a p t o p n l

ÉNERAL

Ñaues a p t o p f i l ; l - ( 3 - m e r c a p t o - 2 - D - m e t h y l - 2 - o x o p r o p y l ) - L -r o l i n e ( S , S ) .

t r u c t u r e

0 || C 9 H 1 5 N 0 3 S

N-C-CH-CHg-SH COOH T

CHj mol . wt. 217.29

Porms A v a i l a b l e

"ree a c i d ( c a p t o p r l l ) .

' f h y s i c a l P r o p e r t i e s

M e l t i n g p o i n t 105-106°C ( 1 ) . S o l u b i l i t y : 1 g i n 6.25 «L of w a t e r , f r e e l y s o l u b l e l n m e t h a n o l , e t h a n o l , i s o -p r o p y l a l c o h o l , c h l o r o f o r m , and m e t h y l e n e c h l o r i d e 1). t a b i l l t y Summary

" a p t o p r l l , b e i n g a t h l o l , u n d ergoes o x i d a t i v e d e g r a d a -t l o n i n aqueous s o l u t i o n . The r a t e of o x i d a t l o n de-pends on pH and oxygen c o n c e n t r a t i o n and i s c a t a l y z e d by l e t a l l o n a . The máximum s t a b i l i t y i s found i n a c i d i c s o l u t i o n s b e l o w pH 4.0. A l t h o u g h c a p t o p r l l c o n t a i n s an a n i d e f u n c t i o n , the d e g r a d a t i o n v i a hy-d r o l y s i s i s m l n i m a l .

In t h e s o l i d s t a t e , puré c a p t o p r l l e x h i b i t s e x c e l -l e n t s t a b i l i t y . E x c i p i e n t s t h a t reléase m o i s t u r e when • i x e d w i t h c a p t o p r l l and s t o r e d under h i g h t e m p e r a t u r e nd h i g h h u m i d i t y c o n d i t i o n s promote d e g r a d a t i o n .

284

Drug K l n e t i c s 285

DRUG KINETICS

R e a c t i o n s and Ra t e E q u a t l o n s

C a p t o p r l l i n aqueous s o l u t i o n i s o x l d l z e d a t i t s t h i o l f u n c t i o n t o y i e l d c a p t o p r l l d i s u l f i d e (Scheme I ) .

0

¡1-C-CH-CHB-SH + Oz

COOH ¿Kj

0 0 .11 II . N-C-CH-CHz-S-S-CHa-CH-C-N

COOH CHj -Ha

+ HsO

COOH

SCHEME I

The f r e e - r a d i c a l - i n i t i a t e d o x i d a t l o n of t h i o l s l n -v o l v e s a c o m p l e x raechanism. The p r e s e n c e of m e t a l i o n s , c h e l a t i n g a g e n t s , or a n t i o x i d a n t s can have s i g -n i f i c a n t e f f e c t s on the r e a c t l o n mechanism. There a r e two i o n i z a b l e f u n c t i o n s i n c a p t o p r l l , t h e c a r b o x y l i c group w i t h a p K a of 3.7 and t h e t h i o l g r o u p w i t h a p K a

of 9.8 ( 1 ) . The p o s t u l a t e d r e a c t l o n mechanism, how-e v e r , i s based on the i o n i z a t i o n of th e t h i o l f u n c t i o n o n l y ( 2 ) .

A u t o o x i d a t i o n

RSH ^ RS" + H +

-> RS' + 0 2" RS" + O2

R S - + 0 2 ~

2RS ' > RSSR

> RS ' + O.

