Dissolution of tiamulin fumarate in eleven pure organic solvents: solubility determination, thermodynamic analysis, and molecular simulation

Tiamulin fumarate (TF) is used to combat bacterial infections in poultry and livestock, and its solubility behavior is strongly influenced by the solvent environment. This study established a comprehensive analysis framework integrating experimental measurements (283.15–323.15 K, 0.1 MPa) across eleven organic solvents with thermodynamic modeling. Five distinct correlation approaches were employed, including empirical models (Modified Apelblat, Van't Hoff, λh), and activity coefficient formulations (Nonrandom Two-Liquid, Wilson equation). Thermodynamic analysis via the Van't Hoff equation revealed endothermic processes predominantly governed by enthalpy changes. Multidimensional evaluation combining Hansen solubility parameters with the KAT-LSER approach further demonstrated hydrogen bonding interaction significantly influence the solubility behavior. Single crystal X-ray diffraction (SC-XRD) confirmed that TF crystallized in a monoclinic system (space group P21). Molecular electrostatic potential and Hirshfeld surface analyses further confirmed that intermolecular hydrogen bonding between the solute and solvent constitutes a key factor in TF dissolution, with the calculated solvation free energies aligning well with the experimentally observed solubility sequence. The solid–liquid equilibrium data, thermodynamic analysis, and molecular simulation results provide valuable insights for optimizing solvent selection, purification, and crystallization of TF.<p></p>