Solubility of clopidogrel hydrogen sulfate polymorphs in ethyl acetate + 2-butanol mixtures at 283.15–313.15 K

Abstract

Aimed at exploring the influence of solvent on crystallization thermodynamics of clopidogrel hydrogen sulfate (CHS), the solubility of CHS polymorphs (Form I and II) in 2-butanol + ethyl acetate mixtures was measured over temperatures from 283.15 to 313.15 K with a static equilibrium method. It was found that the solubility of Form I & II increases first and then decreases with the mole fraction of 2-butanol (x1) increasing, reaching maximum value when x1 = 0.7. The experimental results were well-fitted with the modified Apelblat equation, van’t Hoff equation, CNIBS/R-K model, combined version of the Jouyban-Acree model and NRTL model, respectively. Furthermore, the thermodynamic quantities of dissolution and mixing process were calculated. The results indicate that the dissolution process of CHS polymorphs is endothermic and entropy-driven, and thermodynamic quantities of mixing processes is clearly dependent on the mixture’s composition.