Experimental measurement and thermodynamic modelling of ethenzamide solubility in three binary solvent systems

Highlights: • Solubility of ethenzamide was determined via gravimetric method in three binary solvent mixtures. • Four thermodynamic models were utilized to correlate the solubility data. • Cooperation effect originating from the solute–solvent interaction and solvent–solvent interaction was revealed by radial distribution function. • Thermodynamic properties were calculated. The solid–liquid phase equilibrium of ethenzamide (ETZ), a classic anti-inflammatory drug, in binary solvent systems was experimentally investigated and simulated. The equilibrium solubility of ETZ in binary solvent mixtures of methanol + acetonitrile, ethanol + acetonitrile, and isopropanol + acetonitrile was determined via a gravimetric method at temperatures ranging from 293.15 K to 323.15 K at atmospheric pressure (0.1 MPa). In all binary solvent systems, the solubility of ETZ increases with the increasing of temperature at a given solvent composition, but it initially increased and then decreased with the increase in alcohol composition (good solvent). Additionally, the Jouyban-Acree, van't Hoff-Jouyban-Acree, Apelblat-Jouyban-Acree, and Ma models were utilized to correlate the experimental data. Results showed that the Jouyban-Acree model achieved the best correlation performance. Molecular dynamic simulation and radial distribution function analysis revealed the cooperation effect originating from solute-solvent and solvent–solvent interactions, which explained the dissolution behaviors of ETZ in various solvent mixtures. Calculations of dissolution thermodynamic properties, including enthalpy, Gibbs free energy, and entropy, revealed that the dissolution behavior of ETZ was an endothermic and entropy-driven process. This study provides insights into modulating ETZ crystallization and in understanding solid–liquid phase equilibrium behaviors in mixed solvent systems.