Anomalous Solubility Behavior of Several Acidic Drugs

The “anomalous solubility behavior at higher pH values” of several acidic drugs originally studied by Higuchi et al. in 1953 [1], but hitherto not fully rationalized, has been re-analyzed using a novel solubilitypH analysis computer program, pDISOL-X TM . The program internally derives implicit solubility equations, given a set of proposed equilibria and constants (iteratively refined by weighted nonlinear regression), and does not require explicit Henderson-Hasselbalch equations. The re-analyzed original barbital, phenobarbital, oxytetracycline, and sulfathiazole solubility-pH data of Higuchi et al. is consistent with the presence of dimers in saturated solutions. In the case of barbital, phenobarbital and sulfathiazole, anionic dimers, reaching peak concentrations near pH 8. However, oxytetracycline indicated a pronounced tendency to form a cationic dimer, peaking near pH 2. Under the conditions of the original study, only barbital indicated a slight tendency to form a salt precipitate at pH > 6.8, with a highly unusual stoichiometry (consistent with a slope of 0.55 in the log S – pH plot): K + + A2H + 3HA  KA5H4(s). Thus the “anomaly” in the Higuchi data can be rationalized by invoking specific aggregated species.