PH-metric log P 11. pKa determination of water-insoluble drugs in organic solvent–water mixtures

Abstract

The apparent acid dissociation constants (psKa) of two water-insoluble drugs, ibuprofen and quinine, were determined pH-metrically in acetonitrile–water, dimethylformamide–water, dimethylsulfoxide–water, 1,4-dioxane–water, ethanol–water, ethylene glycol–water, methanol–water and tetrahydrofuran–water mixtures. A glass electrode calibration procedure based on a four-parameter equation (pH=α+SpcH+jH[H+]+jOH[OH−]) was used to obtain pH readings based on the concentration scale (pcH). We have called this four-parameter method the Four-Plus™ technique. The Yasuda–Shedlovsky extrapolation (psKa+log[H2O]=A/ε+B) was used to derive acid dissociation constants in aqueous solution (pKa). It has been demonstrated that the pKa values extrapolated from such solvent–water mixtures are consistent with each other and with previously reported measurements. The suggested method has also been applied with success to determine the pKa values of two pyridine derivatives of pharmaceutical interest.