r e ce i ve s l o n g - te r m , h i g h- d o se t he r a p y w i t h a s ul f o na m id e . Af t e r a pp r o x im a te l y 3 w e ek s o f t he r a p y, t h e p a t i e n t h as a l ow - g r ad e f e ve r , r a s h, an d m u sc l e a n d jo i n t p a in . Wh i ch typ e o f h yp e r s e n s i t i vi t y a c co u n ts f o r th e se s ym p t o m s ? ( A ) Ty p e I ( B ) Ty p e I I ( C ) Ty p e I I I ( D ) Ty p e I V V i e w A n s we r 5 . T h e a n sw e r i s C [ se ea n d] .6 . I n w h ic h t yp e I V h yp e r s e n s i t i vi t y r e a c t io n i s t h e t i ss u e -d a ma g in g d is o r d e r c o ns i de r e d a n i na p p r op r i a te r es p on s e b y t h e i m m un e s ys t e m ? ( A ) P o is on i v y d er m a t i ti s ( B ) C h r on ic t ub e rc ul os is ( C ) A c ut e g r a ft r ej ec t io n ( D ) Tu b e r c u li n te s t V i e w A n s we r 6 . T h e a n sw e r i s A [ se e] . My c o b a c te r i u m .7 . W h i ch a g e n t i s c om m o nl y u s e d t o t r ea t m u l t ip l e s cl e ro s i s ( M S )? ( A ) N e os t ig m i ne ( B ) C y a n oc o ba la m i n ( C ) I F N - β - 1b ( D ) P r o p y lt h io u ra c i l V i e w A n s we r 7 . T h e a n sw e r i s C [ se e] . 8 . T h e t he r a p eu t i c ro l e o f m u r o m on a b - C D3 i n a cut e r e na l g ra f t r ej e c ti o n i s p r ob a b l y b a s e d o n ( A ) a c t i v a ti o n o f T c e ll fun c ti o n a nd s e c r e ti o n o f cy t o k in es . ( B ) d es t ru c ti on o f T c el ls b y c om pl em e nt . ( C ) o ps o ni z a t io n o f T c e ll s fo r p h ag oc y t o s i s . ( D ) s el ec t i v e i nh i bi ti o n of T H c e ll fu nc t io n . V i e w A n s we r 8 . T h e a n sw e r i s C [ se e] . 9 . W h ic h i s a c u r r en t c li n ic a l a p p l ic a t io n o f i n t ra ve no u s hu m an im m un o g lob u l i n ( I V I G ) ? ( A ) P r o ph y l a xi s af t e r h epa t i ti s B v i r us ( H B V ) e xp o s u r e ( B ) Tr e a t m e n t o f h um o ral im m u n od e fi c i en c y ( C ) P r o ph y l ac t ic in f an t im m u n i zat i on fo r po l io ( D ) P r o ph y l a xi s f or R h d is e as e b y i nf a nt im m u ni za t i on V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . 1 0. W hi c h c yt o k i n e i s a p p r o ve d fo r t he t r ea tm e n t o f ce r t a in f o rm s of c a nc e r ? ( A ) I n te r le uk i n 2 (I L - 2) ( B ) I n te r f er o n α ( I F N - α )
( C ) I n te r f e ro n γ (I F N - γ ) ( D ) I m u t hi o l V i e w A n s we r 1 0 . T he a nsw e r i s B [ se e] . P . 22 5
F o r q ue s t io n s 1 1 a n d 12 : A 6 - y e a r - ol d c hi ld ha s a de e p p un c t u r e wo u n d . Th e p a r en t i s u ns u re of th e c h il d ' s hi s to r y o f vac c i n a ti on . 1 1 . If n o o t he r i n fo r m a ti o n is a va i la b le , w ha t sh o u l d t h e p h ys i c i a n r e c o mm e nd ? ( A ) N o v ac c i n at i on ( B ) Te t a n us i m m un o gl obu l in ( TI G ) ( C ) Te t a n us to xo i d ( Td ) ( D ) B o t h TI G a n d Td a t s e p a ra t e s it es V i e w A n s we r 1 1 . T he a nsw e r i s D [ se e] . 1 2. I f t h e c h i l d r e ce i ve d a f u l l se r i es o f d i ph t h e r ia, p e r t us s is , te t a nu s ( DP T ) va c c in a t io n s, t he la s t a t e n t r y i n t o s c h oo l , w h a t sh o u ld t he p h ys i c i a n r e c om me n d ? ( A ) N o v ac c i n at i on ( B ) Te t a n us i m m un o gl obu l in ( TI G ) ( C ) Te t a n us to xo i d ( Td ) ( D ) B o t h TI G a n d Td a t s e p a ra t e s it es V i e w A n s we r 1 2 . T he a nsw e r i s A [ se e] . 1 3. P e r sis t e n t i n f ec t i on s b y o p p o r t un i s ti c pa t h og e ns , s uc h a s Ca n d id a a l b ic a n s a nd P n eu m oc y st i s c a r i n ii , co u ld i nd i ca t e a l l o f t h e f o ll ow i n g e xce p t ( A ) i nh e ri t ed T c el l i m m un o d ef ic ie n c y. ( B ) h um o ra l i m m un o de f ici e nc y . (C) AIDS. ( D ) c om bi n ed im m u no de fi c ie nc y . V i e w A n s we r 1 3 . T he a nsw e r i s B [ se e] . 1 4. W hi c h s t a te m en t ab o u t H I V i n f ec t i on is n o t c o rr e c t ? ( A ) I n di v i du a ls wh o b e c om e i n fe c te d wi t h H I V - 1 al wa y s s h o w o ve r t s y m p to m s s h or t l y af t e r in f ec t io n . ( B ) S e r oc on v e r s i on t o p os i ti v e s t a tu s f o r a n ti - H I V- 1 a nt i bo di es is th e p r i m a r y c ri te r i on fo r di agn o si s o f a vi ra l c a r ri e r . ( C ) Th e i nc ub a ti o n p er i od f o r t he pa t ho g en es is of A I D S is b e li e v ed t o be 8 y ea r s o r l on g e r af t e r th e i ni t ia l i n fe c t i on wi t h H I V. +
( D ) C D 4 T c el ls an d m ac r o ph ag e s m a y b e a bl e to s p r e ad H I V t o +
u n in f ec t ed C D 4 c el ls wi t h o ut r el e as in g a n y e xt r ac e ll ul a r vi ru s p a r ti c l e s . V i e w A n s we r 1 4 . T he a nsw e r i s A [ se e] . D i r e c ti o ns : Th e q u es t io ns a n d i nc om p le t e s t a te m ent s in th is s e c t io n c a n b e c o r re c tl y a ns we r e d o r c om p le t ed b y on e o r m or e o f t h e su g ge s te d a nswe r s . C h o os e t he an s we r , A-E. 1 5 . W h i ch s ta t em e n ts ab o u t th e c u r r e n tl y a p p r o ve d s he e p F a b f r a gm en t u s e d t o co u n te r a ct d igo x i n o ve r d o se a r e t r u e?
