Drug K i n e t i c s

1 9 9

Ampicillin

i n o r d e r t o a v o i d a l t e r a t i o n of b i o a v a 1 l a b l 1 i t y characteristics. The r a t e of d e c o m p o s i t i o n of a m p i c i l l i n l s e n h a n c e d by l n c r e a s i n g the c o n c e n t r a t l o n of dext r o s e and o t h e r c a r b o h y d r a t e s i n s o l u t l o n .

GENERAL ames Ampicillin; Structure D-ct-aminobenzyl penlcillin.

DRUG

KINETICS and Rate Equation

Reactions

As i s g e n e r a l l y t r u e f o r the o t h e r p e n l c l l l l n s , the most i m p o r t a n t s o u r c e of d e g r a d a t i o n of a m p i c i l l i n l s the h y d r o l y t i c c l e a v a g e of the B - l a c t a m r i n g . In acid or n e u t r a l s o l u t l o n the f o l l o w i n g p r o d u c s a r e formedi

1619N304S wt. 349.41

CHJ

,CHj

C00H

mol.

Q-r
NHj Forms Available ampicillin); sodlum salt; ampiF r e e a c i d (anhydrous c i l l i n trihydrate. Physical Properties

N^^COOH H00

XA?
H00C
C H s

a-aminobenzylpenamaldlc acid

o-amlnobenzyl acid

penillic

Solubility: 1 g d i s s o l v e s i n about 90 mL of water a t , 25C, and 1 g i n 250 mL of a l c o h o l ( 1 ) . M e l t n g point 202 to 203C ( 2 ) . Stabillty Summary

At pH v a l e s above 7, d e g r a d a t i o n of a m p i c i l l i n i s a r e s u l t of hydroxide-ion-catalyzed h y d r o l y s i s , glvlng t h e i n d i c a t e d p r o d u c t , and a h i g h l y c o n c e n t r a t i o n - d e pendent d i m e r i z a t i o n r e a c t i o n ( 3 ) ,

CHJ

A m p i c i l l i n i s s u s c e p t i b l e to 8 - l a c t a m r i n g h y d r o l y s i s . Its p H - r a t e p r o f l l e r e v e i s s p e c i f i c - a c i d - and spec 1 f i c - b a s e - c a t a 1 yzed h y d r o l y s i s . G e n e r a l a c i d and g e n e r a l base c a t a l y s i s a r e known to o c c u r i n c i t r a t e and p h o s p h a t e b u f f e r s y s t e m s . The pH of m x i m u m s t a billty i s 5.8. Owing t o d i m e r i z a t i o n , the r a t e of degradation increases substan11 a 1ly with lncreasing i n l t i a l concentratlon. A d d i t i o n of a l c o h o l to s o l u t i o n s o f a m p i c i l l i n has been shcwn to enhance i t s s t a billty. Interconversion of h y d r a t e s must be p r e v e n t e d 198

T
"00C

C00"

'

NHj

o-aminobenzy1 p e n i 1 l o i c a c i d 1 The p r e s e n c e of t h e amino s i d e - c h a i n group o f ampic11 l i n a p p e a r s to have a s i g n i f i c a n t e f f e c t on the rate| of d e g r a d a t i o n . B e l n g a m p h o t e r i c , a m p i c i l l i n can| e x i s t as a c a t i n , a z w i t t e r l o n , and an a n i n . Thep pK a v a l e s of the c a r b o x y l and amino g r o u p s a r e 2.6I

:200

Ampicillin

Drug

Kineics

201

811

7 24 respectively (4). d e m o n s t r a l e d to undergo

s o l u t i o n ;

These t h r e e s p e c i e s have the f o l l o w i n g reactions

nSd11ufce

+ H3N-R-C00H + H +

>

producs

(1)

Hgf-R-COO"

+ H+ k

K2
H Q

>

producs

(2!

