Stability of Drugs and Dosage Forms Sumie Yoshioka

82 Chapter 2 • Chemical Stability of Drug Substances
Figure 52. pH–rate profile for the degradation of a weak base with three ionizable groups. Dashed curves represent
the contributions of all reactions of the different species. (Reproduced from Ref. 355 with permission.)
Although complex pH–rate profiles are often observed, some drug substances exhibit
apparent degradation rate constants that are relatively independent of pH, as exemplified by
the pH–rate profile of estramustine from pH 1 to 10 shown in Fig. 53. 357 The explanation
for this is that estramustine undergoes a spontaneous unimolecular reaction that is catalyzed
by neither acid nor base in this pH range. Other examples of pH–rate profiles for specific
drug substances are presented in the following sections.
2.2.5.1. V-Type and U-Type pH–Rate Profiles
The pH–rate profiles for the hydrolysis of diltiazem, 358 fenprostalene, 359 and E09 (a
derivative of aziridinylquinone) 360 are all V-shaped (Fig. 54), indicating only apparent
hydronium ion and hydroxide ion catalysis. The dehydration reaction of streptovitacin A
shown in Scheme 32 also exhibits a V-type pH–rate profile. 147
As stated earlier, if the degradation of a drug follows Eq. (2.93), its pH–rate profile will
+
be V- or U-shaped—why If we first consider the case where k H2 O = 0 and k H =
– kOH , then
when a
+ H >> aOH
– , Eq. (2.93) reduces to Eq. (2.95) under these pH conditions.
Figure 53. pH–rate profile for hydrolysis of estramustine at 80°C. (Reproduced from Ref. 357 with permission.)