Study Of Agomelatine Crystal Polymorph Induced By Polymer

Agomelatine is a melatonin MT₁,MT₂ receptor agonist,and also a serotonin 2c(5-HT_2C)receptor antagonist.It is used clinically to treat depression and regulate sleep and biological rhythms.At present,six crystal forms were discovered,among which Form II is the most stable crystal form and also the mainly medical one.In this paper,agomelatine and its crystal forms were studied.The details are as follows:At first,the quantitative analysis of agomelatine Form I and Form II was conducted by Powder X-ray diffraction（PXRD）and Differential scaning calorimetry（DSC）.A calibration curve was build.To compare two methods,a better method was chose.The results of proposed method were feasible,accurate and it could satisfy the requirements of project.And then,under the induction of high molecular polymer,a variety of different forms such as FormⅠ,Form II,Form III,Form IV and Form VI were prepared by solvent evaporation,cooling crystallization,melt crystallization,anti-solvent crystallization and etc.The preparation method of FormⅠand FormVI was detailed studied.（1）The selective crystallization of agomelatine form melt induced by ethyl cellulose（EC）was investigated and the influence factors such as EC ratio,cooling temperature and its recrystallization process were also studied.Further research showed that EC could inhibit the transformation of Form I to Form II.The stability of agomelatine FormⅠinduced by EC was better than which prepared without polymer and its solubility was 2.2 times higher than FormⅡin phosphate buffered saline（PBS pH 7.2）.（2）The preparation method of Form VI was optimized.And high purity agomelatine Form VI was prepared.Its forming condition was studied such as solvent ratio,cooling temperature and etc.Besides,the stability of Form VI was also investigated.