K. Takacsnovak et al., POTENTIOMETRIC PK(A) DETERMINATION OF WATER-INSOLUBLE COMPOUNDS - VALIDATION-STUDY IN METHANOL WATER MIXTURES/, International journal of pharmaceutics, 151(2), 1997, pp. 235-248
The apparent ionization constants (p(s)K(a)) of 25 molecules, based on
431 separate potentiometric titrations, were determined in methanol/w
ater mixtures of 15-65 wt% methanol content. The Yasuda-Shedlovsky ext
rapolation (p(s)K(a) + log[H2O] = a/epsilon + b) was used to obtain th
e pK(a) values in zero methanol%. In the case of water-soluble drugs t
he extrapolated data were in very good agreement with pK(a) values mea
sured in aqueous solutions under the same experimental conditions (ave
rage deviation = 0.05). The water-insoluble molecules showed acceptabl
e accordance with spectroscopically measured or with literature pK(a)
values. Concentration dependence between 1-5 mM was not observed while
the range of extrapolation (water-rich: R = 15-35 wt%, or methanol-ri
ch: R = 40-65 wt% significantly influenced the accuracy of pK(a) value
s. Remarkable changes in the solvation structure of weak acids in meth
anol-rich mixtures (> 35 wt%) were suggested from analyzing the slopes
of Yasuda-Shedlovsky equations. Recommendations for the proper applic
ation of a mixed-solvent procedure in order to gain the most reliable
aqueous pK(a) values are suggested. (C) 1997 Elsievier Science B.V.