Comprehensive Solubility Analysis of Fmoc- l -Tyrosine in 12 Monosolvents: Integrating Solvent Effects, Thermodynamic Modeling, and Advanced Molecular Insights via IGMH Analysis

Fmoc-l-tyrosine, an important derivative of l-tyrosine, has significant medicinal applications. Its solubility in 12 monosolvents (including alcohols, esters, acetone, and acetonitrile) was determined from 293.15 to 333.15 K using the static gravimetric method. Experimental data showed that temperature-dependent solubility increases in all solvents. At 308.15 K, the solubility order (mol/mol) was as follows: acetone (0.07795) > isopropanol > sec-butanol > n-butanol > methyl acetate > n-pentanol > ethyl acetate > isobutanol > propyl acetate > butyl acetate > dimethyl carbonate > acetonitrile (0.003820). Four thermodynamic models (Apelblat, Margules, NRTL, UNIQUAC) were correlated, with the Apelblat model exhibiting the highest accuracy (ARD 1.744%, RMSD 0.473 × 10–3). Solvent effect analysis indicated that hydrogen bonding (correlation coefficient of 0.8730) is the dominant factor, surpassing polarity (ET(30)) and cohesive energy density. Hansen solubility parameters (HSPs) revealed that solvent polarity influences solubility, with lower Ra(v) values (e.g., acetone at 6.76 MPa0.5) corresponding to higher solubility. Molecular electrostatic potential surface (MEPS) and Hirshfeld surface (HS) analyses identified hydrogen bond interaction sites, while IGMH quantification confirmed the prevalence of hydrogen bonding. This study provides comprehensive solubility data for the purification process design of Fmoc-l-tyrosine.