Uncovering the Molecular Mechanism and Dissolution Behavior of a Thyroid Inhibitor Methimazole (Form I) in Three Binary Solvents Based on Experiments, Quantum Simulations and Thermodynamic Analysis

In this study, the solid–liquid phase equilibrium data for methimazole (Form I) was measured in three binary solvent mixtures (2-methoxyethanol + butyl acetate, 2-methoxyethanol + isopropyl acetate, 2-ethoxyethanol + ethylene glycol) over a temperature range of 283.15 to 323.15 K under 0.1 MPa using a gravimetric method. The results reveal that in the binary solvents (2-methoxyethanol + butyl acetate, 2-methoxyethanol + isopropyl acetate), the solubility of methimazole increased with increasing mass fraction of 2-methoxyethanol. For the solvent of 2-ethoxyethanol + ethylene glycol, due to cosolvency effects, the mole fraction solubility of methimazole reached its maximum value (0.2914) when the mass fraction of 2-ethoxyethanol was 0.70 at 323.15 K. The solubility data was correlated using the Jouyban-van’t Hoff, Jouyban-Apelblat, GSM and λh model. The reliability of these thermodynamic models was assessed by the average relative deviation (ARD) and the root-mean-square deviation (RMSD). Additionally, the applicability of the four thermodynamic models was evaluated using the Akaike Information Criterion (AIC). The calculated minimum RMSD and ARD values are 0.000729 (λh model) and 0.0027 (GSM model), respectively. The minimum AIC value for the four models selected is −3348.62 (GSM model). These results indicate that the GSM model correlates the solubility of methimazole better than the other three models. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) characterization analysis showed that the crystal morphology of methimazole remains stable before and after the dissolution of methimazole in the three binary solvent systems. In addition, the solute–solvent interaction effect was assessed using Hansen solubility parameters (HSPs). The distribution of surface charge on methimazole was examined through the molecular electrostatic potential surface (MESP) analysis. Furthermore, molecular dynamics simulations were employed to investigate the interactions between solute and solvent molecules via the radial distribution function (RDF). Finally, the standard apparent thermodynamic properties of methimazole in the selected solvents were evaluated, and the results showed that the dissolution of methimazole in this work was an endothermic and entropy increase process.