H3N-R-COOH

>

producs

(3)

Reacions (1) h r o u g h (3) a r e r e s p o n s i b l e f o r the b e h a v i o r of t h e p r o f i l e o v e r pH 3 to 5. The l e v e l i n g of t h e c u r v e frora pH 5.5 t o 6.5 s u g g e s t s p r e d o m i n a n c e of r e a c t i o n s (2) and (3) i n t h e d e g r a d a t i o n p r o c e s s . At pH g r e a t e r t h a n 7,5 r e a c t i o n (5) l s e s s e n t i a l l y r e s p o n s i b l e f o r the observed r a t e , c l e a r l y deraonstrati n g t h e e f f e c t of s p e c i f i c base c a a l y s i s . The m x i mum s t a b i l i t y o c c u r s a i pH 5.8, i n d i c a l i n g t h a t t h e zwilerionic form i s the l e a s t s u s c e p i b l e species wih rsped lo hydrolysis. The t$ a i pH 6.6 i s a p p r o x i m a e l y 39 days .
3.8

k4 H2N-R-C00" ^

>

producs

(4!
4.2

H 2 N-R-C00 _

* "OH

k5 ^0>

producs

(5)
4.6

This

series

of

reacions

l s summarized

by

he rae
5.0

equaion 1rae

- k : [H3N-R-COOH][H + ] + k 2 [H3N-R-COO-][H*]

Ti/)
*
O) _0

5.4

+ k 3 [H 3 N-R-C00-] + k 4 [ H 2 N - R - C 0 0 - ] k5[H2N-R-C00-][OH"] (6)

I
5.8

In h i s e x p r e s s i o n k j and k 2 a r e s e c o n d - o r d e r s p e c i f i c a c i d c a a l y s i s r a e c o n s a n s , k 3 and k 4 a r e f i r s t order c o n s t a n t s f o r h y d r o l y s i s o f z w i t t e r i o n i c and a n i o n i c a m p i c i l l i n , and ks i s a s e c o n d - o r d e r s p e c i f i c base c a t a l y s l s c o n s a n l . A i h i g h c o n c e n r a l o n s and pH v a l e s a b o v e 7, b a s e - c a a 1 y z e d and u n c a a l y z e d d i n e r i z a i o n r e a c i o n s have been f o u n d o be an a d d i t i o n a l i m p o r t a n i cause of d e g r a d a i o n ( 3 ) . pH-Rate Profile

6.2 6.6

1.0

3.0 PH

5.0

7.0

9.0

FIGURE 1. Ampicillin. pH-rate p r o f i l e f o r h y d r o l y s i s of a m p i c i l l i n at 35'C ( r a t e c o n s t a n t s i n s - 1 ) -

F i g u r e 1 l s the pH-rate p r o f i l e f o r the h y d r o l y s i s of a low c o n c e n t r a i o n of a m p i c i l l i n a t 35"C and c o n s t a n t ionic strength. T h i s p l o t r e p r e s e n s E q . (6) w i h a l l c o n s a n s e x r a p o l a e d o zero b u f f e r c o e c e n r a i o n . A i pH l e s s h a n 1.5 s p e c i f i c a c i d c a a l y s i s involving he a m p i c i l l i n c a i o n p r e d o m n a l e s . The s h o u l d e r i s due o h e i o n i z a i o n of h e c a r b o x y l i c acid group.

Activation

Energy

The t e m p e r a l u r e d e p e n d e n c e of a m p i c i l l i n hydrolysis has been r e p o r t e d (2) and i s shown a t pH 4.93 i n the f o r m o f an A r r h e n i u s p l o t i n F i g u r e 2. The paeudo-

202

Aipiclllin

Drug

Klnetics

203

i
F i g u r e s 3 and 4 show the dependence of the o b s e r v e d r a t e c o n s t a n t s on t o t a l b u f f e r c o n c e n t r a t l o n i n c i t r a t e and p h o s p h a t e b u f f e r s , r e s p e c t l v e l y .

f i r s t - o r d e r c o n s t a n t s were o b t a i n e d under conditions of c o n s t a n t i o n i c s t r e n g t h . The a c t i v a t i o n e n e r g i e a o b t a i n e d f r o n t h e s l o p e s of such p l o t s a r e t a b u l a t e d i n T a b l e 1.

i i

i
DA

I / T

x o

FIGURE 2. Anpicillin. A r r h e n l u s p l o t showlng t e n p e r a t u r e d e p e n d e n c e of r e a c t i o n r a t e s of h y d r o l y s i s o f a n p i c i l l i n a t pH 4.93.

