Inclusion of mother liquids inside the pharmaceutical crystals poses a great challenge and threat to the product quality and purification efficiency. Herein we demonstrate how growth kinetics tune the formation of liquid inclusion and its occluded mechanism.

The solubility of tetramethylpyrazine (TMP) in nine monosolvents (methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, acetonitrile, methyl acetate, and ethyl acetate) and two binary solvent mixtures of (methanol + acetonitrile) and (n-butanol + acetonitrile) was determined by a static method using UV–vis spectroscopy at temperatures ranging from 273.15 to 313.15 K. Expectedly, the solubility displays monotonously rising temperature dependence, and the most remarkable change was found in acetonitrile. In binary solvent mixtures, TMP solubility bears a maximum value at 0.8 mole fraction of alcohols independent of both temperature and solvent nature. The statistical correlations were well performed by the λh equation, Apelblat equation, and NRTL model, and the NRTL model achieves the best fitting results. The mixing enthalpy, entropy, and Gibbs free energy were derived on the basis of thermodynamic relations and the NRTL model. The results suggest a spontaneous and entropy-driven mixing process of TMP in studied solvent systems. The solubility data, correlated models, and derived thermodynamic functions provide thermodynamic fundamentals for the separation and purification of TMP crystallization in industrial production.

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