Solid-liquid phase equilibrium of nimesulide (Form I) in twelve mono-solvents: Solubility determination, molecular dynamic simulation, solvent effect, model correlation and thermodynamic analysis

The equilibrium solubility of nimesulide (NIMS) in twelve single solvents was accurately measured by a laser monitoring method. It was indicated that the positive impact of experimental temperature on the solubility data of NIMS (Form I) in twelve mono-solvents within the investigated temperature range of 278.15-323.15 K under 101.3 KPa. The solubility shows a clear non-linear trend and decreased in the order methyl acetate > ethyl acetate >2-methoxyethanol > n-propyl acetate > n-butyl acetate >2-ethoxyethanol >2-propoxyethanol >2-butoxyethanol > methanol > ethanol > n-propanol > n-butanol. NIMS (Form I) has the highest solubility (x(1) = 5.223e-2) in methyl acetate at 323.15 K and the smallest solubility (x(1) = 6.800e-6) in n-butanol at 278.15 K. And then, the solvent polarity, radial distribution function obtained from molecular dynamic simulation and solvent effect (KAT-LSER model) were implemented to investigate the effect of solute-solvent interactions on solid-liquid phase equilibrium of NIMS (Form I). The results demonstrated that the whole dissolution behavior of NIMS (Form I) in organic solvents was a complicated process, and the solvent-solute interactions are mainly affected by the dipolarity/polarizability. Moreover, five widely used activity coefficient models including NRTL, NRTL-SAC, Wilson, Two-Suffix Margules, and UNIQUAC models had been fitted to experimental solubility data. Deviation analysis reveals that the UNIQUAC model reflects the best agreement between the measured data and calculated values, with the minimum mean values of 100ARD (0.89) and RMSD (1.22e-4). Finally, the thermodynamic parameters (Delta(dis)G(o), Delta H-dis(o), Delta S-dis(o), zeta(H) and zeta(TS)) of NIMS (Form I) dissolution process in investigated 12 single solvents were evaluated based on the van't Hoff equation. The positive Delta(dis)G(o), Delta H-dis(o) and Delta S-dis(o) indicate that the dissolution process of NIMS (Form I) is an entropy-driven non-spontaneous endothermic process in all chosen single solvents, and the zeta(H) is the main contributor of Delta(dis)G(o). (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The experimental temperature has a positive impact on the solubility of NIMS, showing a non-linear trend influenced mainly by solvent polarity. The UNIQUAC model best fits the experimental solubility data, with the lowest deviation values.