Original scientific paper

Transition-state Acidities and the pH Dependence of Drug Stability

K. Barbara Schowen ; Departments of Chemistry and Pharmaceutical Chemistry Higuchi Biosciences Center, University of Kansas, Lawrence, Kansas 66045-0046, USA
Richard L. Schowen ; Departments of Chemistry and Pharmaceutical Chemistry Higuchi Biosciences Center, University of Kansas, Lawrence, Kansas 66045-0046, USA

Abstract

The pH dependence of hydrolytic reactions of drugs allows some control of their stability through adjustment of the pH of storage. The transition-state acidity concept of J. L. Kurz is shown to apply to the systematics of relevant pH rate profiles. As limiting cases for the hydrolysis of a series of carboxylic acid derivatives (often employed in pro-drug modifications) in neutral and basic solution, two situations are considered: 1) larger structural effects in basic solution, in which case the most stable compound of the series has the highest transition-state pKa, and 2) larger structural effects in neutral solution, in which case the most stable compound will have the lowest transition-state pKa. The former is the expected situation for variations of reactant electronic features because the negatively charged transition state for the hydroxide-promoted reaction in basic solution should respond more sensitively to electronic effects than should the dipolar transition state for the »un- catalyzed« reaction in neutral solution. Available data for some important substrates in fact do not show the expected behavior, which may be indicative of a concerted reaction (no tetrahedral intermediate) for reactive substrates with hydroxide ion, a mechanism for which others have already provided evidence, and possible reaction through an ion pair for the reaction of reactive substrates with water. 

Keywords

Hrčak ID:

135985

URI

https://hrcak.srce.hr/135985

Publication date:

2.12.1996.

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