I . I t i s ob t a in e d b y t h e im m u ni za t i o n o f s h ee p w i t h a di g ox i n -p r o t e in c o n j ug a te a nd su b se q ue n t p r ot e o l yt i c c l e a va ge o f th e c o l le c te d a n t i bo d y. I I . I t s pe c i fi c al l y b i n d s d i g o xi n , p r e ve n t in g i ts a c t i vi t y. I I I . It h as a s e ru m ha l f -li f e o f a p p ro x im a t el y 3 w e ek s . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t +
V i e w A n s we r 1 5 . T he a nsw e r i s C [ se e] . 1 6. C D 4 T c e l l s s p e ci f i ca l l y r e c o g n i z e a n t i ge n s i n w hi c h fo r m? I . B o u nd t o m aj o r h is t oc o m pa t i bi l i t y ( M H C ) c l as s I m o le c ul e s o n th e s u r f a ce o f a n y b o d y c e l l I I . I n f r e e, so l u bl e fo r m i n ex t r a ce l lu l a r fl u i ds I I I . B ou n d t o M H C c la s s I I mo l ec u l es on t he sur f a c e o f sp e ci a l a n t ig en p r e s en t i n g c el l s ( AP C s ) A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 6 . T he a nsw e r i s B [ se e] . 1 7. W ha t i s a n o r ma l o u t c om e o f t he ac t i va t io n o f th e c o mp l em e n t sys t e m b y e i t h e r t h e c l a ss i c o r al t e r na t i ve pa t hw a y? I . Ac u t e in f l am m a ti o n I I . O p so n iz a t io n of i mmu n e c o m pl e xe s I I I . C yt o l yt i c a c t i o n A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 7 . T he a nsw e r i s E [s e e] . 1 8. I n a n tivi r a l i m mu n i t y, w h a t d i r ec t l y r e c o g n i z es a nd k il l s vi r al - i n fe c ted c e ll s ? I . C yt o t o x i c T c e ll s ( CTL s ) I I . An t i vi r a l an t i b od i es I I I . In t e r fe r o n s A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 8 . T he a nsw e r i s A [ se e] . P . 22 6
1 9 . A p a t ie n t i s t re a t ed w i t h p en i c il l i n a nd p r od u c es an t i b od i es ag a i ns t t h e d r ug . Th e y a r e s t i l l m o s t l y p r e s e n t . An e mer g e n c y s i t u a t i o n r e q u i r es ad m i ni s t r at i o n o f a n i n t ra ve n o us d ose o f pe n ic i l li n . I f t he p a t i en t ha s a t yp e I p e ni c i l li n h yp e r s e n s i t i vi t y r e a c t io n , w hi c h p a t h ol o g ic co n se q u en ce w o u l d b e e xp e c te d , an d w i t h in w h a t t i me c o u r se o f c l in i c al on s et ? I . H e mo l yt i c a n em i a, w it h a n o n se t o f 1 -2 h r a ft e r t h e i n t r a ve no u s d ose I I . An a p h yl a x i s , w it h an o n se t o f a few m i nu t es a f t e r th e i n t r a ve n ou s dose I I I . C ut a ne o u s u r t ic a r i a a n d p r u r i t us , w i th a n on s e t o f a f ew mi n u te s a f t e r t he in t r a ve n o us do s e A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 9 . T he a nsw e r i s D [ se ea n d] .2 0 . Wh i c h s i t ua t i on o c c u rs i n a l l t yp e I V h yp e r s en s i t i vi t y r e a c t i o ns ? I . I n fi l t r a ti o n o f t he a ff ec t e d ti s su e b y m o n o n uc l e a r c e ll s I I . A d e l a y o f 1 2 h r o r lo n g e r i n t he on s e t o f c li n i c al s ym p t o m s a f te r a l l e r ge n c o n ta c t I I I . Si g n i fi c an t be n e fi c ia l e f fe c t o f th e ad m in i st r a t i o n o f H 1 -a n ta g o ni s ts A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 0 . T he a nsw e r i s C [ se ea n d] .2 1 . Wh i c h i m mu n o lo g ic f i n d i ng is n o t u n iq u e t o s ys t e m i c lu p u s e r yt h e m a t o su s (S L E ) ? I . H yp e r g a m m ag l o bu l i ne m i a I I . Th e p re s en c e o f c i r cu l a t i ng an t i nu c le a r an t ib o d i es I I I . Th e p r e se n ce o f c i rc u l a ti n g rh e um a t oi d fac t o r s A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 1 . T he a nsw e r i s E [s e e] . 2 2. An o rg a n do n o r w ho i s h u m an l eu k oc yt e a n t i ge n ( H L A) m a tc h ed w i t h t h e r ec i p ie n t o f a g r a f t i s s o u g ht . Wh i c h i n di vi d ua l i s a t l e as t so mew h a t l i k el y t o p r o vi d e a t o t al HLA match? I . A s i b l in g o f t h e g r a f t r e c i p ie n t I I . A p a r e n t o f th e g r a f t r e c i pi e n t
I I I . A c a da ve r A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 2 . T he a nsw e r i s A [ se e] . 2 3. G r a f t -ve r s u s - h os t ( G V H ) d i s ea s e i s a ss o c ia t ed pr i m a r i l y w i t h w hi c h t yp e o f t ra n s pl a n ta t i on ? I . K i d ne y I I . H ea r t I I I . B on e m a r r ow A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 3 . T he a nsw e r i s B [ se e] . 2 4. T he pr o p h yl a c t i c us e o f c yc l o s p o r i n e i n g r a f t rej e c t io n is p r ob a bl y b a s e d o n i t s a b il i t y t o I . i nh i b i t s yn t h e s i s o f an t i b o di e s, t he r e b y p r e v e n t i ng h yp e r a c u t e r e j e c ti o n . I I . i nh i bi t ac t i va t i on o f T c e l l s , t h e re b y p r e ve n t i n g ac u te r e je c t io n . I I I . bl o ck t r an s c r ip t i on o f t h e i n te r l e uk i n 2 ( IL -2 ) g en e a n d s yn t h e s i s o r s e c r e ti o n o f IL - 2 . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 4 . T he a nsw e r i s D [ se e] . 2 5. W hi c h i s a va l i d c o m pa r i s on o f l i ve , a t te n u a te d a n d k i ll e d , i nac t i va t e d a c ti ve va c c i nes ? I . R e pl i ca t i o n o f th e o r g a n is m s i n a l i ve , a t te nu a t e d va c c in e in c r ea s es t h e s ti m ul a t io n o f t h e im m u ne s ys t e m a n d a l ow e r d o se i s o f t en r e q u i r ed . I I . At t e n u a te d va cc i ne s o f t e n r e q ui r e m u l t ip l e d o s es . I I I . A k i l le d , i n ac t i va t ed va c c i ne p r ob a b l y p r o d u c e s l i fe l o ng im m u ni t y i n o n e o r tw o d os es . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 5 . T he a nsw e r i s A [ se ea n d] .2 6 . Wh i c h a c t i ve va c c i n e i s re c om me n d ed f o r he a l th c a re w o r ke r s b u t i s n o t r ou t i ne l y g i ve n t o i n f an t s ? I . M e a sl e s, mu m ps , r ube l l a ( M M R ) va cc i n e
