Engineering cocrystal thermodynamic stability and eutectic points by micellar solubilization and ionization

Abstract

Pharmaceutical cocrystals are of great interest because of their potential to enhance solubility and bioavailability of poorly water-soluble drugs. Cocrystal development is however limited by their poor thermodynamic stability in aqueous environments. The work presented here describes the mechanisms by which cocrystal stability can be fine-tuned via micellar solubilization and ionization of cocrystal components. An important feature of cocrystal solution equilibria is the existence of eutectic points involving coexistence of three phases, a liquid and two solids. The solution composition at the eutectic points is a critical parameter that defines the conditions of thermodynamic stability. Equations that describe the sensitivity of eutectic points and phase diagrams to micellar surfactants and pH are presented. Predictions are in excellent agreement with the behavior of several carbamazepine cocrystals in aqueous solutions of sodium lauryl sulfate. Increasing the magnitude of micellar solubilization for one of the cocrystal components is found to confer greater thermodynamic stability to the cocrystal and expand its stability region. These findings provide an unprecedented level of control over cocrystal-solution phase behavior, and are applicable to multiple additives and solubilization mechanisms that may be required for the stabilization of highly soluble cocrystals.