Predicting the solid-liquid phase diagram of a ternary system with cocrystal formation

Cocrystals are commonly synthesized to improve a target solute's physicochemical properties. Solvent-based cocrystallization is the most widely used process to obtain cocrystals. Developing and scaling up the production of cocrystals by solvent-based methods require the knowledge of the solid-liquid equilibrium (SLE) phase diagram of the target solute/coformer/solvent system. However, the experimental determination of the complete SLE phase diagram of a ternary system at different temperatures over the entire composition range is tedious. In this work, we propose a thermodynamic approach to predict the SLE phase diagram of a ternary system with cocrystal formation. First, the solubility of the coformer and cocrystals in the solvent is measured at different temperatures. Second, these data are fitted to obtain the binary interaction parameters of the non-random two-liquid (NRTL) model. Finally, the SLE phase diagram of the target solute/coformer/solvent system at different temperatures is predicted, utilizing the activity coefficients of the components and the melting properties of the cocrystal. Two systems were used to validate the approach: choline chloride (ChCl)/catechol/acetonitrile with ChCl : catechol 1 : 1 and 1 : 2 cocrystals and tetramethyl ammonium chloride (TMACl)/catechol/acetonitrile with TMACl : catechol 1 : 1 and 1 : 2 cocrystals. The proposed approach predicted the SLE phase diagram of the two systems, unraveling the solubility of catechol and the cocrystals of the two systems in acetonitrile as well as the dissolution behavior of the cocrystals, i.e., congruent or incongruent dissolution. The proposed methodology highlights the benefit of using thermodynamic modeling for cocrystal engineering and design.