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

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.

• Erik N. A. Sundén¹
• Staffan Karlsson¹
• Christoph Bauer²
• Per-Ola Norrby²

•   ¹Early Chemical Development, Pharmaceutical Sciences, R&D AstraZeneca, Gothenburg, Sweden
• ²Data Science and Modelling, Pharmaceutical Sciences, R&D AstraZeneca, Gothenburg, Sweden

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