I I . I nf l u en z a p ol yva l e n t I I I . Te t an u s t o x oi d (T d ) A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 6 . T he a nsw e r i s D [ se e] . 2 7. W hi c h s t a te m en t ab o u t p n e um o c oc c us an d m en i n g oc o cc u s va c c in e s is t r u e? I . T he y a r e c o m po s ed of p u r i f ie d p o l ys a c c h a r id e s . I I . Th e y a r e r e c om m en de d f o r c h il d r e n < 2 ye a r s o f a g e . I I I . Th e va cc i ne s p r o t ect a g ai n s t a l l s e ro t yp e s o f d i se as e c a us i n g p n e um o c oc c us o r m en in g o c oc c us . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 7 . T he a nsw e r i s A [ se e] . P . 22 7
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee 1 . C . 2 a nd 3] . A p r im a r y i m m u ne re s pon s e t o a n i n fe ct i on is c ha r a c t e ri ze d b y t h e i ni t ia l p r o du c ti on o f I g M, b e gi nn i ng ab o u t 4 d a ys a f te r a n t ig en is en co u nt e re d . A s wi t c h t o a di f f er e nt im m u n o gl ob u li n i so t y p e ( i .e . , I g G , Ig E , o r Ig A ) occ u rs b e f o re th e p e ak o f an t ibo d y p r od uc t io n i s r e ac hed . Th e pe ak pr im a r y i m m u ne r es po ns e o c c u rs 1 0 - 14 da y s a f t er t he an ti g en is en c o u nt e re d , a n d t h e s e ru m c on t ai ns bo t h I g M a n d I g G . 2 . T he an sw e r is A [ s ee I . D . 2. b ; I . E ] . I g G h as a s e r um ha l f- l if e o f 25 - 35 da y s , l o ng e r t ha n th a t o f a n y o th e r cl as s , a l t ho ug h m as t c el l - bo und I g E h as th e l o ng es t h al f - l i f e . I n g en e ra l , i m m une c om p le xe s c on t ai ni n g I gG a r e op s o ni ze d fo r ph ag o c y to s i s t h r ou gh bi n di ng t o t he Ig G r ec e pt o rs on n e u t ro ph i ls a n d m a c ro p ha g es an d a d di t io na l l y t h r o ug h t h e ac t i v a ti on o f c om pl em e nt . Ig M a l s o op s on i z es , bu t o nl y t h r oug h t h e a c ti v a t io n o f c om pl em e nt . 3 . T he an sw e r is A [ s ee I I . A .5 . a a nd b ]. F o o d a ll e rg i es a r e u s u a lly t y p e I re ac t io ns . In a pa t i en t wi t h p r ee xi s t i ng h yp e r se c re t ed Ig E s p ec i fi c to a f oo d a ll e r ge n a n d b o un d t o m as t c el ls , th e a l le r g ic re s p o ns e us u al l y o c c u rs s h o rt l y af t e r i ng e s t io n . Ma s t c el l s ec re t ion s l e ad t o vo m i t in g . S y s t em i c s pi l lo v e r of al le r g en int o t he c i rc ul a ti o n m a y l ea d t o m i ld e r e f fe c ts i n o t he r t i s s ue s ( e .g . , u r ti c a r i a) . 4 . T he an sw e r is C [ s ee I I . C .1 a nd 2. c; I II . D . 2. b ].
I n G r a ves ' d is ea s e , a n an t i bo d y ac ti n g as a TS H a g o ni s t h ype r s t im u la t es t h e th yr o id . In S LE , pe r s i s te n t c ir cu l at i ng im m u ne c om pl e xe s a re r e s po ns ib l e f o r m uc h o f th e pa t ho g en es is ( t y pe I II) . I n I D D M, T c e l l c yt o t o xi c it y t o b e ta is le t c e ll s is p ro b ab l y re s po ns i b le f or t he m a jo r p a t ho g en es is ( t y pe I V ). In H a s h im o to ' s t h y r oi d it is, a n ti bo d ie s t o t h y r oi d p e r o xi d as e m a y in i ti a te in f l am m a ti o n b ut T H 1 c e l ls an d m ac r op h ag es i n f il t ra t e t h e o rg a n ( Ty p e I V ) . 5 . T he an sw e r is C [ s ee I I . D .2 . c ; I I. D . 4 .a an d b ; I I . D . 5. a ] . O n e o f t he m o s t c o m m on c au s e s o f t y pe I II h ype rs e ns it i vi t y is t h e r es p on se t o d ru gs . Th is t y pe o f r ea c ti o n is o ft e n se e n a f te r l o ng - t er m , h ig h -d os e t h e r ap y. Th e t re a tm en t of c ho ic e i s t o d is c o n ti nu e t r e at m e n t a nd s u bs t it u te a n un r el a te d d r u g. 6 . T he an sw e r is A [ s ee I I . E .1 ] . P o i so n i v y c on t ai ns a h ap t e n, pe n ta d ec y l c a te c ho l , wh ic h i s n o t kn o wn t o b e t o xi c . Th e r e fo r e , i ts c apa c it y t o e l ic it an im m u ne r e s p o ns e is in a pp r op r i ate b e ca us e i t s e r v es no us ef u l f u nc ti o n . I n c h r o ni c tu b e rc ul os is , th e i m m un e r e s po ns e i s a t te m p t in g , a l t ho ug h un s u cc es s f ul l y , t o el im in a te th e m yc o ba c t e ri a l p at h og e n. A c u te gr a f t r ej ec t io n i s a l s o ap p ro p r ia t e, bu t u n f o rt u na t e, be c a us e i t is a r e s p on s e ag a in s t f o re i gn t is s u e. A tu b er cu l in t e s t is an ap p r op r ia t e m an i f es ta t io n o f th e e xi s t e nc e o f ac ti v e im m u ni t y o r m em o r y t o My c o ba c te r ium . 7 . T he an sw e r is C [ s ee I I I . D .8 . b] . Tr e a t m en t wi t h I F N - β - 1b l o we r s th e f r eq u en c y of a t t ac ks b y 3 3 -5 0 % a t 2 ye a r s i n MS p a ti e nt s . N eo s ti gm i ne is u s e d a s a n a n t ic ho li n e rg ic ag e nt in m ya s th e ni a g r a v is . C y ano c ob a la m i n i s a dm in is t ere d i n au t oi m m un e p e r ni ci o us a n em ia to r epl a c e no n ab s o r be d vi ta m in B 1 2 . P r op yl t hi o u ra c i l is u s ed as an an ti t h y r oi d i n G r a v e s ' di s e as e . 8 . T he an sw e r is C [ s ee V . D . 2 .e ] . Mu r o m o n ab - C D 3 is a m ou s e a nt i - C D 3 m on oc lo n al a nt i bo d y th a t b in ds t o al l T c e l ls be c a us e C D3 is a c on s ta n t p a rt of t he an t ig e n re c e p to r of ea c h T c e ll . Th e b in d in g o f m u rom o na b - C D 3 o ps on i z es t he T c e ll s f o r p h a go c y to s i s . Th e r e fo r e , t h e t o ta l n um b er o f T c el l s is r ed uc e d. Mo u s e a n t ib od i es ar e i n ef f ic ie n t a t ac ti v a t in g h um a n c om p le m e n t. S om e T c e ll a c ti va t io n wi t h c y t ok in e s ec r e ti o n oc c u r s , b ut it is an un d es i ra bl e s id e e f fe c t o f m u r om on a b - C D3 ad m in i s t r a ti o n. 9 . T he an sw e r is B [ s ee V I . B . 1. c ; Ta b le 10 - 2 ]. I V I G s ar e u s e d to r ep la c e a nt i bo d y in im m u no d efi c ie n t i nd i vid u al s. H e pa t it i s B i m m un o gl ob u li n ( H BI G ) i s a dm in is t e re d i n tr am us cu l a rl y . A nt i - R h a nt i bo dy i s a ls o a dm i ni s t e r ed in t ra m us c u la r l y to t he m o the r im m e d ia t el y p os tp a r tum ( s om e ti m e s d u ri n g p re g na n c y ) , b u t n ot to t he in f an t . P ro p h y la ct ic in f an t i m m u ni z a t io n f o r p o li o is p r o v i de d t h ro u gh ac t i v e, n o t p as si ve , vac ci n at io n. P.228
1 0 . Th e a n sw e r i s B [ s ee V I I . D] .
