Uncovering dissolution behavior and thermodynamic properties of metronidazole benzoate in twelve mono-solvents by experiments and molecular simulation

In this study, metronidazole benzoate (MBZ), a nitroimidazole antibiotic, was selected to measure the solubility in 12 solvents by the gravimetric method in the temperature range of 278.15 K to 323.15 K. The intermolecular interactions dominated by H & sdot;& sdot;& sdot;H and O & sdot;& sdot;& sdot;H contacts in the solid phase were determined using Hirshfeld surface analysis (HS). Subsequently, molecular simulations involving molecular electrostatic potential surface (MEPs), hydrogen binding energy (EHB) and mean square displacement (MSD) revealed the effect of the solvent polarity, hydrogen bonding and diffusion process on the dissolution behavior of MBZ. Furthermore, six thermodynamic models, all with values of ARDs less than 5 %, were successfully correlated with the experimental solubility results. The Apelblat model achieved the best fitting. Based on the NRTL models, relevant thermodynamic parameters were obtained, indicating that the dissolution process of MBZ in various solvents is spontaneous and entropy-driven. In the measured temperature range, the solubility of MBZ in different solvents increased from 4times to 25-times as the temperature changed, which provided an important theoretical basis for the industrial production of MBZ.