Potentiometric pK(a) determination of water-insoluble compounds: Validation study in methanol/water mixtures

The apparent ionization constants (p(s)K(a)) of 25 molecules, based on 431 separate potentiometric titrations, were determined in methanol/water mixtures of 15-65 wt% methanol content. The Yasuda-Shedlovsky extrapolation (p(s)K(a) + log[H2O] = a/epsilon + b) was used to obtain the pK(a) values in zero methanol%. In the case of water-soluble drugs the extrapolated data were in very good agreement with pK(a) values measured in aqueous solutions under the same experimental conditions (average deviation = 0.05). The water-insoluble molecules showed acceptable accordance with spectroscopically measured or with literature pK(a) values. Concentration dependence between 1-5 mM was not observed while the range of extrapolation (water-rich: R = 15-35 wt%, or methanol-rich: R = 40-65 wt% significantly influenced the accuracy of pK(a) values. Remarkable changes in the solvation structure of weak acids in methanol-rich mixtures (> 35 wt%) were suggested from analyzing the slopes of Yasuda-Shedlovsky equations. Recommendations for the proper application of a mixed-solvent procedure in order to gain the most reliable aqueous pK(a) values are suggested. (C) 1997 Elsievier Science B.V.