I F N - α i s a pp r o v ed f or us e i n p at i en ts wi t h ha i r y c e l l l eu k e m i a a n d i n p a t ie n ts wi t h AI D S an d Ka p os i s a rc om a. S om e o f i t s b en e fi c i a l e ff e c t s p r o ba b l y d e r i v e f r om i t s a b il i t y to in h ib it g ro wt h . Th e o t he r c y t o k i n es a r e in va r i o us s t ag es o f c l i ni c a l t r i al s as an t in e op l as ti c th e r ap i es , a l th ou g h I F N -γ i s a p p ro v e d f o r u s e in pat i e nt s wi t h c h r o ni c g ra n ul o m a t ou s d is ea se . I m u th io l i s n ot a c y t ok ine b ut a s y n th e ti c d r ug . 1 1 . Th e a n sw e r i s D [ s ee V I . D .3 . a; Ta b le 10 - 3 ]. A p a ti e nt wi t h an un c e r tai n hi s t o r y of v a c c in a ti o n a n d a te t an us - p r on e wo u n d r e qu i re s b ot h a c tiv e a n d p as s i v e v ac c i n at io n . TI G p ro v i d es i m m e di a te p ro t ec ti o n i f th e in di v i d ua l d o es n o t ha v e m e m o r y. Td b eg i ns th e s e r ie s t ha t l e ad s t o t h e es t ab l is hm en t o f m em o r y . A t e ta nu s -p r o ne wo u n d i n a n in di vi d ua l wi t h a fu ll s e r i es of ac ti v e v a cc in a ti on s re q ui r es no t re a tm en t i f th e l as t v ac c i n a ti on in t h e s e ri es wa s ad m i ni s ter e d l e s s t h an 5 yea r s e a r li e r . Th e s e r ec om m e nd a t io ns a re ge ne r a l g ui de l in es . 1 2 . Th e a n sw e r i s A [ s ee V I . D .3 . a; Ta b le 10 - 3 ]. 1 3 . Th e a n sw e r i s B [ s ee I V . A ; I V . B. 6 ] . O p p o r tu n is ti c i n fe c t i on s b y f u ng i , vir us e s , an d p ar a s it es ot h e r t ha n e xt r a c e l lu la r p y og e ni c ba c te r i a s u g ge st a d e fi ci en c y o f T c el l fu nc t io n . I n h e ri t ed T c e l l im m u n ode f ic i en c y a n d A I D S ar e in h e ri t ed an d a c q u i re d T c e ll de f ic ie nc ie s , r es p ec ti v e l y . C om bi n ed im m u nod e f ic ie nc y i nc lu d es b o th h u m o r al an d T c e l l d ef ic ie n c y . O nl y h um or a l im m u n o d e fi c i e nc y is a p r im ar i l y h u m o r al de f ic ie nc y i n whi c h t he e xp e c te d s ig ns ar e r ec u r re n t i nf ec t io ns by e xt r a c e l lu la r p y og e ni c ba c te r i a. 1 4 . Th e a n sw e r i s A [ s ee I V . B .6 . a. ( 1 )] . I t is no t k no wn wh a t p e rc e n t ag e o f i n di vi d ua ls s ho ws o v e r t s y m p to m s a f t er i n i ti al in f ec ti o n. Th o s e wh o do , h o we v e r , ge n e ra lly s h o w m on o nu cl e os is -l ik e s ym p to m s fo r a p p ro xi m at e l y 3 we ek s . S om e i nd i vi d ua l s di s p l a y no o ver t s ym p to m s . 1 5 . Th e a n sw e r i s C ( I , II ) [ s e e I . A .4 ; I. D . 2 ; I . D .5; V I I . A] . D i g o xi n is a h ap t en , a m o l ec ul e th a t is t oo s m a l l t o st im u la t e r es po n s e s (b e a n im m u no g en ) i n i t s f r ee f o rm , b u t c a n b e re co gn i z e d b y a nt i bo d ie s . To o b t ai n s he e p a nt i di go xi n a n ti b od ie s , t he sh ee p i s i m m un i z e d wi t h di g o xi n t h a t h as be en c o u pl ed t o a la r g er m o le cu l e, in t his c a s e , a p ro t ei n . Th e a n t ib od i es ob t ai ne d fr om t h e s he ep a re c l ea v e d wi t h p r o te o l y ti c e n z y m es t o yi e l d t h e F ab f ra gm e nt . Th i s f ra gm e nt is s p ec if ic t o an d c an bi nd di g o xi n , b l oc ki n g i ts b i ol og ic ac t iv i t y . A n im al an t ib o di es h a ve a s h or t e r s e r um ha l fl i f e wh e n in je c te d i n to hu m an s , an d al l F ab f ra gm e n t s , e v e n h um an , h a ve a s h o rt ha l f -l i fe c om p ar e d t o c o m p le t e a n ti bo d y m ol e c u le s . O n l y c o m p le t e h u m a n I g G ha s a ha l f- l ife o f a pp r o xi m a te l y 1 m on t h . 1 6 . Th e a n sw e r i s B ( I I I) [ s e e I. B . 3; I . B. 5 ] . +
C D 4 , o r h e lp e r, T c el ls h a v e r ec ep t o rs t h a t r ec og n i ze f r a gm en ts ( ep i to p es ) o f im m u ni z i n g a nt i ge ns (i m m u no g en s ) on l y wh e n t h e fr a gm en t s a re bo u nd t o an MH C c l a s s I I m o lec u le on th e s u r fa c e of AP C s . As a r es u lt , T c e l ls +
c a nn o t b e a c t i v a te d i n app r o p ri a te l y b y s ol u bl e a nt i g en s. C D 8 T c e l ls r e c og ni z e f r ag m e n ts b o un d to MH C c l a s s I m o le c u l es .
