Drug K l n e t i c s

DRUG

KINETICS

Reactions

aptopnl

285

andRate

Equatlons

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 ) .
NERAL
0

aues

1-C-CH-CHB-SH + Oz

aptopfil;
l-(3-mercapto-2-D-methyl-2-oxopropyl)-Lroline (S,S).

Kj

COOH

tructure
0

||
N-C-CH-CHg-SH
COOH

C H
9

1 5

N0 S
3

0
.11

mol . w t . 2 1 7 . 2 9

CHj

Porms
"ree

0
II .

acid (captoprll).

COOH

SCHEME I

Properties

M e l t i n g p o i n t 105-106C ( 1 ) .
Solubility:
1 g i n 6.25
L o f 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 propyl a l c o h o l , c h l o r o f o r m ,
and methylene chloride

1).
tabillty

-Ha

CHj

COOH

Available

'fhysical

+ HsO

N-C-CH-CHz-S-S-CHa-CH-C-N

The
f r e e - r a d i c a l - i n i t i a t e d oxidatlon of thiols l n volves
a complex
raechanism.
The p r e s e n c e o f m e t a l
i o n s , c h e l a t i n g a g e n t s , o r 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 t h e r e a c t l o n m e c h a n i s m .
There a r e
two
ionizable functions i nc a p t o p r l l , the carboxylic
g r o u p w i t h a p K o f 3.7 a n d t h e t h i o l g r o u p w i t h a p K
o f 9.8 ( 1 ) . T h e p o s t u l a t e d
r e a c t l o n m e c h a n i s m , howe v e r , i s based on t h e i o n i z a t i o n o f t h e t h i o l
function
only ( 2 ) .
a

Summary

" a p t o p r l l , being a t h l o l , undergoes o x i d a t i v e degradatlon i n aqueous s o l u t i o n .

The r a t e o f o x i d a t l o n d e pends on pH a n d o x y g e n 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
lona.
T h e mximum 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 .
Although c a p t o p r l l
contains
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 hydrolysis i s mlnimal.
In t h e s o l i d s t a t e , pur c a p t o p r l 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 t h a t relase m o i s t u r e when
ixed with c a p t o p r l l and s t o r e d under high temperature
nd h i g h h u m i d i t y c o n d i t i o n s p r o m o t e d e g r a d a t i o n .

Autooxidation
RSH

RS" + H

RS"

+ O2

RS

+ 0 ~

2RS '

->
2

>
H 0
2

284

(1)

RS' + 0 "

(2)

RS ' + O.

(3)

>

(4)

RSSR
-> 20H"

50

(5)

286

Metal-ion

catalyzed

RSH + M
^

Drug K i n e t l c s

Captoprll

( n

+1

RS- M

( n +1

2RS-

>

RSSR

2M
0

n +

2 2 _

+ 0

>

+ H 0
n + 1

2 8 l

oxidatlon

>

RS' + H + + M

>

RS" + M

n +

n +

(6)
(7)
(8)

2M
>

where M ^
state.
pH-Rate

( n +1) +

+ 0

2 2 _

20H" + \Q

i s a metal

ion i n i t s highest

(9)
(10)
oxidatlon

Proflle

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, w h e r e k i s t h e 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 50C ( 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 o f 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 t h e p r e s e n c e o f o x y g e n ( a i r ) .
No c h e l a t i n g a g e n t was e m p l o y e d t o p r e v e n t
metal-ion-catalyzed
oxidatlon.
Because of the complex nature of the o x i datlon
reactlon
( 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 a n d
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 n o t p o s s i b l e
from the e x p e r i m e n t a l
data to 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 t h e shape of t h e p r o f i l e .
The
increase i n the apparent rate constant f o r oxidat l o n a b o v e pH 4 i s c o n s i s t e n t w i t h t h e 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 t h e t h i o l .
However, t h e
t h i o l i t s e l f must u n d e r g o o x i d a t l o n t o a c c o u n t f o r t h e
o b s e r v e d k i n e t l c b e h a v i o r b e l o w pH 4.
Activation

4
pH

FIGURE 1.
Captoprll.
p H - r a t e p r o f i l e f o r oxidation
o f c a p t o p r l l a t 50C a n d l 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 "

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

Concentration
Temperature
( C)

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 c o m p a r e d t o t h e
oxidatlon i n the o v e r a l l degradation
of c a p t o p r l l .
However, 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 hydrolysis
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 a n d t h e r e s u l t s a r e summar i z e d i n Table 1
( 1 ) . U s l n g t h e 0.5 M
hydrochlorlc

90
80
70

E s t i m a t e d pH
parenthesis.

48 ,
(0,
22
(0
9
(0

61
46)
81
45 )
44
45)

valu

24
(0
12
(0
8
(0

x 1 0 for

o f HC1 S o l u t i o n

0. 2

0. 5

39
85 )
25
84 )
89
, 83)

56
13)
97
12)
,44
.11)

f o r the s o l u t i o n

()

0 .05

0 . 1

17
(1
4
(1
2
(1

9.5
(1.41)

i s shown H

References

289

Captoprll
88

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

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

lon-

ORMULATIONS AND
egradation

COMBINATIONS

Reactions

aqueous s o l u t i o n , o x i d a t i o n i s the
predominant
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 that
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 tensin, and
solution concentration.
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
s i c media.
The
o x i d a t i o n i s c a t a l y z e d by
metal
with c
co
op
pp
pe
er
r and i r o n b e i n g t h e most e f f e c t i v e
ons
i r o n a r e t h e most l i k e l y
conC o p p e r and
atalysts
aainants 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 ,

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 . ) ,
cal
P r o f i l e s of Drug Stibstances,
Volume
d e m i c P r e s s , New Y o r k ,
1982.

11,

AnalytiAca-

2.

P. T i m m i n s ,
Pharmaceut.,

I . M. J a c k s o n , and
11, 329
(1982).

Y.

J . Wang, Int.

J.

l o s u r e s , or m a n u f a c t u r i n g e q u i p m e n t .
The
catalytic
f f e c t of m e t a l i o n s c a n be p r e v e n t e d by a d d i n g s o d i u m
detate, a c h e l a t i n g agent.
The d e g r a d a t i o n
o f c a p t o p r l l i n v i a l s and a m p o u l e s
s e n h a n c e d by t h e p r e s e n c e o f o x y g e n i n t h e h e a d s p a c e
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 solution.
The o x i d a t l o n o f 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
solution.
A n t i o x i d a n t s have been
und t o 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
olutions .
C a p t o p r l l as a b u l k p o w d e r has
excellent solldtate 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
r e s e n c e o f c e r t a i n e x c i p l e n t s t h a t relase
moisture.
he d e g r a d a t i o n
r e a c t l o n follows apparent
zero-order
lnetics.
The r a t e o f e x c i p l e n t - m e d i a t e d
degradation
f c a p t o p r l l i n t h e s o l i d s t a t e d e p e n d s on
moisture,
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 t h e
drug-toexcipient r a t i o i n c r e a s e s .
tabllization

Methods

Optimum s t a b i l i t y o f c a p t o p r l l i n a q u e o u s s o l u t i o n i s
a c h l e v e d by a d j u s t i n g pH on t h e 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 p u r g e

B . Ja i n
(Kansas)