Engineering cocrystal solubility, stability, and pHmax by micellar solubilization

Cocrystals offer great promise in enhancing drug aqueous solubilities, but face the challenge of conversion to a less soluble drug when in contact with solvent. This manuscript shows that differential solubilization of cocrystal components by micelles can impart thermodynamic stability to otherwise unstable cocrystals. The theoretical foundation for controlling cocrystal solubility and stability is presented by considering the contributions of micellar solubilization and ionization of cocrystal components. A surfactant critical stabilization concentration (CSC) and a solution pH (pHmax) where cocrystal and drug are thermodynamically stable are shown to characterize cocrystal stability in micellar solutions. The solubility, CSC, and pHmax of carbamazepine cocrystals in micellar solutions of sodium lauryl sulfate predicted by the models are in very good agreement with experimental measurements. The findings from this work demonstrate that cocrystal CSC and pHmax can be tailored from the selection of coformer and solubilizing additives such as surfactants, thus providing an unprecedented level of control over cocrystal stability and solubility via solution phase chemistry.