1 7 . Th e a n sw e r i s E ( I , II , I I I) [s e e I . E .2 ] . W hen co m p l em en t i s a c t iv a t e d , d i ff e re n t p r o te in s o f t he c om p le m e n t s e qu e nc e h a v e f un c ti on s t h a t le a d t o a ll t hr e e a c ti o ns . Ac u te i n fl am m at io n a l lo ws g r ea t e r m o v em en t o f pl as m a pr o te i ns an d p h a g o c y te s f r om bl oo d to t i ss ue . O ps o ni z a ti o n o f im m u n e co m pl e xe s en han c es th ei r ph a go c yto si s . C yt o l ys is of m i c ro o rg a nis m s of t en r es ul ts in t he i r k il li n g . 1 8 . Th e a n sw e r i s A ( I ) [ s ee I .F . 2 ]. A n t i vi ra l a n ti b od ie s a r e p r o ba b l y m os t i m p o r ta n t i n e xt r a c e l lu la r im m u ni t y t o vi r u s es , b in d in g v ir u s p ar t i c l es fo r op so n i zat i on a n d p re ve n ti ng ad d it i on a l i n f ec ti o n o f c el ls . I n te r f er o n s a re s e c re t ed f ro m v i r a l -i n fe ct e d a nd ot h e r c e ll s ( e .g . , m ac r op ha g es , T c e ll s ) a nd , a f te r bi n din g to r ec ep t o rs , i nd uc e t h e a p pe a ra n c e of an t i v ir a l p r o te i ns i n o t he r c e lls . C TL s r e c o gn i z e vi ra l i n f ec te d c el ls an d c a us e d i r ec t c y t o to xi c i t y. P.229
1 9 . Th e a n sw e r i s D ( I I , I I I ) [s ee I I. A . 2. d ; I I . A .6 an d 7; I I. C . 1 .b ; II . C . 5] . I f t he pa t ie n t p r od uc e d an t i bo di es t ha t a r e s ti l l p re s en t a n d t he h yp e r se ns i ti v i t y r ea c t i on i s t y p e I , th es e a n ti b od ie s a r e I g E , m os tl y b ou n d t o m a st c e ll an d b as o ph il I g E re c e p to r s . Th e i r h alf - l i fe is s e v e ra l m on t hs to ye a r s . I n t ra v e no u s i nt r odu c ti o n o f p en ic i ll in c a us e s r ap i d ac t i vat i on of a nd s ec r e ti o n b y bl o od ba s op h il s . S ym p to m s o f t y pe I h y p e rs en si t i v it y o c c u r wi t h i n m i nu t es . Th es e s ym p to m s m a y be s e ve r e (a n a ph y l a xi s ) o r le ss s e ve r e ( c u t an e ou s , ga s t ro i n te s t i na l , o r re s p i ra t o ry ) , d e pe n di ng on t he i n di vi d ua l . H e m o l y ti c a ne m ia is a n e xp e c t e d r esu l t o f a t yp e I I h yp e r se ns i ti v i t y r ea c t i on t o pe ni c i l li n , b as ed on th e p re se nc e o f Ig M o r I gG a n t ib od i es i n th e s e ru m . Th e o ns e t i s d el a yed b y a f e w h o ur s i n a pa t ie n t wi t h p r e e xi s ti n g a nt i bo die s . 2 0 . Th e a n sw e r i s C ( I , II ) [ s e e I I . E .3 , 4 , 5 a nd 6]. Typ e I V h y p e rs e ns it i v i t y r e a c t i on s a r e d el a y ed a fte r t he in t r od uc t io n o f a l le r g en be c a us e a l le r gen - s pe c i f ic T c e ll s b ec om e a c t i v a te d a nd a tt r ac t o t h e r ce l ls , s u c h as m a c r o p ha g es , t o th e s it e o f a l le r g en in t ro d uc ti o n ( e .g . , t h e e p id e rm is of th e s k i n i n c on t ac t s en si t i v i t y, t he l un gs in tu b e rc ul os is ) . Th e s e s i te s a r e in f il t r at ed b y m o no n uc le a r c el ls . I n f la m m a ti on is pr im a r il y c a us ed b y ti s s ue di s ru p tio n an d n ec r os is as we l l a s b y s ec r et i on of c yt o ki ne s b y t he in f il t r at in g c e ll s. A lt h ou g h h is tam i ne s ec r e ti o n c a n a ls o o cc u r fr om lo c a l m as t c el l s , H 1 -a n ta g on is t s o f h is t a m i n e us u al l y do no t h av e s i gn i fi ca n t e f fe c t s b ec aus e T c e l l a nd m ac r o ph age ac t i v a ti on , m i gr a ti o n, a n d s ec r et i on a re no t g re a t l y a f f ec te d b y t h es e dr u g s . 2 1 . Th e a n sw e r i s E ( I , II , I I I) [s e e I I I. C . 3 .b ] . A l l th r ee f in di n gs a r e c om m o n to m o r e t ha n o n e n o n -o r g an - s p ec i fi c a u t oi m m un e d is o rd e r , b ut t h e y o c c u r i n d if f e re n t p e r c e n ta ge s o f p a ti e nt s wi t h s pe c i f ic di s o r de r s . F o r e xa m pl e , a nt i nu cl e ar a n ti b od ie s a r e p r ob a bl y p r e se n t i n a ll pa ti e nt s wit h S L E b ut a re fo u nd in o n l y a f r ac ti o n o f p a ti en ts wi t h r h e um at o id a rt h ri t is a n d Sj ög r e n 's s y n d r om e. R h e um a to id f ac to r s a r e
m o r e co m m on in r he um at o i d a r th r i ti s t ha n i n SL E o r S jö g re n ' s s y nd r om e , a n d h yp e rg a m m ag lo b ul ine m ia is m o re p re va le n t in S L E t h an in S jö g re n ' s s yn d r om e. 2 2 . Th e a n sw e r i s A ( I ) [ s ee V . A .3 ; V. B ] . P a r e nt s a n d c h i ld r en a re r a r el y H L A m a tc he d b u t a r e us ua ll y h al f m a tc he d. A n H L A m a tc h f r om a c ad a v e r - de r i v e d o rg a n is un l ik el y. Th e p ro b ab il i t y th a t t wo s i bl i ng s a r e H L A m a tc h ed is 2 5 %; t he p ro ba b il i t y th a t t h e y a r e h a lf m a tc he d i s 5 0% . 2 3 . Th e a n sw e r i s B ( I I I) [ s e e V . C. 1 ] . I n bo n e m a r r o w t r a ns pl an t a ti o n, m a r r o w c o n ta i nin g c om p et e n t l y m p h oc yte s i s tr a ns pl a nt e d t o a ge ner a l l y i m m u no s u pp r es s e d h o s t . Th e g r ea t es t p r o bl em is an im m u ne res p on s e b y th e g r a ft ag a in s t HL A s a nd ot h e r t is sue a n t ig en s o f th e h os t . I n re n al an d c a rd i ac tr a ns pla n t at i on , th e g r ea t es t p r o bl em is re j ec ti o n o f t he f o re i gn or g an b y th e im m u n e s y st em o f t he hos t ( H V G d i s e as e ) . 2 4 . Th e a n sw e r i s D ( I I , I I I ) [s ee V . B .2 ; V. D . 2 .a ] . C e l l -m ed i at e d im m u n e m e c ha n is m s a r e t ho u gh t to b e m o r e i m p o r ta n t i n a c ut e g r a ft r ej ec t io n , a nd t he in h ib i ti on o f T c el l a c ti v a t io n a p pe a rs to be t h e k e y el em e nt in im m un o s u p pr e s s io n . R es p on di n g T c e ll s r e qu i re s i gn al i ng f ro m I L -2 t o r ea c h f ul l a c ti va t io n a nd p ro g r es s t o c el l d i v is io n . IL - 2 i s p r o du c e d b y ac t i v a te d T c e ll s a n d c a n a c t in an a ut oc r i ne m a nn e r . C yc l o sp o ri n e b lo c k s t ra ns c ri p ti o n o f t he I L -2 ge ne d u ri ng T c el l a ct i v a ti o n, i n hi b it s t h e s y n th es is of I L - 2 , a nd p re ve n ts fu ll T c e ll ac ti v a t io n a n d d i vi si on . I ts e f fe c ts a r e l im i te d to ac ti va t ed T c el ls . B ec au s e it ha s n o d i rec t e f f ec t o n a n ti b od y s y n the s is , i t i s n ot us e fu l i n t he h yp e ra c u t e r e je ct i on p h e no m e na t ha t a r e b as e d on an t ib o d y-m e di at e d m ec ha n is m s . H y p e r ac u te r e j ec ti o n i s es s e n ti a ll y un t r e at a bl e b ec au s e i t d ep e n ds o n t h e p r es en c e of a n t ib od i es i n th e g r a ft r ec i pi en t . 