Stability of Drugs and Dosage Forms Sumie Yoshioka

2.2. • Factors Affecting Chemical Stability 85
Figure 57. pH-rate profiles for hydrolysis of various cephalosporins: (a) cephaloglycin; (b) cephalexin; (c)
cefadroxil; (d) cephradine. (kpH): Rate constants obtained by extrapolating the buffer concentration to zero at 35°C.
(Reproduced from Refs. 70 and 71 with permission.)
is an intramolecular attack of the side-chain amino group on the ß-lactam ring, resulting in
the formation of a diketopiperazine product (Scheme 70). The inflection in the pH-rate
profile follows the change in the state of ionization of the side-chain amino group.
Although ampicillin also has a side-chain amino group in a position similar to that in
the cephalosporins, the hydrolysis rate is not significantly affected by the state of ionization
of the amino group. Ampicillin does exhibit an inflection point around pH 2–3 in its pH–rate
profile due to ionization of the carboxyl group, as shown in Fig. 59. 65 The side-chain amino
group in penicillins cannot attack the β-lactam ring to form the diketopiperazine, presumably
due to conformational restrictions. A pH–rate profile similar to that of ampicillin, with an
inflection point due to ionization of the carboxyl group, has been reported for the hydrolysis
of carbenicillin 363 as well as other penicillins.
A classical pH–rate profile demonstrating the effect of ionization of a neighboring group
on a chemical reaction can be seen in the pH-rate profile for the hydrolysis of aspirin 11,364
Figure 58. pH–rate profile for hydrolysis of loracarbef at 35°C. (Reproduced from Ref. 362 with permission.)