The Effect of Co-solvents on pKa

Most methods of pKa measurement were developed using water-soluble samples. However, many drugs are poorly soluble in water alone, and require the presence of a water-miscible co-solvent to keep them in aqueous solution. The solvent affects the pKa in two ways (i) it causes the pH scale to shift and (ii) it causes the pKa to shift. The consequence is that apparent pKa values measured in the presence of solvent are different from aqueous values. 

The semi-empirical Yasuda-Shedlovsky technique of extrapolating a series of apparent pKa values obtained in several ratios of water/solvent to obtain an aqueous value is well established [32, 33], but three or more experiments are required and this adds significantly to assay times. A method of calculating aqueous pKas for various classes of organic acids and bases from single apparent pKa values obtained in water/solvent mixtures has been reported [34], and shows promise as a means of further speeding pKa measurement. 

The pH-metric method is an important reference method because it can be used to measure all pKas between 2 and 12, with or without a UV chromophore, provided that the sample can be dissolved in water or water/co-solvent over the pH range of interest. In this method, the sample solution is titrated with acid or base, the titration is monitored with a glass pH electrode, and the pKa is calculated from the 

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