Solid-liquid phase equilibrium of clozapine in aqueous binary solvent mixtures

Abstract The solid-liquid phase equilibrium solubility of clozapine in six of aqueous binary solvent mixtures (i.e., water + methanol, water + ethanol, water + n-propanol, water + acetone, water + N, N-dimethylformamide, and water + tetrahydrofuran) was determined from 278.15 K to 323.15 K at approximately 101.3 kPa with a gravimetric method. The solubility increases with the increase of temperature and the composition of good-solvent in all the selected binary solvent mixture systems. Polarity is an essential factor affecting the solubility of clozapine in mixed solvents. Hansen solubility parameters were used to analyse the solubility behaviour. Four thermodynamic models, including the CNIBS/R-K model, the modified Jouyban-Acree model, the NRTL model, and the Wilson model were chosen to fit the experimental solubility data. Relative average deviation, and root mean square deviation were employed to evaluate the fitting degree of each thermodynamic model. NRTL model fits best with the maximum RAD and RMSD value of 0.0177 (water + methanol) and 0.000847 (water + THF), respectively. Solubility data are the basis for calculation of supersolubility and induction time of the crystallization process. The basic solubility data play an important role in the process optimization of clozapine crystallization.