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

Abstract

The solid−liquid phase equilibrium data of theophylline and isonicotinamide in selected solvents (isopropanol, N,Ndimethylformamide, 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.

Stoichiometric Diversity of Caffeine and 4-Hydroxybenzoic Acid Cocrystals in Batchelor Vortex Flow

“…The phase solubility diagram (PSD) and TPD were crucial tools for identifying cocrystal formation regions, understanding solution chemistry, and analyzing solubility behavior. − Additionally, the PSD offered insights into the thermodynamic stability of various stoichiometric cocrystals and informed on the pathway of cocrystal formation. , To gain a deeper understanding of the cocrystallization process between CAF and 4-HBA, the PSD of the CAF/4-HBA/methanol system at 10 °C was determined (refer to Supporting Information Figure S4). The graph’s symbols represent experimental solubility data for the CAF crystalline, (2:1), (1:2), and (1:3) cocrystals, and 4-HBA crystalline phases.…”

“…Previous research has indicated that the phase transformation rate in Taylor and Batchelor vortex flows surpasses that in random turbulent eddy flows. Therefore, increasing the rotational speed significantly impacts the phase transformation process in these systems. ,,, …”

“…Numerous studies have illustrated the significant influence of kinetics on cocrystallization. − For instance, the kinetic pathways of cocrystallization depend on the position within the phase diagram, leading to the development and competition of carbamazepine/nicotinamide cocrystals and carbamazepine crystals. , Furthermore, kinetic factors such as nucleation and growth rates can affect the composition of the cocrystallizing phase before reaching equilibrium. As a result, the initial nucleation phase may deviate from the thermodynamically stable phase predicted by the ternary phase diagram (TPD). − Reliance solely on thermodynamic data is therefore insufficient for elucidating the nucleation and phase transformation of cocrystals with varying stoichiometries throughout the entire process.…”