Potentiometric and spectrophotometric pKa determination of water-insoluble compounds: validation study in a new cosolvent system |
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Authors: | Völgyi Gergely Ruiz Rebeca Box Karl Comer John Bosch Elisabeth Takács-Novák Krisztina |
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Institution: | a Semmelweis University, Department of Pharmaceutical Chemistry, Högyes E. u. 9, H-1092 Budapest, Hungary b Departament de Quimica Analitica, Universitat de Barcelona, Diagonal 647, 08028 Barcelona, Spain c Sirius Analytical Instruments Ltd., Riverside, Forest Row Business Park, Forest Row, East Sussex RH18 5DW, United Kingdom |
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Abstract: | 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. |
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Keywords: | pKa Cosolvent procedure Methanol/dioxane/acetonitrile-water (MDM) Validation |
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