TABLE

1.

Activation Anpicillin

E n e r g i e s of Hydrolysis
Total citrate x 10 /moh liter
3 - 1

pH

Ea

(kcal/mol)

FIGURE against pH

3.

Ampicillin. citrate pH 2.76; B,

Plot buffer C, pH

of o b s e r v e d 3.12; D, pH

rate

constant E. p H

total

concentratlon

a t 3 5 C C (A, 4.75;

2.25;

1 .35 4 .93 9 . 78

16.4 18.3 22 . 3

6.80).

Other

Data has also been shown t o undergo general(2).

Anpicillin acldand

g e n e r a 1 - b a s e - c a t a 1 y z e d - h y d r o 1 ys1s

At 35C and pH 1.2 a s l i g h t l i n e a r p o s i t l v e salt e f f e c t on a m p i c i l l i n h y d r o l y s i s i s o b s e r v e d ( 2 ) . No? s a l t e f f e c t i s o b s e r v e d at pH 4.94. At pH 1.2 the addition of a l c o h o l to t h e s o l u t l o n results in d e c r e a s e i n h y d r o l y s i s r a t e ; t h i s has been a t t r l b u t e d to the d e c r e a s e i n s o l v e n t d i e l e c t r i c c o n s t a n t ( 4 , 5 .

Formulations

and

Comblnations

205

modrate level. I n t e r e o n v e r s i on o f the h y d r a t e d and unhydrated f o r m s of a m p i c i l l i n can have s i g n i f i c a n t e f f e e t s on t h e d i s s o l u t i o n r a t e of f o r m u l a t i o n s and thus a f f e c t the b i o a v a i l a b i 1 i t y ( 7 ) . The a n h y d r o u s form i s more soluble than the t r i h y d r a t e , but i t s s o l u b i l i t y dec r e a s e s with l n c r e a s i n g temperature. Solubility has been d e t e r m i n e d a t 37C as a f u n c t i o n of pH f o r both c r y s t a l forms ( 8 ) . T e m p e r a t u r e and h u m i d i t y c o n t r o l a r e e s s e n t i a l t o p r e v e n t t h i s change i n c r y s t a l l i n e form. C o m p o n e n t s of commonly used d i l u e n t s f o r i n t r a v e nous i n f u s i n of sodium a m p i c i l l i n can a f f e c t the r a t e of h y d r o l y t i c d e g r a d a t i o n . D e x t r o s e has been shown to have a c a t a l y t i c e f f e c t on the d e c o m p o s i t l o n of ampicillin (9,10). Freezing of r e c o n s t i t u t e d solutlons has a v a r i a b l e e f f e c t w i t h r e s p e c t to l e n g t h of time required f o r 10% degradation in s e v e r a l diluents (Table 2 ) .

TABLE 2.

Mximum Storage Time D l l u e n t and T e m p e r a t u r e

as (9)

Function

of

Solutlon

ro
-20 5 27 5 27 4 27

M x i m u m Time of Storage ( t 9 0 )

Total phosphate x 10 /mol liter '

2 -

FIGURE 4. A m p i c i l l i n . P l o t of o b s e r v e d r a t e against t o t a l phosphate b u f f e r c o n c e n t r a t l o n (A, pH 7.11; B, pH 6.60) .

constant 'at 35C

25* Sodium a m p i c i l l i n In s t e r i l e water In r e c o n s t i t u t e d v i a l 1* In 1* In Sodium normal ampicillin saline

48 h 4 h 1 h 5 days 24 h 4 h 2 h

FORMULATIONS AND Degradation

COMBINATIONS

fc

Reactions

Sodium a m p i c i l l i n d e x t r o s e 5%

At h i g h t e m p e r a t u r e s and h u m i d i t i e s , and d e s p i t e f i r m b l n d i n g w i t h i n the t r i h y d r a t e c r y s t a l , the water molec u l e s are s u f f i c i S t l y f r e e to p a r t i c p a t e i n a s o l i d state h y d r o l y t i c r e a c t i o n ( 6 ) . Care must be e x e r c i s e d to e x e l u d e water as much as p o s s i b l e from s o l i d dosage forms and t o m a i n t a i n t h e s t o r a g e t e m p e r a t u r e at a