2 5 . Th e a n sw e r i s A ( I ) [ s ee V I . C. 2 . a a nd b] . L i ve , a t t en ua t ed v a c c in es in t r od uc e o r g an is m s t ha t a re c o m p e te n t t o r e p li ca t e . Th i s r e pl ic a ti on s ti m u la t es th e i m m un e r e s p o ns e. F or t hi s a nd p r o ba b l y o t he r r ea s o ns , a l i v e, at t e nu a te d vacc i ne ( b ut no t a k i ll e d, i n ac t i vat e d v a c c i ne ) p r ob a bl y p r o vid es li f el o ng im m u n it y i n o ne o r t wo d o se s. 2 6 . Th e a n sw e r i s D ( I I , I I I ) [s ee V I . C. 1 .d ; Ta b le 1 0 - 3 ]. Th e M M R v a c c in e i s a dm i n is t er e d t o i n fa n ts wi t hin o r s ho r t l y a f t er t he 1s t ye a r o f l if e . A s e c o n d d os e i s r e c o m m en de d a t s ch o ol en t r y . In f lu e n z a a c ti ve va c c in e i s t a rg e ted t o wa r d s pe c i f ic ad ul t po p ul a ti o ns . He a lt hc a r e wo r k e r s a r e i nc lu d ed in th i s t a rg e t p op u la t io n , as a r e i n f an ts an d c hi l dr e n a t r i sk ; h o we v e r , t he v a c c ine is no t ro u ti n el y a dm in is t e re d t o i n fa n ts . Td i s no t r o u ti n el y a dm in is t e re d t o i n fa n ts , wh o i ns t ea d re c e i v e D TP . Td is us ed p r i m a r il y f o r i ni t ia l v ac c in a t io ns in ad ul t s wh o we r e n ot p re v i ou sl y va c ci n at e d a nd f or 10 - y ea r b oo st e r v ac c i na t io ns in a ll in di vi d ua ls , i nc l ud ing h e al t hc a re wo r k e rs . P.230
2 7 . Th e a n sw e r i s A ( I ) [ s ee V I . C. 2 ; Ta bl e 1 0 -3 ] . Th e p n eu m o c o c c al an d m e ni n go c o c c al vac c i n es a r e m u l t i v al e n t a nd c o nta i n p u r if i ed po l y s a c c h ar i de fr o m a nu m b e r o f d i f fe r ent s er o t y p es . H o we ve r , t h es e vac c i n es d o n o t c on t a in po l y s a cc ha r i de f rom al l t h e r e le va n t i n f ec ti o us a g en ts . P ur i fi ed p ol y s ac ch a ri d es d o n o t s t im ul a te i m m u ne r e s po ns es in c h il d re n y ou n g er t ha n 2 y e a rs o f a ge . F or po l ys a cc h ar i de va c ci n es to be ef f ec t i v e in y o u ng c h il d re n , t h e p ol y s a cc h ar i de m u s t be c o nj u ga t ed to a p r ot e in a s i n th e Hi b v ac c i ne .
11 Biotechnology Drug Products Godwin W. Fong Charles Lee I. INTRODUCTION. Advances in biotechnology have made many formerly unstable or difficult-to-produce biologic products available for therapeutic use. Some life-threatening diseases are now treated with biotechnology products. A. Interferon (INF) is an example of a drug that was genetically engineered to inhibit certain types of cancer cells and some viruses. B. Cellular hormones known as interleukins, lymphotoxins, and tumor necrosis factor are now used to treat cancer and immunodeficiency diseases. C. Monoclonal antibodies (MAbs) can deliver toxins specifically to cancer cells and destroy them. MAbs are also used with radioisotopes to diagnose and visualize cancer cells. Monoclonal antibodies have been developed to target signaling pathways associated with immune response and are being used to treat various immunological disorders, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and moderate to severe asthma. D. Many biopharmaceutical products derived from the body tissues (through cell lines) are now produced on a large scale. Modified natural products also may be further improved. E. A synthetic analogue of thyrotropin-releasing hormone prevents paralysis after spinal cord injuries in animal studies. F. Superoxide dismutase may be useful in preventing damage to tissues that are deprived of oxygen. G. New biotechnologic treatments have been developed for emphysema, congestive heart failure, ulcers, atherosclerosis, and an increasing number of medical conditions. Table 11-1 lists the biotechnology products that are approved for human use. II. BASIC TERMINOLOGY A. An antigen is a substance that stimulates the production of antibodies. B. An antibody is an immunoglobulin produced by the body in response to stimulation from an antigen. C. Antisense DNA is a complementary strand of DNA that is specifically synthesized to attach to the sense DNA and prevent genetic transcription. The sense DNA that carries the information that affects the disease process is usually elucidated before an antisense drug is designed. D. Colony-stimulating factors (CSFs) are a class of glycoprotein hormones. CSFs regulate the differentiation and formation of blood cells from precursor cells. E. Cytokines are a group of special proteins (nonantibodies) released by cells to trigger action in other cells. F. DNA is the molecule that contains the genetic instructions of a cell. DNA consists of deoxyribose, phosphate, and repeating bases as building blocks. The four bases are adenine, guanine, thymine, and cytosine. P.232
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Table 11-1. Approved Recombinant Therapeutics and Vaccines Drug (Trade Name) Indication(s) Company; Year Introduced Human insulin (Humulin) Diabetes Eli Lilly, Genentech; 1982 Somatrem for injection Human growth hormone deficiency in Genentech; 1985 (Protropin) children Interferon α-2a (Roferon- Hairy cell leukemia Hoffmann-La A) Roche; 1986 Interferon α-2b (Intron A) Hairy cell leukemia Schering-Plough, Biogen; 1986 Extension of therapy for chronic 1997 hepatitis C from 6 months to 18-24 months Follicular lymphoma in conjunction 1997 with chemotherapy Hepatitis B vaccine Prevention of hepatitis B Merck, Chiron; recombinant (Recombivax 1986 HB) Muromonab-CD3 Reversal of acute kidney transplant Ortho Biotech; (Orthoclone OKT3) rejection 1986 Somatropin for injection Human growth hormone deficiency in Eli Lilly; 1987 (Humatrope) children Alteplase (Activase) Acute myocardial infarction Genentech; 1987 Acute pulmonary embolism 1990 Restoration of function to central 2001 venous access devices (as assessed by the ability to withdraw blood) Interferon α-2a (Roferon- AIDS-related Kaposi sarcoma Hoffmann-La A) Roche; 1988
Interferon α-2b (Intron A) AIDS-related Kaposi sarcoma Genital warts Hepatitis C Interferon n3 (Alferon N Genital warts injection) Hepatitis B vaccine Hepatitis B prevention (Engerix-B)
