On the automated determination of pKa by NMR in DMSO : water mixtures

Abstract

The measurement of pK_a values for water insoluble compounds has long posed a challenge to pharmaceutical development. Previous work has focused on solubilizing such compounds by admixture of water miscible organic solvents followed by potentiometric titrations. Herein, a method to determine aqueous pK_a values in water : dimethylsulfoxide (DMSO) mixtures is presented using automated NMR titrations. The aqueous pK_a was calculated by the Yasuda–Shedlovsky extrapolation. This method offers several advantages notably that sparingly water-soluble compounds can be measured and the location of each pK_a value in the molecular structure can be determined. The method was benchmarked against several well-known pK_a values as well as demonstrated on some heterocyclic building blocks and an FDA approved drug.