H 20 -> 20H" 5í02

(1)

(2)

(3)

(4)

(5)

286 C a p t o p r l l

M e t a l - i o n c a t a l y z e d o x i d a t l o n

RSH + M ( n + 1 ) + > RS' + H + + M n + (6)

^ RS- • M ( n + 1 ) + > RS" + M n + (7)

2RS- > RSSR (8)

2 M n + + 0 2 > 2 M ( n + 1 ) + + 0 2 2 _ (9)

0 2 2 _ + H 20 > 20H" + \Q2 (10)

where M ^ n + 1 ^ + i s a m e t a l i o n i n i t s h i g h e s t o x i d a t l o n s t a t e .

pH-Rate P r o f l l e

F i g u r e 1 shows t h e p H - r a t e p r o f i l e ( p l o t t e d as l o g k v s . pH, where k i s the a p p a r e n t f i r s t - o r d e r r a t e c o n -s t a n t ) f o r t h e o x i d a t l o n o f c a p t o p r l l a t 50°C ( 2 ) . The a p p a r e n t f i r s t - o r d e r r a t e c o n s t a n t s were measured i n M c l l v a i n e b u f f e r of i o n i c s t r e n g t h 0.5 M ( a d j u s t e d w i t h KC1) i n the p r e s e n c e of oxygen ( a i r ) . No c h e l a t -i n g agent was employed t o p r e v e n t m e t a l - i o n - c a t a l y z e d o x i d a t l o n . Because of the complex n a t u r e of the o x i ­d a t l o n r e a c t l o n ( c o m b l n a t i o n o f a u t o o x i d a t i on and • e t a 1- 1 o n - c a t a 1 y z e d o x i d a t l o n ) , i t i s not p o s s i b l e from the e x p e r i m e n t a l d a t a t o e s t a b l i s h a q u a n t i t a t i v e r a t e e q u a t i o n t o a c c o u n t f o r the shape of the p r o f i l e . The i n c r e a s e i n the a p p a r e n t r a t e c o n s t a n t f o r o x i d a ­t l o n above pH 4 i s c o n s i s t e n t w i t h the t h i o l a t e b e i n g more r e a d i . l y o x i d i z e d than the t h i o l . However, the t h i o l i t s e l f must undergo o x i d a t l o n t o a c c o u n t f o r the o b s e r v e d k i n e t l c b e h a v i o r below pH 4.

A c t i v a t i o n Energy

C a p t o p r l l i s h y d r o l y z e d a t i t s amlde l i n k a g e i n a c i d i c s o l u t i o n s a t e l e v a t e d t e m p e r a t u r e s ( 2 ) . The c o n t r i b u -t l on o f h y d r o l y s i s i s 1 n s i g n i f i c a n t compared t o the o x i d a t l o n i n t h e o v e r a l l d e g r a d a t i o n of c a p t o p r l l . H owever, t h e t e m p e r a t u r e dependence of c a p t o p r l l hy­d r o l y s i s i n h y d r o c h l o r l c a c i d s o l u t i o n s of v a r i o u s c o n c e n t r a t 1 o n s was s t u d i e d and the r e s u l t s a r e summa-r i z e d i n T a b l e 1 ( 1 ) . U s l n g the 0.5 M h y d r o c h l o r l c

Drug K i n e t l c s ; 2 8 l

1 2 3 4

pH

FIGURE 1. C a p t o p r l l . p H - r a t e p r o f i l e f o r oxidation of c a p t o p r l l a t 50°C and l o n i c s t r e n g t h 0.5 M.

TABLE 1. A p p a r e n t Rate C o n s t a n t s , k i n s " 1 x 10 7 for H y d r o l y s i s of C a p t o p r l l (2)

Te m p e r a t u r e ( °C)

90

80

70

C o n c e n t r a t i o n of HC1 S o l u t i o n («)

0 . 5 0 . 2 0 . 1 0 .05

48 , ( 0 , 22 (0 9

(0

61 4 6 ) a

81 45 ) 44 45)

24 (0 12 (0 8

(0

39 85 ) 25 84 ) 89 , 83)

17 (1 4

(1 2

(1

56 13) 97 12)

,44 .11)

9.5

(1.41)

a E s t i m a t e d pH valué f o r t h e s o l u t i o n i s shown H p a r e n t h e s i s .