Schering-Plough, Biogen; 1988
1991 Interferon Sciences; 1989 SmithKline Beecham, Biogen; 1989 Chronic hepatitis C infection 1998 Erythropoietin (Epogen) Anemia associated with chronic renal Amgen, Johnson & failure Johnson, Kirin; 1989 Erythropoietin (Procrit) Anemia associated with AIDS or Amgen, Ortho zidovudine administration Biotech; 1990 Anemia associated with chronic renal 1990 failure Chemotherapy-associated anemia in 1993 patients with nonmyloid malignancy Anemia associated with cancer and 1993 chemotherapy PEG-adenosine ADA-deficient severe combined Enzon, Eastman (ADAGEN) immunodeficiency Kodak; 1990 Interferon γ-1b Management of chronic granulomatous Genentech; 1990 (Actimmune) disease Delaying time to disease progression in InterMune patients with severe, malignant Pharmaceuticals osteopetrosis (2000) CMV immunoglobulin Prevention of CMV in kidney Medimmune; 1990 (CytoGam) transplant recipients Filgrastim; G-CSF Chemotherapy-induced neutropenia Amgen; 1991 Acute myeloid leukemia 1998 Glucocerebrosidase Type I Gaucher diseasea Genzyme; 1991 (Ceredase) Glucocerebrosidase Type I Gaucher diseasea Genzyme; 1994 (Cerezyme) Sargramostim (GM-CSF) Autologous bone marrow Hoechst-Roussel, (Prokine) transplantation Immunex; 1991 Sargramostim (GM-CSF) Neutrophil recovery after bone marrow Immunex, Hoechst(Leukine) transplantation Roussel; 1991 Antihemophilic factor Hemophilia B Armour; 1992 (Mononine) Antihemophilic factor Hemophilia A Genetics Institute, (Recombinate) Baxter Healthcare; 1992 Interleukin 2 (Proleukin) Renal cell carcinoma Chiron; 1992 Metastatic melanoma 1998 111 Indium-labeled Detection, staging, and follow-up of Cytogen, Knoll; antibody (OncoScint colorectal cancer 1992 CR103)
111
Indium-labeled antibody (OncoScint OV103) Interferon β-1b (Betaseron) DNase alfa (Pulmozyme) Factor VIII (Kogenate) Filgrastim (G-CSF) (Neupogen) PEG-l-asparaginase (Oncaspar) Human growth hormone (Nutropin) Abciximab (ReoPro)
Detection, staging, and follow-up of ovarian cancer
1992
Relapsing/remitting multiple sclerosis Chiron, Berlex; 1993 Cystic fibrosis Genentech; 1993 Hemophilia A Genentech, Miles; 1993 Bone marrow transplant Amgen; 1994
Refractory childhood acute Enzon; 1994 lymphoblastic leukemia Short stature caused by human growth Genentech; 1994 hormone deficiency Antiplatelet prevention of blood clots Centocor; 1994 Treatment of a broader range of patients undergoing percutaneous coronary intervention; revised dosage and patient management to reduce bleeding Unstable angina that does not respond to conventional medical therapy when percutaneous coronary intervention is planned within 24 hr Live varicella virus Active immunization of persons 12 Merck; 1995 vaccine (Varivax) months of age and older RSV immunoglobulin Prevention of serious lower respiratory Massachusetts (RespiGam) tract infection in children younger than Public Health 24 months old Biologic Labs; 1996 Inactivated hepatitis A Immunization against hepatitis A in Merck; 1996 vaccine (Vaqta) children older than 6 years of age Interferon β-1a (Avonex) Multiple sclerosis Biogen; 1996 Human antihemophilic Hemophilia A Centeon; 1996 factor Haemophilus b conjugate Immunization of individuals 6 weeks Merck; 1996 (meningococcal protein to 15 months of age born of HBsAgconjugate) and hepatitis B negative mothers (recombinant vaccine) (Comvax) Cryoprecipitated Control of bleeding associated with Blood Bank of the antihemophilic factor A Factor VIII deficiency Redwoods; 1996 Reteplase (Retavase) Acute myocardial infarction in adults Boehringer Mannheim; 1996 DTaP vaccine (Infanrix) Primary and booster immunization of SmithKline infants and children except as a fifth Beecham; 1997 dose in children who previously received four doses of DTaP Recombinant coagulation Control and prevention of hemorrhagic Genetics Institute; Factor IX (BeneFix) episodes in patients with hemophilia B, 1997
including perioperative management of patients with hemophilia B who are undergoing surgery Autologous cultured Repair of clinically significant, Genzyme Tissue chondrocytes (Carticel symptomatic, cartilaginous defects of Repair; 1997 SM Service) the femoral condyle (medial, lateral, or trochlear) caused by acute or repetitive trauma Interferon alfacon-1 Treatment of chronic HCV infection in Amgen; 1997 (Infergen) patients 18 years of age or older who have compensated liver disease and anti-HCV serum antibodies or HCV RNA Subsequent treatment of HCV-infected 1997 patients who tolerated an initial course of interferon therapy Rabies vaccine Preexposure and postexposure Chiron; 1997 (RabAvert) immunization of children and adults Oprelvekin (Neumega) Prevention of severe thrombocytopenia Genetics Institute; and reduction of the need for platelet 1997 transfusions after myelosuppressive chemotherapy in patients with nonmyeloid malignancies who are at high risk for severe thrombocytopenia Rituximab (Rituxan) Treatment of patients with relapsed or Genentech; 1997 refractory low-grade or follicular B cell non-Hodgkin lymphoma Daclizumab (Zenapax) Prophylaxis of acute organ rejection in Hoffman-La patients receiving renal transplants; Roche; 1997 part of an immunosuppressive regimen that includes cyclosporine and corticosteroids Becaplermin (Regranex) Lower-extremity diabetic neuropathic OMJ ulcers that extend into the Pharmaceuticals; subcutaneous tissue or beyond and 1997 have an adequate blood supply HTLV-I and -II Detection of antibodies to HTLV-I and Organon Teknika; (Vironostika HTLV-I and -II in human serum or plasma 1998 -II MicroELISA System) Fibrin sealant (Tisseel VH Adjunct to hemostasis in surgeries that Osterreichisches kit) involve cardiopulmonary bypass Institut fur Haemoderivate; 1998 Treatment of splenic injuries caused by blunt or penetrating trauma to the abdomen when control of bleeding by conventional surgical techniques, including suture, ligature, and cautery, is ineffective or impractical Closure of colostomies
Pooled plasma, solvent detergent treated (VIPLAS/SD)
Basiliximab (Simulect)
Palivizumab (Synagis)
Sacrosidase (Sucraid) Eptifibatide (Integrilin)
Diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (Certiva) Infliximab (Remicade)