S u c r o s e has been shown to c a t a l y z e the d e g r a d a t i o n of a m p i c i l l i n (11,12). A l i n e a r r e l a t i o n s h i p between the d e g r a d a t i o n r a t e and sucrose concentratlon up to 10* has been o b s e r v e d ( 1 2 ) , O r a l s u s p e n s i o n s i n u n l t dose containers m a l n t a i n e d more t h a n 90* actlvity after s t o r a g e f o r 60 days at -10 to -20C ( 1 3 ) . Although

206

Ampicillin

Ref e r e n c e s i 8.

207

differences i n d e g r a d a t i o n r a t e h a v e been o b s e r v e d among o r a l l i q u l d p r o d u c t s m a n u f a c t u r e d by d i f f e r e n t c o m p a n i e s , a l l tested products maintalned acceptable p o t e n c y a t room t e m p e r a t u r e f o r at l e a s t seven days (14). S t a b i 1 i z a t i o n Methods To p r e v e n t h y d r o l y s i s o f the B - l a c t a m r i n g , water s h o u l d be p r e v e n t e d from coming i n c o n t a c t w i t h s o l i d ampicillin. T e m p e r a t u r e a l s o p l a y s an i m p o r t a n t r o l e i n r a t e s o f d e g r a d a t i o n i n t h e s o l i d and solution states. B e c a u s e of the l i m i t e d h a l f - l i v e s i n s o l u t i o n s and s u s p e n s i o n s , s o l i d dosage forms are the o n l y f o r m u l a t i o n s s t a b l e over extended p e r i o d s of t i m e . L o w e r i n g o f t h e d i e l e c t r i c c o n s t a n t of s o l u t i o n s of a m p i c i l l i n with a l c o h o l has r e s u l t e d i n b e t t e r s t a b i l i t y than i n f u l l y aqueous s o l u t i o n s at low pH. Buff e r i n g at the p H - r a t e m n i m u m and s t o r a g e at r e l a t i v e l y low c o n c e n t r a t 1 o n s a r e v i a b l e a l t e r n a t i v e s f o r e n h a n c i n g the s t a b i l i t y of l i q u i d f o r m u l a t i o n s .

A. T s u j i , E. Nakashima, S. Hamano, and,T. Yamana, J . Pharm. Sel., 67, 1059 (1978). D. R. Savello 28, 754 and and R. F. Shangraw, Am. J. Hosp,

9.

Piara., 10. H. 3, 11. S.

(1971). C. Larsen, I n t . J . Pharmaceut.,

Bundgaard 1 L. (1979). Hem,

E.

J . Russo, Sel., 62,

S. 267

M.

Bahal,

and

R.

S,

L e v ! , J . Pharm. 12. H. Bundgaard and

(1973). J . Piaroaceut.,

C.

L a r s e n , Int.

1 , 95 13. L. 209 14. V.

( 1978). Alien and P. L o , Am. J. Hosp. Pharm., 36,

(1979). J a f f e , N. M. Am. C e r t o , P. P i r a k i t i k u i r , J. Hosp. Pharm., 33, and J.

J . M. L.

Colaizzi,

1005

(1976).

REFERENCES 1. Remington's Pharmaceutical Philadelphia College Philadelphia, 1975. J . P. Hou and 447 ( 1 9 6 9 ) . H. J . W. Sciences Pharmacy (15th e d . ) , and S c i e n c e ,

- R i c h a r d A. Pyter (Wisconsin) of

2.

P o o l e , J . Pharm.

Sel.,

58,

3. 4.

B u n d g a a r d , Acta

Pharm.

Suec.

, 13, Pharm.

9 ( 1976). Sci., 58,

J . P. Hou and 1510 (1969). G.

J . W.

P o o l e , J.

5. 6.

S c a t c h a r d , Chem. and H.

Rev., E.

10,

229

(1932). Nature, 207, 645

N. H. G r a n t ( 1965 ) .

Album,

7.

J . W. P o o l e and 1945 ( 1968 ) .

C. K.

B a h a l , J . Pharm.

Sel.,

57,