Solubility, solvent effect, molecular simulation and thermodynamic properties of clozapine in twelve pure solvents

Abstract

In this article, laser monitoring technology was used to study the solubility of clozapine in 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, ethanol, n-propanol, n-butanol, n-pentanol, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, n-pentyl acetate under the pressure of 0.1 MPa (at 278.15 K–323.15 K). Obviously, the mole fraction solubility of clozapine is positively correlated with the increase of experimental temperature. KAT-LSER model was used to study the solvent effect of clozapine solubility in 12 pure solvents. The results show that the interaction of solvent–solute is mainly due to the dipolarity/polarizability and solvent’s self-cohesiveness. The interaction between solute–solvent molecules was analysed by MD simulation, and the results show that the interaction between solute–solvent molecules has an important influence on the solubility of clozapine. Then the solubility data of clozapine were put into five classical thermodynamic models for simulation, namely the λh model, Apleblat model, NRTL model, Margules model and UNIQUAC model. The values calculated by the five solubility models are in good agreement with the measured solubility, it means that the five models have a higher level of simulation accuracy. On the other hand, the apparent thermodynamic properties of clozapine dissolved in solvent were calculated by van’t Hoff equation, the results show that the dissolution process of clozapine in solvents is an endothermic and driven by enthalpy.