Documented deficiencies of V.I. Technologies; coagulation factors for which there are 1998 no concentrate preparations available, including congenital single-factor deficiencies of Factors I, V, VII, XI, and XIII and acquired multiple coagulation factor deficiencies Reversals of warfarin effect Thrombotic thrombocytopenic purpura Prophylaxis of acute organ rejection in Novartis; 1998 patients undergoing renal transplantation Part of an immunosuppressive regimen that includes cyclosporine and corticosteroids Use in renal transplantation in 2001 combination with triple immunosuppressive therapy Use in pediatric renal transplantation Use of an IV bolus injection Prophylaxis of serious lower Medimmune; 1998 respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease Congenital sucrose isomaltase Orphan Medical; deficiency 1998 Acute coronary syndrome COR Therapeutics; 1998 Treatment of patients undergoing percutaneous coronary intervention Active immunization of individuals 6 North American weeks to 7 years of age (before the 7th Vaccine; 1998 birthday) Treatment of moderately to severely Centocor; 1998 active Crohn disease to reduce the signs and symptoms in patients who have an inadequate response to conventional therapies Treatment of patients with fistulizing Crohn disease to reduce the number of draining enterocutaneous fistula(s) For reduction in signs and symptoms 1999 of rheumatoid arthritis in patients who have had an inadequate response to methotrexate Inhibition of progression of structural 2000 damage in patients with rheumatoid arthritis who have had an inadequate response to methotrexate
Improving physical function in patients 2002 with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate Reducing signs and symptoms, and 2002 inducing and maintaining clinical remission in patients with moderately to severely active Crohn disease who have had an inadequate response to conventional therapy Reducing the number of draining 2003 enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn disease Improving physical function in patients 2003 with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate Primary immunization of infants at 2, Wyeth-Ayerst 4, and 6 months of age Laboratories; 1998
Rotavirus vaccine, live, oral, tetravalent (RotaShield) Trastuzumab (Herceptin) Metastatic breast cancer in patients Genentech; 1998 whose tumors overexpress the HER-2 protein and who have received one or more chemotherapy regimens for metastatic disease Median survival 2001 (Etanercept) Enbrel Reduction in signs and symptoms of Immunex; 1998 moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to one or more DMARDs Reducing the signs and symptoms and 2000 delaying structural damage in patients with moderately to severely active rheumatoid arthritis, including those who have not previously failed treatment with a DMARD Reducing signs and symptoms of 2002 active arthritis in patients with psoriatic arthritis Recombinant OspA Active immunization against Lyme SmithKline (LYMErix) disease in people 15-70 years old Beecham; 1998 Vitravene (Fomivirsen) Local treatment of CMV retinitis in Isis patients with AIDS who are intolerant Pharmaceuticals, of or have a contraindication to other Ciba Vision; 1998 treatments for CMV retinitis or who were insufficiently responsive to previous treatments
Antithymocyte globulin (Thymoglobulin)
Acute rejection in renal transplant patients
Pasteur-Mérieux Serums et Vaccines—France; 1998 Denileukin diftitox Treatment of patients with persistent or Seragen; 1999 (Ontak) recurrent cutaneous T cell lymphoma whose malignant cells express the CD25 component of the interleukin 2 receptor Hepatitis B Treatment of acute exposure to Nabi; 1999 immunoglobulin (Nabi- HBsAg, perinatal exposure of infants HB) born to HBsAg-positive mothers Sexual exposure to HBsAg-positive individuals Household exposure of infants to people with acute hepatitis B virus infection Recombinant coagulation Treatment of bleeding episodes in Novo Nordisk factor VIIa (NovoSeven) hemophilia A or B with inhibitors to A/S— Denmark; Factor VIII or Factor IX 1999 Interferon α-n1, Chronic HCV infection in patients 18 GlaxoWellcome; lymphoblastoid years of age or older who do not have 1999 (Wellferon) decompensated liver disease Antihemophilic factor/vonUsed in adult patients for treatment and Centeon Pharma— Willebrand factor prevention of bleeding hemophilia A Germany; 1999 complex (Humate-P) (classic hemophilia) Used in adult and pediatric patients for treatment of spontaneous and traumainduced bleeding episodes in severe von Willebrand disease Used in mild and moderate von Willebrand disease when use of desmopressin is known or suspected to be inadequate Hetastarch (Hextend) Plasma volume expander for treatment BioTime; 1999 of hypovolemia during surgery Pneumococcal 7-valent Immunization of infants 2, 4, 6, and Lederle conjugate vaccine 12-15 months of age to prevent Laboratories (diphtheria CRM197 invasive pneumococcal disease Division American protein) (Prevnar) Cyanamid; 2000 Immunization of infants and toddlers 2002 against otitis media caused by vaccine serotypes Antihemophilic factor Control and prevention of hemorrhagic Genetics Institute; (recombinant) (ReFacto) episodes and for short-term routine and 2000 surgical prophylaxis in patients with hemophilia A BCG, live (PACIS) Treatment of CIS in the absence of BioChem associated invasive cancer of the Pharma—Canada; bladder 2000
Tenecteplase (TNKase) Crotalidae polyvalent immune Fab (ovine) (CroFab) Botulinum toxin type B (MYOBLOC) Botulinum toxin type A (BOTOX or BOTOX COSMETIC)
Reduction of mortality associated with AMI Treatment of minimal and moderate North American Crotalidae envenomation Treatment of cervical dystonia to reduce the severity of abnormal head position and neck pain Treatment of cervical dystonia
Genentech; 2000 Protherics; 2000
Elan Pharmaceuticals; 2000 Allergan; 2002
Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients ≥ 65 years of age Peginterferon α-2b (PEG- Treatment of chronic hepatitis C in Schering; 2001 Intron) patients not previously treated with interferon-α who have compensated liver disease and are at least 18 years of age Alemtuzumab (Campath) Treatment of patients with B cell Millennium and chronic lymphocytic leukemia who ILEX Partners; have been treated with alkylating 2001 agents and who have failed fludarabine therapy Hepatitis A inactivated Active immunization of people 18 SmithKline and hepatitis B years of age or older against disease Beecham (recombinant) vaccine caused by hepatitis A virus and Biologicals; 2001 (TWINRIX) infection by all known subtypes of hepatitis B virus Digoxin immune Fab Treatment of patients with lifeProtherics; 2001 (ovine) (DigiFab) threatening or potentially lifethreatening digoxin toxicity or overdose Darbepoetin α (Aranesp) Treatment of anemia associated with
