Predicting the Effect of pH on Stability and Solubility of Polymorphs, Hydrates, and Cocrystals

Cocrystal formation processes from aqueous solutions are often affected by pH-dependent dissociation, polymorphic transitions, and formation of hydrates and salts. To enhance the efficiency of those processes, the aqueous stability and solubility of pharmaceutical cocrystals were predicted in this study using the perturbed-chain statistical associating fluid theory (PC-SAFT). The solubilities in the binary systems caffeine/water and oxalic acid/water were modeled including hydrate formation and polymorphic transitions between the corresponding anhydrate forms I and II. Moreover, pH-dependent solubilities of these hydrate-forming components, their 2:1 cocrystal, and all appearing salts were measured and modeled at 298.15 K. It was found that the pH-dependent acid–base equilibria of caffeine and oxalic acid directly influence the stability and solubility of their cocrystal, their hydrates, and salts. In consideration of the thermodynamic nonideality of the components in the cocrystal system, PC-SAFT enables solubility predictions of the before-mentioned components as well as if any cocrystal is formed at given conditions of pH and temperature