88 C a p t o p r l l

s o l u t i o n d a t a , an e n e r g y of a c t l v a t l o n of 21.4 C Í l / m o l can be c a l c u l a t e d f o r the h y d r o l y s i s r e a c -lon-

ORMULATIONS AND COMBINATIONS

e g r a d a t i o n R e a c t i o n s

aqueous s o l u t i o n , o x i d a t i o n i s t h e p r e d o m i n a n t 0 u t e of d e g r a d a t i o n of c a p t o p r l l . The f a c t o r s t h a t f f e c t s o l u t i o n s t a b i l i t y a r e pH, p r e s e n c e of m e t a l

o x y g e n tensión, and s o l u t i o n c o n c e n t r a t i o n . a p t o p r i l i s more s t a b l e i h a c i d i c s o l u t i o n t h a n i n a s i c m e d i a . The o x i d a t i o n i s c a t a l y z e d by m e t a l

w i t h c o p p e r and i r o n b e i n g the most e f f e c t i v e and i r o n a r e t h e most l i k e l y con-f o r m u l a t i o n a d d i t i v e s , c o n t a i n e r s ,

ons c o p p e r Copper

found i n a t a l y s t s a a i n a n t s l o s u r e s , or m a n u f a c t u r i n g e quipment. The c a t a l y t i c f f e c t of m e t a l i o n s can be p r e v e n t e d by a d d i n g sodium d e t a t e , a c h e l a t i n g a g e n t .

The d e g r a d a t i o n of c a p t o p r l l i n v i a l s and ampoules s enhanced by t h e p r e s e n c e of oxygen i n the headspace f the c o n t a i n e r . A n i t r o g e n purge p r o t e c t s c a p t o p r l l n s o l u t i o n .

The o x i d a t l o n of c a p t o p r l l i s i n v e r s e l y p r o p o r t i o n -1 to i t s c o n c e n t r a t i o n i n the s o l u t i o n , t h a t I s , a ore c o n c e n t r a t e d s o l u t i o n o x i d i z e s more s l o w l y t h a n a 'ess c o n c e n t r a t e d s o l u t i o n . A n t i o x i d a n t s have been óund to o f f e r no a d v a n t a g e i n s t a b i l i z i n g c a p t o p r l l o l u t i o n s .

C a p t o p r l l as a b u l k powder ha s e x c e l l e n t s o l l d -t a t e s t a b i l i t y ; however, i t r e a d i l y o x i d i z e s i n the resence of c e r t a i n e x c i p l e n t s t h a t reléase m o i s t u r e . he d e g r a d a t i o n r e a c t l o n f o l l o w s a p p a r e n t z e r o - o r d e r l n e t i c s . The r a t e of e x c i p l e n t - m e d i a t e d d e g r a d a t i o n f c a p t o p r l l i n the s o l i d s t a t e depends on m o i s t u r e ,

t e m p e r a t u r e , and oxygen p r e s s u r e . The s t a b i l i t y of 1 1 o p r i 1 -e x c i p i e n t b l e n d i n c r e a s e s as the d r u g - t o -

e x c i p i e n t r a t i o i n c r e a s e s .

t a b l l i z a t i o n Methods

Optimum s t a b i l i t y of c a p t o p r l l i n aqueous s o l u t i o n i s achleved by a d j u s t i n g pH on the a c i d i c s i d e , u s l n g s o ­dium e d e t a t e as a c h e l a t i n g a g e n t , and n i t r o g e n purge

R e f e r e n c e s 289

t o elimínate ox y g e n . In the s o l i d s t a t e , p r o p e r c o n ­t r o l o f h u m i d i t y and t e m p e r a t u r e a r e e s s e n t l a l f o r s t a b i l l z a t i o n of f o r m u l a t l o n s .

REFERENCES

1. H. K a d i n , " C a p t o p r l l " i n K. F l o r e y ( E d . ) , Analyti-cal P r o f i l e s of Drug Stibstances, Volume 11, A c a -demic P r e s s , New Y o r k , 1982.

2. P. Timmins, I . M. J a c k s o n , and Y. J . Wang, Int. J . Pharmaceut., 11, 329 ( 1 9 8 2 ) .

- N B . Ja i n ( K a n s a s )