Determination of the Asymmetric Ternary Phase Diagram and Preparation of Theophylline–Isonicotinamide Cocrystals

The solid-liquid phase equilibrium data of theophylline and isonicotinamide in selected solvents (isopropanol, N,N-dimethylformamide, and n-pentanol) were determined by using the static method at 298.15 and 308.15 K under 101.325 kPa. The ternary phase diagram was plotted, and it was concluded that it is an asymmetric phase diagram. The mechanism of solid-phase formation of cocrystals during the determination of the ternary phase diagram is discussed. Excessive amounts of THE and INA cause the system to become supersaturated. As the cocrystal forms, the solubility of THE and INA decreases. When the system is on the solvation curve of the cocrystal, the activity coefficients of THE and INA drop to critical values and cocrystal formation stops. Based on the analysis of phase solubility diagrams for cocrystals, two routes for obtaining the cocrystal of THE-INA from solution have been proposed and validated. For route 1, concentrations of THE and INA in the solution are adjusted to the appropriate concentrations, and then, solvent evaporation is performed to achieve crystallization. For route 2, an amount of THE was added to a highly concentrated INA solution. The variation of the main constitutive forces of cocrystal formation is explored by molecular simulation simulations. The types of interaction forces and their interaction energies in ternary systems are identified. In addition, the melting temperature and enthalpy of fusion of the THE-INA cocrystal obtained during ternary phase diagram determination were determined to be 462.26 K (onset) and 131.69 J/g, respectively.