pKa determination of benzhydrylpiperazine antihistamines in aqueous and aqueous methanol solutions

The pKa1 and pKa2 values of three benzhydrylpiperazine antihistamines, cyclizine (I), chlorcyclizine (II), and hydroxyzine (III), were determined at 24.5 +/- 0.5 degrees by potentiometric titration in aqueous solution to be 2.16 +/- 0.02 and 8.05 +/- 0.03, 2.12 +/- 0.04 and 7.65 +/- 0.04, and 1.96 +/- 0.05 and 7.40 +/- 0.03, respectively. The pKa2 values were also determined by titration in seven aqueous methanol solutions in the range of 11.5-52.9% (w/w) methanol. The apparent dissociation constants of I-III in the aqueous methanol solutions, psKa2, were plotted according to two linear regression equations from which the values in water, p omega Ka2, were extrapolated. The plotted variables were psKa2 versus methanol concentration (%w/w) and psKa2 + log (water concentration, M) versus 1000/epsilon, where epsilon is the dielectric constant of the aqueous methanol solution. The maximum difference between pKa2 and p omega Ka2 was observed in the case of II where p omega Ka2 was 5.23% higher. Statistical analysis of the linear regression data obtained from the plots showed that slightly better accuracy (p less than 0.13) and correlation (p less than 0.16) were obtained, but the precision was essentially equal with both methods. The observed ratio of Ka1/Ka2 in I-III, 2.75 X 10(5)-7.76 X 10(5), was attributed to solven- and space-mediated field effects and electrostatic induction between nitrogen atoms in the piperazine ring.