A potentially simpler approach to measure aqueous pKa of insoluble basic drugs containing amino groups

The aqueous pK values ((w/w)pK(a)) of several sparingly water-soluble drugs with amino groups have been calculated from pK values determined in several methanol/water mixtures ((s/s)pK(a)) by means of the Yasuda-Shedlovsky equation and by a linear equation that relates ((w/w)pK(a)) of amino compounds with ((s/s)pK(a)) obtained in any particular methanol/water mixture. Parameters of this last equation for amino compounds can be easily calculated from solely the methanol content of the solvent. Results from both approaches are consistent. However, Yasuda-Shedlovsky equation requires several ((s/s)pK(a)) determinations in solutions with different methanol content and can be used only from measurements in solutions with a maximum methanol content of about 65% in weight. In contrast, the linear proposed equation allows a very good estimation of ((w/w)pK(a)) from only one experimental ((s/s)pK(a)) value, and it permits this estimation from ((s/s)pK(a)) determined in a solution very rich in methanol. Therefore, it is suitable for very insoluble compounds. The examined amino compounds cover a wide range ((w/w)pK(a)) from 6.7 to 10.6, which have been estimated from experimental ((s/s)pK(a)) values in the whole composition range. In all instances consistent and satisfactory results have been achieved.