Differential potentiometric method for determining dissociation constants of very slightly water-soluble drugs applied to the sulfonamide diuretic chlorthalidone.

A renewed application of potentiometric acid-base titrations is described, by which dissociation constants of practically water-insoluble drugs can be measured accurately. The method uses the difference in the amount of titrant between a suitable aqueous solvent and a solution of the drug in that solvent. Such potentiometric difference titrations were conducted on a 3.7 X 10(-4) M solution of chlorthalidone in 0.1 M aqueous KCl in the pH 3.5--10.6 range at 25 degrees. Nonlinear least-squares regression analysis was applied to the data. From four determinations, a value of 9.24 +/- 0.02 (mean +/- SEM) resulted for the apparent dissociation constant of the first chlorthalidone acid group. The thermodynamic dissociation constant was calculated at pKa1 = 9.35 (25 degrees) by using a correction for activity.