Study On Solid-liquid Equilibrium And Crystallization Process Of Clozapine

As an atypical antipsychotic drug,clozapine has a good effect on a series of refractory mental diseases,which is a good news for most patients with mental illness.The particle size of clozapine crystals has an impact on its performance,and crystallization is an effective method to control the particle size of drug crystals.Therefore,it is of great significance to study the crystallization process of clozapine.However,there are few studies on the crystallization process of clozapine,and the basic solid-liquid equilibrium data is in suffcient the study of the drug crystallization process.Based on this,this article carried out research on the solid-liquid equilibrium and crystallization process of clozapine,measured the solid-liquid equilibrium data of clozapine in a series of pure solvents and mixed solvents,and discussed the process conditions of clozapine dissolution and crystallization,to achieve the preparation of clozapine crystals with large particles,uniform particle size distribution and high yield.The solid-liquid equilibrium data of clozapine in twelve pure solvents and four mixed solvents were measured by laser dynamic method.The results showed that the solubility of clozapine in both pure and mixed solvents increased with the increase of temperature.The solubility order of clozapine in twelve kinds of pure solvents was determined:2-propoxyethanol>2-ethoxyethanol>2-methoxyethanol>n-pentyl acetate>n-butyl acetate>n-propyl acetate>ethyl acetate>n-pentanol>n-butanol>methyl acetate>n-propanol>ethanol.Besides,the solubility of clozapine becomes larger as the growing carbon chain and smaller polarity of solvents,which conforms to the principle of similar compatibility.The solubility of clozapine in mixed solvents increases with the increase of the proportion of2-methoxyethanol,2-ethoxyethanol and 2-propoxyethanol.The six models（λh model,modified Apelblat model,Jouyban-Acree model,Margules model,NRTL model and UNIQUAC model）were used to correlate the solubility data of clozapine in twelve pure solvents and four mixed solvents.The results are evaluated,which shows that theλh model and the modified Apelblat model have the best fit for the solid-liquid equilibrium results of clozapine than other vestigated models.The radial distribution function（RDF）obtained by analyzing the intermolecular interaction of clozapine in eight pure solvents using Materials Studio software,the results are consistent with the order of solubility.Besides,theΔ_solH°、Δ_solG°、Δ_solS°and thermodynamic parameters of clozapine pure solvent and mixed solvent were calculated through the Vant’t Hoff equation.The calculated results ofΔ_solH°andΔ_solG°are all positive values,which shows that the dissolution process of clozapine in twelve pure solvents and four mixed solvents is an endothermic and entropy increase process.According to the measured solid-liquid phase equilibrium data,the crystallization process of clozapine was determined with selecting 2-propoxyethanol+water as the solvent to optimize the crystallization process of clozapine.The influence of factors such as the addition amount of the anti-solvent,the dropping rate of the anti-solvent,the stirring rate,the crystallization temperature,the aging time,and the addition amount of the seed crystal on the yield and particle size of clozapine were investigated,and determined the most suitable process conditions for the solventing-out crystallization:anti-solvent addition amount 2.2 g/g（anti-solvent/solvent）,anti-solvent addition rate 1.0 m L/min,stirring rate 350 r/min,crystallization temperature 25°C,aging time 2 h,seed crystal addition amount 1.0%.According to this condition in crystallization process of clozapine,the yield can reach93.1%,and the average particle size and the coefficient of variation achieved 21.05μm and 1.0070.