title: Potentiometric and spectrophotometric pKa determination of water-insoluble compounds: validation study in a new cosolvent system.
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 (p(s)Ka) 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.
authors: Semmelweis University, Department of Pharmaceutical Chemistry, Högyes E. u. 9, H-1092 Budapest, Hungary.
authors: Gergely
authors: G
authors: Völgyi
authors: Rebeca
authors: R
authors: Ruiz
authors: Karl
authors: K
authors: Box
authors: John
authors: J
authors: Comer
authors: Elisabeth
authors: E
authors: Bosch
authors: Krisztina
authors: K
authors: Takács-Novák
mesh_terms: D002623:Chemistry Techniques, Analytical / Q000379:methods*; D006863:Hydrogen-Ion Concentration; D011199:Potentiometry / Q000379:methods; D012995:Solubility; D012997:Solvents / Q000032:analysis* / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D014867:Water / Q000032:analysis* / Q000737:chemistry
chemical_list: D012997:Solvents; D014867:Water