Unraveling Solid–Liquid\nPhase Equilibrium Behavior\nof Prednisolone Form I in 13 Pure Solvents through Synergistic Experimental\nand Simulation Approaches

Prednisolone\n(PDL), a corticosteroid extensively used in the treatment\nof allergic and autoimmune inflammatory diseases, faces limitations\nin clinical application due to its poor water solubility. Consequently,\ngrasping the solid–liquid equilibrium behavior across diverse\nsolvents is imperative for advancing the development of solid formulations\nwith improved bioavailability. This study measured the solubility\nof PDL Form I in 13 pure solvents using gravimetric analysis and employed\nmolecular dynamics, including molecular electrostatic potential surface\nanalysis, Hirshfeld surface analysis, the independent gradient model\nbased on Hirshfeld partitioning, radial distribution function, and\nsolute–solvent interaction energy calculations, to explore\nthe solid–liquid equilibrium behavior. The solubility of PDL\nForm I across various solvents exhibited a temperature-dependent increase,\nshowing the largest variation in acetone. Radial distribution function\nanalysis indicated multiple hydrogen-bonding interactions between\nthe PDL molecule and the solvents tested. The calculations of solute–solvent\ninteraction energy revealed that ethanol had the highest interaction\nenergy with PDL, correlating with its the highest solubility. The\nvalidity of the solid–liquid equilibrium data was confirmed\nby fitting to the Apelblat equation, λ<i>h</i> model,\nvan’t Hoff equation, and NRTL equation, with an average relative\ndeviation below 2.5, indicating good correlation.