Solubility measurement, thermodynamic modeling, and molecular dynamic simulation of regorafenib in pure and binary solvents

• Solubility of regorafenib in pure and binary solvents were determined. • Four thermodynamic models were used to correlate the experimental solubility. • Solute–solvent and solvent–solvent interactions were investigated by molecular dynamic simulation. • The apparent thermodynamic properties were calculated by van’t Hoff equation. The solubility of regorafenib in six pure solvents (ethanol, acetonitrile, methanol, n-propanol, isopropanol, and acetone) and binary solvent mixtures (acetone + acetonitrile) was determined by the gravimetric method from 278.15 K to 313.15 K. The mole solubility of regorafenib increased monotonously with increased temperature. The solubility data were fitted by four thermodynamic models, namely, the modified Apelblat, λh, non-random two-liquid, and Wilson models. The modified Apelblat model showed the most accurate correlation with solubility data. Molecular dynamics simulation including solvation free energy calculations and radial distribution function were performed to understand the influence mechanism of solute–solvent and solvent–solvent interaction on solubility. The results of solvation free energy calculations well agreed with the solubility order of regorafenib in selected solvents. However, the solvent–solvent interaction had no significant effect on solubility. Moreover, the thermodynamic properties ( Δ dis H 0 , Δ dis S 0 a n d Δ dis G 0 ) of regorafenib were calculated using the van’t Hoff equation. The positive value of Δ dis H 0 a n d Δ dis S 0 indicated an entropy-driven and endothermic process of dissolution of regorafenib. These findings can serve as a reference for future synthesis process selection, formulation research, and optimization, as well as for understanding the solid–liquid equilibrium of regorafenib and predict its solubility which is of great significance to production.