Enhancement of clozapine solubility in three aqueous choline chloride-based deep eutectic solvents: Experimental and COSMO-RS prediction

Abstract

• Solubility behaviors of clozapine in aqueous DESs solutions were revealed by COSMO-RS. • Solubility of clozapine in aqueous DESs solutions was measured. • Solubility of clozapine was enhanced by increasing weight fraction of DES and temperature. • Dissolution thermodynamics of clozapine was calculated via van't Hoff equation. The clozapine (CLZ) solubility (molar fraction) in three aqueous choline chloride (ChCl) based deep eutectic solvents (DESs) with urea (U), glycerol (G) and ethylene glycol (EG) was determined at T = (293.15 to 313.15) K under an atmospheric pressure. As neoteric green co-solvents, DESs can apparently enhance the CLZ solubility more than 550-fold than that in pure water at T = 293.15 K, especially in ChCl/G. At the same DESs proportion (weight fraction) and same temperature, the CLZ solubility in aqueous DESs solutions is ranked as ChCl/G > ChCl/EG > ChCl/U. Furthermore, the experimental solubility of CLZ in aqueous DES solutions has been correlated by NRTL, three-Suffix Margules, UNIQUAC and Wilson models, suggesting NRTL model to be the best correlation. In addition, the SLE CLZ solubility data was also predicted by reference solubility method using COSMO-RS model, and the predicted results are consistent with the experiment data. The basic mechanism of the solubility behavior of CLZ and solvent molecules was analyzed by studying σ profiles of DESs as well as the molecular interaction energies, implying that the CLZ dissolution is a complex process affected by the synergy of molecular interactions. Based on van’t Hoff equation, the solution thermodynamic properties (Δ G dis o , Δ H dis o and Δ S dis o ) have been estimated, indicating the dissolution process of CLZ in aqueous DES solutions is endothermic and entropy-driven. The improved solubility of CLZ in aqueous DES solutions provides reference for its application in novel crystallization development for the CLZ manufacture.