Solubility Behavior of Baloxavir Marboxil in 13 Pure Solvents: Combined Experimental Measurement and Molecular Simulation Analysis

Abstract This study was designed to determine the solubility of Baloxavir marboxil (BXM) in 13 solvents (i.e., water, methanol, ethanol, n-propanol, i-propanol, i-butanol, s-butanol, n-pentanol, i-pentanol, acetone, ethyl formate, ethyl acetate, pentyl acetate) by high-performance liquid chromatography (HPLC) over the temperature range of 283.15 to 323.15 K, so as to investigate its solid–liquid equilibrium behavior. Among all experimental solvents, BXM has the highest solubility in acetone and the lowest solubility in water. The solubility of BXM in all solvents increases with increasing temperature. Based on the solid–liquid equilibrium theory, the modified Apelblat, λh, and Yaws thermodynamic models were used to fit the experimental solubility data. Among the 13 pure solvents, the modified Apelblat model showed a slightly better fit to the experimental data than the other two models, with a relative average deviation (RAD) of 1.46 × 10–2 and a root mean square deviation (RMSD) of 9.30 × 10–6. Finally, the solubility of BXM was predicted via molecular simulation, which unravels the influencing mechanism of solute and solvent intermolecular interactions and solvation effects on the dissolution process. The solubility data of BXM will provide theoretical guidance for the design and optimization of crystallization processes.