Ethionamide solubility in twelve solvents at saturation: Thermodynamic analysis, solvent effect and molecular simulation

This study investigates the solubility of ethionamide in twelve pure solvents—2-methoxyethanol, 2-ethoxyethanol, methanol, ethanol, n-propanol, i-propanol, acetone, ethyl acetate, dimethylformamide (DMF), dimethylacetamide (DMAC), methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO)—across a temperature range of 278.15–323.15 K using a laser monitoring methodology. The solubility data were examined utilizing various thermodynamic models in Wolfram Mathematica, including NRTL, NRTL-SAC, UNIQUAC, and Wilson, with molecular dynamics (MD) simulations to explore interactions between solute and solvent molecules. Furthermore, the solvent effect of ethionamide in the chosen solvents has been interpreted using the KAT-LSER model. The thermodynamic properties associated with dissolution and mixture processes can be well evaluated by Wilson model. The results demonstrate that the solubility of ethionamide escalates with temperature, with the highest solubility observed in NMP (x₁ = 0.2768 at 323.15 K) and the lowest in i-propanol (x₁ = 0.002916 at 278.15 K). Among four evaluation models, UNIQUAC and Wilson demonstrate superior correlation with experimental data satisfactorily. The KAT-LSER analysis can highlight that solubility is predominantly influenced by solvent self-cohesiveness and dipolarity/polarizability, with hydrogen bond acidity playing a lesser role. Thermodynamic analysis further reveals that the mixing and dissolving processes of ethionamide are spontaneous and driven by entropy, with entropy being the primary factor influencing the Gibbs free energy during dissolution (Δ_disG). Hydrogen bonding sites, predicted through molecular electrostatic potential surface (MEPs) and Hirshfeld surface (HS) analyses, are validated through MD simulations, highlighting the role of hydrogen bonding in enhancing ethionamide solubility. Moreover, with the exception of DMF, DMAC, NMP and DMSO, the lnγ₁ values in the majority of solvent combinations approximate lnγ₁^∞, whereas lnγ₂ values are nearly equivalent to 1, suggesting that most solvent mixtures exhibit ideal solution behaviour. Accordingly, these findings provide valuable insights for optimizing crystallization and purification processes of ethionamide.