Unraveling Solid–Liquid Phase Equilibrium Behavior of Prednisolone Form I in 13 Pure Solvents through Synergistic Experimental and Simulation Approaches

Prednisolone (PDL), a corticosteroid extensively used in the treatment of allergic and autoimmune inflammatory diseases, faces limitations in clinical application due to its poor water solubility. Consequently, grasping the solid–liquid equilibrium behavior across diverse solvents is imperative for advancing the development of solid formulations with improved bioavailability. This study measured the solubility of PDL Form I in 13 pure solvents using gravimetric analysis and employed molecular dynamics, including molecular electrostatic potential surface analysis, Hirshfeld surface analysis, the independent gradient model based on Hirshfeld partitioning, radial distribution function, and solute–solvent interaction energy calculations, to explore the solid–liquid equilibrium behavior. The solubility of PDL Form I across various solvents exhibited a temperature-dependent increase, showing the largest variation in acetone. Radial distribution function analysis indicated multiple hydrogen-bonding interactions between the PDL molecule and the solvents tested. The calculations of solute–solvent interaction energy revealed that ethanol had the highest interaction energy with PDL, correlating with its the highest solubility. The validity of the solid–liquid equilibrium data was confirmed by fitting to the Apelblat equation, λh model, van’t Hoff equation, and NRTL equation, with an average relative deviation below 2.5, indicating good correlation.