Understanding and Predicting the Effect of Cocrystal Components and pH on Cocrystal Solubility

Understanding how cocrystal solubility−pH dependence is affected by cocrystal components is important to engineer cocrystals with customized solubility behavior. Equations that describe cocrystal solubility in terms of solubility product, cocrystal component ionization constants, and solution pH are derived for cocrystals with acidic, basic, amphoteric, and zwitterionic components. Studies with carbamazepine-salicylic acid and carbamazepine-4-aminobenzoic acid show that cocrystals of a nonionizable drug achieve pH-dependent solubility when cocrystallized with ionizable coformers. These findings are in good agreement with predicted behavior and provide insight on the ability of coformer to determine the shape of the pH−solubility curve. It is shown that measurement of solution concentrations and pH at the eutectic point, Ctr, is valuable to (a) estimate cocrystal solubility−pH dependence, (b) evaluate the effectiveness of coformer in stabilizing or precipitating cocrystal, and (c) guide cocrystal selection without the time and material consuming determination of full phase solubility diagrams.