| Amitriptyline hydrochloride(AMT)is a traditional tricyclic antidepressant,which is widely used for the treatment of various types of depression.The particle size,purity and crystal morphology of drug crystallization are important factors affecting drug efficacy.At present,there are few studies on the preparation and purification of amitriptyline hydrochloride.Therefore,a systematic study on the crystallization process of amitriptyline hydrochloride was conducted in this paper.The solid-liquid equilibrium data of amitriptyline hydrochloride in 14 organic solvents and binary mixed solvents were experimentally measured under atmospheric pressure with the aid of laser dynamic method.The solubility of AMT as a function of temperature can be regressed using 5 models(Wilson model,NRTL model,modified Apelblat equation,three-parameter Van’t Hoff equation and λh equation)with good accuracy.The mixing thermodynamic properties well as the activity coefficient and the reduced excess enthalpy at infinitesimal concentration of the AMT solution systems were evaluated based on the Wilson model.The values of mixed gibbs free energy are all negative and decrease with increasing temperature,indicating that both the mixing and the dissolution processes of amitriptyline hydrochloride are spontaneous and favorable in the selected solvent systems.The simulation software Materials Studio(MS)was used to analyze the unit cell parameters,crystal system and the space group of amitriptyline hydrochloride with a X-Cell indexing program based on the PXRD data.In addition,the theoretical crystal habit of amitriptyline hydrochloride under vacuum was simulated using the BFDH model.The simulated crystal is in a short rod shape,which is consistent with the crystal morphology obtained by dilution crystallization.Based on the dissolution phase equilibrium data and thermodynamic properties,the dilution crystallization process of amitriptyline hydrochloride in ethanol/isopropyl ether solution was determined.The single factor controlled variable method was used to optimized the crystallization process parameters.According to the particle size,yield and crystal habit,the optimal crystallization process conditions was discovered:the amount of seed crystal added is 0.8%,the initial concentration is 0.1 g/mL,the crystallization temperature is 25℃,the stirring rate is 180 rpm,the dropping rate of the antisolvent is 0.25 mL/min,and the antisolvent ratio is 6:1.The yield of optimized crystallization process reached 84%and the crystal habit is complete with a large particle size. |
