| Rimantadine hydrochloride（Rim HCl）is a specific drug for the treatment of influenza virus and has a broad application prospect.At present,the crystallization process of rimantadine hydrochloride is rarely explored in China,and there is almost no relevant literature reported.The crystallization process of rimantadine hydrochloride was studied comprehensively and systematically.First,the laser dynamic method was used to measure the temperature of rimantethylamine hydrochloride from 283.15K to 323.15K in thirteen organic reagents including nine monoalcohols（methanol,ethanol,propanol,isopropanol,butanol,iso-butanol,sec-butanol,pentanol,iso-pentanol）,two dialcohols（ethylene glycol,triethylene glycol）,chloroform and N,N-dimethylformamide（DMF）was positively correlated with the set temperature,that is,the solubility increased with the increase of temperature.Based on this,five thermodynamic models（three empirical models are Apelblat model,Van’t Hoff model,λh equation and two activity coefficient models are Wilson model and NRTL model）were used to fit and evaluate the solubility.In addition,the thermodynamic mixing properties(ΔmixG、ΔmixH、ΔmixS、?1?and1HE,?)of rimantadine hydrochloride in the above reagents were estimated.The gibbs free energy and enthalpy of rimantadine hydrochloride were both negative and decreased with the increase of temperature,indicating that the dissolution process of rimantadine hydrochloride was spontaneous and exothermic.Secondly,Materials Studio（MS）molecular simulation software was used to simulate the mixing thermodynamics（Chi parameters,binding energy and mixing energy）of rimantadine hydrochloride.Crystal structure of rimantadine hydrochloride was analyzed by crystal characterization map,and the crystal pattern and space group of rimantadine hydrochloride were obtained.The theoretical crystal behavior of rimantadine hydrochloride in high vacuum was predicted by BFDH model.Finally,by comparing the crystallization methods,the solution crystallization of rimantadine hydrochloride was determined,and the system selected was ethanol/acetonitrile/rimantadine hydrochloride.The optimized crystallization conditions were as follows:the initial concentration of solution was 0.060g/ml,the ratio of solvent（ethanol）to solvent（acetonitrile）was 1:4,the dropper acceleration rate of solvent（acetonitrile）was 2ml/min,the stirring rate was 150rmp,the crystallization temperature was 10℃,the crystallization time was 30min,and the seed was added（1%）.After optimization,the yield of rimantadine hydrochloride was 84.95%,and the product uniformity was good.This study provided the condition support for the separation and purification of rimantadine hydrochloride in industrial production. |
