Captopril

GENERAL

Nanea
Captopril ; l-(3-aercapto-2-D-aethyl-2-oxopropyl)-L-
p r o l ine (S , S) .

Structure

a o l . wt. 217.29

Foria Available

Free a c i d (captopril).

Physlcal Prop.erties

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
aL of water, f r e e l y s o l u b l e i n a 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 i , and a e t h y l e n e c h l o r i d e
(1) .
Stability Suiiary

C a p t o p r i l , being a t h i o l , undergoes o x i d a t i v e degrada-

t i 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 i o n de-
penda 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 i o n s . The l a x i i u i s t a b i l i t y l s found i n
a c l d i c s o l u t i o n s below pH 4.0. Although c a p t o p r i l
c o n t a i n s an a i i d e f u n c t i o n , the d e g r a d a t i o n v í a hy-
drolysia i s ainiaal.
In the s o l i d s t a t e , p u r é c a p t o p r i l e x h i b i t s e x c e l -
lent s t a b i l i t y . E x c i p i e n t s that r e l é a s e a o i s t u r e when
• i x e d with c a p t o p r i l and s t o r e d under h i g h t e a p e r a t u r e
and high h u a i d i t y c o n d i t i o n s proaote d e g r a d a t i o n .

284
 Drug Kinetics 285

DRUG KINETICS

R e a c t i o n s and Rate Bquations

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

N-C-CH-Ch^—S-S-C^—CK-C-N

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 i o n o f t h i o l s i n -
v o l v e s a cosiplex l e c h a n l s i . The p r e s e n c e of « e t a l
l 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 e t s on the r e a c t i o n í e c h a n i s s . There a r e
two i o n l z a b l e f u n c t i o n s i n c a p t o p r i l , t h e c a r b o x y l i c
group with a pK a o f 3.7 and t h e t h i o l group w i t h a pK a
of 9.8 ( 1 ) . The p o s t u l a t e d r e a c t i o n a e c h a n l s a , how-
e v e r , i s based on the l o n i z a t i o n of t h e t h i o l f u n c t i o n
only ( 2 ) .

Autooxldation

RSH RS~ + H + (1)

RS" + 02 > RS" • 02~ (2)

RS~ + 02~ > RS* + 0 2 2 ~ (3)

2RS' > RSSR (4)

022 + H20 > 20H- + * 0 2 (5)

286 Captopril

Metal-ion catalyzed oxidation

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

or
RS" + M(n +1 ) + > RS* + Mn+ (7)

2RS * > RSSR (8)

2M n + + 0¡> > 2M ( n + 1 ) + + 022_ (9)

022~ + H20 > 20H~ + Íí02 (10)

where M* n + 1 * + is a setal ion in i t s hlghest oxidation

state.

pH-Rate Profile

F i g u r e 1 shows the pH-rate 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 con-
s t a n t ) f o r t h e o x i d a t i o n o f c a p t o p r i l at 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 a e a s u r e d
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 (adjusted
with 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 e a p l o y e d to p r e v e n t « e t a l - i o n - c a t a l y z e d
oxidation. Because of the c o i p l e x n a t u r e of the o x i -
dation reaction ( c o i b i n a t l o n of a u t o o x i d a t i o n and
• e t a 1 - i o n - c a t a l y z e d o x i d a t i o n ) , i t i s not posslble
f r o n the e x p e r l a e n t a l d a t a to e s t a b l i s h a q u a n t i t a t l v e
r a t e e q u a t i o n to 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 i 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
• o r e r e a d i . l y o x i d l z e d than the t h i o l . However, the
t h i o l i t s e l f a u s t undergo o x i d a t i o n to a c c o u n t f o r the
o b s e r v e d k i n e t i c b e h a v i o r below pH 4.

