Potentiometric pKa determination of water-insoluble compounds. Validation study in methanol/water mixtures

The apparent ionization constants (psKa) 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 (psKa+log[H2O]=a/ϵ+b) was used to obtain the pKa values in zero methanol%. In the case of water-soluble drugs the extrapolated data were in very good agreement with pKa 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 pKa 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 pKa 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 pKa values are suggested.