Revealing dissolution behavior and thermodynamic properties of tinidazole in 12 mono-solvents based on experiments and molecular simulation

• The solubility of Tinidazole in different mono-solvent was measured. • Molecular simulations were used to explain the dissolution behavior of TNZ. • The thermodynamic models were employed to correlate the solubility data of TNZ. • The mixing thermodynamic properties of Tinidazole in twelve mono-solvents were calculated by the NRTL equation. The crystal structure and thermodynamic properties of Tinidazole (TNZ), an antiprotozoal and antibacterial drug, were investigated in the solid phase and liquid phase. The solubility of TNZ in 12 solvents was also measured in detail by the gravimetric method in the temperature range from 288.15 K to 328.15 K. The intermolecular interaction was confirmed by Hirshfeld surface analysis, demonstrating that H···H and O···H contacts were decisive in the solid-state structure. Furthermore, the statistical correlations results of the heatmap indicated that the solubility of TNZ in the liquid phase was related to the aspects in terms of solvent-solute intermolecular interactions and solvent properties. Following that, the molecular simulations involving molecular polarity Index (MPI), molecular electrostatic potential surface (MEPs), hydrogen binding energy (E HB ) and mean square displacement (MSD) were applied successfully to the interpretation of the effect of polarity, hydrogen bond formation and diffusion, to better understand the dissolution behavior of TNZ in 12 solvents. More importantly, five thermodynamic models were used to examine the solubility data as the ARD% values were all less than 7%. Subsequently, based on the NRTL model, the related thermodynamic parameters were obtained, showing that the dissolution process of TNZ in various solvents was spontaneous and entropy-driven. Through experiments and molecular simulation, these results can provide an important theoretical basis for the industrial production of TNZ.