Uncovering solubility behavior of Prednisolone form II in eleven pure solvents by thermodynamic analysis and molecular simulation

Abstract

Thermodynamic analysis and molecular simulation were used to investigate the solubility behavior of prednisolone (PDL) form II, which is a widely used corticosteroid. Solubility data were collected in eleven solvents (methanol, ethanol, n-propanol, i-propanol, n-butanol, methyl acetate, ethyl acetate, n-propyl acetate, acetone, tetrahydrofuran, and 1,4-dioxane) using a gravimetric method at temperatures from 283.15 K to 323.15 K. The modified Apelblat equation, λh equation, and Van't Hoff equation were employed to correlate the experimental solubility data. The dissolution process of PDL form II was endothermic and entropy-driven. The intermolecular interactions (PDL-PDL) were analyzed by molecular electrostatic potential surface and Hirshfeld surface analyses. The solvent properties, solvation free energy, and radial distribution function were investigated to explore the influence of intermolecular interactions (PDL-solvent and solvent–solvent) on the solubility. The solubility behavior of PDL form II is related to several solvent parameters, such as the hydrogen-bonding donor propensity and polarity. According to regression analyses, the PDL-solvent interactions play a crucial role in the dissolution process.