Multi‐pH QSAR: II. Regression Analysis Sensitive Enough to Determine the Transition‐State p K a of Human Buccal Absorption

An analysis of published human buccal absorption data of an acid and a base at six pH values extends multi‐pH QSAR to an extreme: QSAR on a single compound. The compounds analyzed are 4‐ n ‐hexylphenylacetic acid and propranolol. This analysis might be considered as much an analysis of the model as the compound, itself. Ionizable compounds undergo a p K a change in the process of absorption. Multi‐pH QSAR allows determination of the p K a of the presumed rate‐limiting step for absorption, which we label the transition‐state p K a (p K a TS ). Comparison of the p K a TS with the corresponding aqueous and membrane p K a values provides the extent of molecular penetration at the transition state. It is 49 % of the path length for the arylacetic acid and 73 % for propranolol.