Insight into the solubility and solution thermodynamics of fosfomycin phenylethylamine in water and ethanol for its cooling crystallization

Suitable solvent and the related solution thermodynamics of fosfomycin phenylethylamine (FPEA) are essential for its purification by cooling crystallization. Two candidate solvents of ethanol and water are systematically investigated and compared, including the solubilities in them from 278.15 to 348.15 K with an interval of 5 K and the dissolution enthalpies at different concentrations at 303.15 K, which were measured using a static equilibrium method and solution calorimetry at atmospheric pressure, respectively. In addition, densities of FPEA in the two solvents at a diluted region were accurately measured for compositional analysis of equilibrium samples. Meanwhile, we explored the thermal stability of solid FPEA by using thermogravimetry. Crystalline FPEA was thermal stable blow 378.15 K and its molar heat capacity increased from 42.2 to 119.7 J.mol(-1).K-1 when heated from 308.15 to 363.15 K, as determined by differential scanning calorimetry. When FPEA was further heated, it started to decompose at around 453.15 K without prior melting and then continued to decompose in several steps with the subsequent increase of temperature. When it was dissolved in the two solvents, endothermic effect was observed and the molar enthalpy of dissolution FPEA in ethanol at infinite dilution was about 2 kJ/mol higher than that in water, suggesting more hydrogen bond formation in water. The molality solubility of FPEA in water was generally higher than that in ethanol, but the difference decreased significantly with the increase of temperature. From 347.15 down to 279.15 K, the solubility in water decreased from 1.292 to 0.237mol.kg(-1), while that in ethanol decreased from 1.247 to 0.084 mol.kg(-1), which justified the suitableness of using ethanol as the solvent for the cooling crystallization of FPEA with respect to product yield. The thermodynamic functions of solubility and solvation processes were estimated. An integrated approach by van't Hoff plot, enthalpy-entropy compensation analysis and solution calorimetry showed that enthalpy-entropy compensation was occurring in the dissolution of FPEA in both solvents and the enthalpic effect dominantly controlled the Gibbs free energy change of the process. (C) 2020 Elsevier B.V. All rights reserved.