Solubility of polymorphic glycine in mixed solutions with molecular dynamics simulation and thermodynamic analysis

Abstract

A deep insight into the solubility behavior of glycine is essential for optimizing its application in the fields such as pharmaceutical formulations and crystallization. Although the solubility of glycine has been extensively studied, the solubility of polymorphic glycine in mixed solvents still needs to be further investigated, especially in the presence of impurities. In this study, the solubility of polymorphic glycine in three mixed solutions (water–methanol, water–methanol–NH₄Cl, and water–methanol–HMTA) was determined using in situ ATR-FTIR over the temperature range of 293.15 to 333.15 K. The solubility of glycine decreased with increasing methanol concentration. And it is enhanced with the increase of NH₄Cl concentration, while the addition of hexamethylenetetramine inhibited the dissolution of glycine. The modified Apelblat equation, the λh equation and the non-random two-liquid (NRTL) model were utilized to correlate the experimental solubility data. All the models produce good correlations for the solubility data. Molecular dynamics simulation was employed to calculate intermolecular interactions to better understand the glycine dissolution behavior. The solvation free energy indicated that the solubility of glycine increased with the increase of solute–solvent interaction. The presence of impurities significantly affects the solvation free energy of glycine, thus impacting the glycine solubility. Radial distribution function analysis further demonstrated that impurities also impacted the interaction between water molecules and altered the interactions between glycine and water molecules. In addition, the apparent standard thermodynamic properties (Δ_solH⁰, Δ_solS⁰, and Δ_solG⁰) of glycine in the three mixed solutions were calculated using the van't Hoff equation. The results revealed that glycine dissolution is both endothermic and entropy-driven, with enthalpy being the primary contributor to the Gibbs free energy variation during dissolution.