Potentiometric and spectrophotometric pKa determination of water-insoluble compounds: Validation study in a new cosolvent system

In this paper the validation of pKa determination in MDM–water mixtures is presented. The MDM–water mixture is a new multicomponent cosolvent mixture (consisting of equal volumes of methanol, dioxane and acetonitrile, as organic solvents) that dissolves a wide range of poorly water-soluble compounds. The cosolvent dissociation constants (psKa) of 50 chemically diverse compounds (acids, bases and ampholytes) were measured in 15–56 wt% MDM–water mixtures by potentiometric or spectrophotometric titration and the aqueous pKa values obtained by extrapolation. Three different extrapolation procedures were compared in order to choose the best extrapolation in MDM–water mixture using a sub-set of 30 water-soluble compounds. The extrapolated results are in good agreement with pKa values measured in aqueous medium. No significant difference was found among these extrapolation procedures thus the widely used Yasuda–Shedlovsky plot was proposed for MDM cosolvent also. Further we also present that the single point estimation based on measurement in 20%/v MDM-mixture using a general calibration equation may be suitable for rapid pKa determination in the early phase of drug research.