TRANSITION-STATE ACIDITIES AND THE PH-DEPENDENCE OF DRUG STABILITY

The pH dependence of hydrolytic reactions of drugs allows some control of their stability through adjustment of the pH of storage. The trans ition-state acidity concept of J. L. Kurz is shown to apply to the sys tematics of relevant pH rate profiles. As limiting cases for the hydro lysis of a series of carboxylic acid derivatives (often employed in pr o-drug modifications) in neutral and basic solution, two situations ar e considered: 1) larger structural effects in basic solution, in which case the most stable compound of the series has the highest transitio n-state pK(a), and 2) larger structural effects in neutral solution, i n which case the most stable compound will have the lowest transition- state pK(a). The former is the expected situation for variations of re actant electronic features because the negatively charged transition s tate for the hydroxide-promoted reaction in basic solution should resp ond more sensitively to electronic effects than should the dipolar tra nsition state for the ''uncatalyzed'' reaction in neutral solution. Av ailable data for some important substrates in fact do not show the exp ected behavior, which may be indicative of a concerted reaction (no te trahedral intermediate) for reactive substrates with hydroxide ion, a mechanism for which others have already provided evidence, and possibl e reaction through an ion pair for the reaction of reactive substrates with water.