Activation Energy

C a p t o p r i l i s hydrolyzed at i t s aaide linkage i n a c i d i c

s o l u t i o n s at e l e v a t e d t e a p e r a t u r e s ( 2 ) . The c o n t r l b u -
t i o n o f h y d r o l y s i s i s i n s i g n i f i c a n t conpared to the
o x i d a t i 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 i l .
H o w e v e r , the t e i p e r a t u r e dependence of c a p t o p r i l hy-
d r o l y s i s i n h y d r o c h l o r i c a c i d s o l u t i o n s of varlous
concentrations was s t u d i e d and the r e s u l t s are suaaa-
r i z e d in Table 1 (1). U s i n g the 0.5 M hydrochloric
I
Drug K i n e t i c s 287

• I ' I I I " I I I I

6.0

6.5 —

7.0

7.5 l i l i
4
PH

FIGURE 1. Captopril. pH-rate p r o f i l e f o r o x i d a t i o n

of c a p t o p r i l at 50°C and i o n i c s t r e n g t h 0.5 M.

TABLE 1. Apparent Rate C o n s t a n t s , k i n s - 1 x 10 7 f o r

H y d r o l y s l s o f C a p t o p r i l (2)

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

Teaperature
(°C) 0.5 0.2 0.1 0.05

48 . 61 24 . 39 17 .56
(0.46)a (0.85) (1.13)
22 .81 12.25 4 . 97
(0.45) (0.84) (1.12)
9.44 8 . 89 2 . 44
(0.45) (0.83) (1.11)
a Estiaated pH valué f o r the solution i s shown in
parenthesis.
288 Captopril

a c i d s o l u t i o n d a t a , an energy of a c t i v a t i o n of 21.4
k c a l / i 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 reac-
tion.

FORNULATIONS AND COMBINATIONS

Degradation Reactions
In a q u e o u s s o l u t i o n , o x i d a t i o n i s the predoninant
r o u t e of d e g r a d a t i o n of c a p t o p r i l . The f a c t o r s t h a t
a f f e c t s o l u t i o n s t a b i l i t y are pH, presence of s e t a l
i o n s , o x y g e n t e n s i ó n , and s o l u t i o n concent ra t i o n .
Captopril i s more s t a b l e iñ a c i d i c s o l u t i o n than i n
basic media. The oxidation i s c a t a l y z e d by metal
i o n s , 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 l v e
catalysts. Copper and i r o n are the most l i k e l y con-
taminants found i n 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 ,
c l o s u r e s , or m a n u f a c t u r i n g equipment. The c a t a l y t l c
e f f e c t of metal i o n s can be p r e v e n t e d by a d d i n g sodium
edetate, a c h e l a t i n g agent.
The d e g r a d a t i o n of c a p t o p r i l i n v i a l s and ampoules
i s enhanced by the p r e s e n c e of oxygen i n the headspace
of 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 i l
in s o l u t i o n .
The o x i d a t i o n of c a p t o p r i l i s i n v e r s e l y p r o p o r t i o n -
a l t o 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
more 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 than a
less concentrated solution. A n t i o x i d a n t s have been
f o u n d to o f f e r no advantage i n s t a b i l i z i n g c a p t o p r i l
solutions.
C a p t o p r i l as a b u l k powder has e x c e l l e n t solid-
s 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
p r e s e n c e of c e r t a i n e x c i p i e n t s t h a t r e l é a s e m o i s t u r e .
The d e g r a d a t i o n r e a c t i o n f o l l o w s apparent z e r o - o r d e r
kinetics. The r a t e of e x c i p i e n t - m e d i a t e d d e g r a d a t i o n
of c a p t o p r i 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
ca p t op r i 1 - exc i p i en t b l e n d i n c r e a s e s as the d r u g - t o -
excipient r a t i o increases.

S t a b i 1 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 i l i n aqueous s o l u t i o n i s
a c h i e v e d by a d j u s t l n g pH on the a c i d i c s i d e , u s i n g so-
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
 References 289

to e l i m í n a t e oxygen. In the s o l i d s t a t e , proper con-

t r o l o f h u m i d i t y and t e i p e r a t u r e are e s s e n t l a l f o r
s t a b i 1 i z a t i o n of f o r a u l a t i o n s .

REFERENCES

1. H. K a d i n , " C a p t o p r i l " i n K. F l o r e y ( E d . ) , Analytl-

cal Profilas of Drug Substancas, Voluma 11, Aca-
d e a i c P r e s s , New Y o r k , 1982.

2. P. T l a m l n s , I . M. J a c k s o n , and Y. J . Wang, Int. J.

Pharmacaut., 11, 329 ( 1 9 8 2 ) .

- N. B. J a i n
(Kansas)