Critical validation of a new simpler approach to estimate aqueous pKa of drugs sparingly soluble in water

A simple linear approach to estimate the aqueous pK_a of compounds sparingly soluble in water, mainly drugs, from solely one pK_a value determined in any methanol/water mixture is evaluated. The parameters (slope and intercept) of the linear relationships are related to the solvent composition and can be easily calculated according to the acidic or basic functional group of the compound. The method has been tested using the available literature data for phenols, aliphatic carboxylic acids, benzoic acid derivatives, both ortho and non-ortho substituted, amines and imidazole derivatives. The study involves the whole range of solvent composition and about one hundred compounds which show a wide variety of aqueous pK_a, from 1.3 to 12.4. The differences between calculated and previously published aqueous pK_a values are less of 0.2 pK units. Consistent values are obtained whatever the composition of methanol/water mixture employed in the experimental measurements. The results support the usefulness of the tested method as a very simple approach to get reliable aqueous pK_a values for sparingly soluble drugs.