Wei Gao, Weikun Tang, Junjie Li, Hangjia Sun, Linxin Dai, Weitong Wang, Guqin Xie, Peng Wang, Yanxia Ge
In this study, the solubility of N -acetyl- l -phenylalanine in 14 single solvents was measured by static gravimetric method from 283.15 to 323.15 K. The experimental solubility peaked in ethanol ( x 1 = 6.403 × 10 –2 mol/mol at 323.15 K) and was lowest in butyl acetate (8.8 × 10 –4 mol/mol at 283.15 K). Thermodynamic correlation utilizing the Yaws model yielded the highest precision (ARD = 0.876%, RMSD = 1.041 × 10 –4 ), outperforming the modified Apelblat model. Hansen Solubility Parameters (HSPs) analysis indicated that the solvent’s hydrogen bond donor ability (∑β) was the primary driving factor, exhibiting a strong positive correlation with solubility (Spearman coefficient r = 0.866). Furthermore, Molecular Electrostatic Potential (MEP) analysis quantified the interaction sites, revealing distinct potential extrema ranging from −206.28 kJ/mol (C═O acceptor) to +242.79 kJ/mol (−COOH donor). IGMH visualization further confirmed that hydrogen bonding dominated the dissolution process. Comparative analysis with N -acetyl- l -tyrosine showed that phenolic hydroxyl substitution significantly increased solubility by forming additional hydrogen bond networks. This work establishes an integrated framework of Hansen solubility parameters, thermodynamics, and molecular insights for rational solvent selection in pharmaceutical crystallization.