Measuring Nintedanib esylate solubility in binary mixed solvents: Molecular dynamic simulation, solid-liquid phase equilibrium and thermodynamic analysis

By laser monitoring method, the solid-liquid phase equilibrium solubility of Nintedanib esylate in the four binary mixtures (including methanol (MeOH) + ethyl acetate (EtOAC), N,N-Dimethylformamide(D MF) + ethyl acetate (EtOAC), N,N-Dimethylacetamide (DMAC) + ethyl acetate (EtOAC), and methanol (MeOH) + methyl tert-butyl ether(MTBE)) was achieved at different temperatures and atmospheric pres-sure. The result demonstrated that the solubility in the four binary mixed solvents was positively corre-lated with temperature and the mass fractions of DMAC, DMF and MeOH at a certain temperature. Correlation fitting was performed for the solubility data through Apleblat model, Ma model, kh model, CNIBS/R-K model and NRTL model, and the result showed that the CNIBS/R-K model had much lower rel-ative average deviations than the others for the four solvents being researched. By using RDF and MD simulation, the intermolecular interactions of Nintedanib esylate and the chosen solvents proved that the ranks of the interactions between solute and solvent, as well as solvent and solvent, were bound up with the order of the saturation solubility of Nintedanib esylate in the chosen solvents. The calculation of Hansen solubility parameters of the solute molecules showed that the Hansen solubility parameters could explain the solubility of the solute in the four binary solvents and the solubility of the solute in the four binary solvents was affected by various factors such as dispersion force, hydrogen bond force and polarity force between molecules. The NRTL model and Van't Hoff equation were used to calculate the thermodynamic properties of the solute mixing process and the apparent thermodynamics of the solute dissolution process in the mixed solvent. The results show that: The mixing process of Nintedanib esylate in the selected four mixed solvents is spontaneous and entropy increasing process, and the dissolution process is enthalpy driven, endothermic and non-spontaneous process. (c) 2022 Elsevier B.V. All rights reserved.