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 titration 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 × 10−4 M solution of chlorthalidone in 0.1 M aqueous KCl in the pH 3.5‐10.6 range at 25°. Nonlinear least‐squares regression analysis was applied to the data. From Four determination, 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°) by using a correction for activity. Copyright © 1979 Wiley‐Liss, Inc., A Wiley Company