Determination of the aqueous pKa of very insoluble drugs by capillary electrophoresis: Internal standards for methanol-water extrapolation

• Published in: Journal of Chromatography A Vol. 1665; p. 462795
• Main Authors: Albishri, Abdulkarim, Cabot, Joan M., Fuguet, Elisabet, Rosés, Martí
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 22.02.2022
• Subjects: Capillary electrophoresis; Extrapolation; Internal standard; Methanol; pKa determination; Solubility; Solvent mixture; Extrapolation; Capillary electrophoresis; Internal standard; Solubility; Solvent mixture; pKa determination; Methanol
• ISSN: 0021-9673
• DOI: 10.1016/j.chroma.2021.462795

•The IS-CE method allows pKa determination of highly insoluble compounds.•A set of compounds were proposed to be systematically employed as IS.•The IS-CE method was tested for commercial drugs with solubility < 10-6 mol L-1.•Aqueous pKa values were determined through Y-S using MeOH/H2O 10% to 40% (v/v) range. A fast determination of acidity constants (pKa) of very insoluble drugs has become a necessity in drug discovery process because it often produces molecules that are highly lipophilic and sparingly soluble in water. In this work the high throughput internal standard capillary electrophoresis (IS-CE) method has been adapted to the determination of pKa of water insoluble compounds by measurement in methanol/aqueous buffer mixtures. For this purpose, the reference pKa values for a set of 46 acid-base compounds of varied structure (internal standards) have been established in methanol-water mixtures at several solvent composition levels (with a maximum of 40% methanol). The IS-CE method has been successfully applied to seven test drugs of different chemical nature with intrinsic solubilities lower than 10−6 M. pKa values have been determined at different methanol/aqueous buffer compositions and afterwards Yasuda-Shedlovsky extrapolation method has been applied to obtain the aqueous pKa. The obtained results have successfully been compared to literature ones obtained by other methods. It is concluded that the IS-CE method allows the determination of aqueous pKa values using low proportions of methanol, becoming then more accurate in the extrapolation procedure than other reference methods.