Study On Polymorphism And Stability Of Lorcaserin Hydrochloride And Ticagrelor

Lorcaserin hydrochloride and Ticagrelor are polymorphism drugs, have many crystal forms, the different drugs crystal forms will directly affect the physical and chemical properties, such as stability, dissolution rate and bioavailability, melting point, density and appearance et al, these are further influence the clinical curative effect, so the study of drug polymorphism is more and more important. For lorcaserin hydrochloride, three crystal forms(FormⅠ, FormⅡ and Form Ⅲ) have been reported in patents till now. For ticagrelor, four crystal forms and an amorphous have been reported in patents till now.This subject mainly research the preparation and characterization of single crystal lorcaserin hydrochloride Form Ⅲ, the conversion relations between three kinds of crystal forms and the study of the stability of single crystal. In addition, by adjusting the solvent, the crystallization temperature and other conditions to explore high-purity ticagrelor crystal Ⅱ preparation of new technologies, while exploring its stability. Details are as follows:(1) First with a mixed solvents to cultivate single crystal of lorcaserin hydrochloride Form Ⅲ at a low temperature, the size is 0.7mm × 0.8mm × 1.0mm, meet the single crystal test requirements. The use of single crystal X-ray diffraction resolved the crystal structure, the data showed that: lorcaserin hydrochloride Form Ⅲ belongs to orthorhombic, space group P212121, with cell parameters a=8.2396(4)?, b=11.5169?, c=26.5462?, α=β=γ=90°, cell volume V=2519.1(2)?3, the number of molecules within the unit cell Z=4. In addition, by controlling the growth rate of the single crystal growth time and other factors to control the grain size of lorcaserin hydrochloride, thereby improving their liquidity, easier preparation.(2) Using recrystallization and high temperature heating process for preparing the lorcaserin hydrochloride meta-stable crystalline FormⅠand Ⅱ, clear the mutual transformation relationship between three crystal forms of lorcaserin hydrochloride: Form Ⅲ dissolved in tetrahydrofuran, atmospheric pressure evaporated to get FormⅠ, FormⅠ transition at 60% humidity for Form Ⅲ; Form Ⅲ dissolved in ethanol, rapid cooling to 0 ℃, to obtain FormⅡ, FormⅡ transition at 30% humidity for Form Ⅲ; FormⅡ, keep 15 min at 160℃, can be transformed into FormⅠ, and FormⅠcan not be converted to crystalline FormⅡ. Study on the relationship among the three polymorphs conversion and transformation conditions help to improve crystal preparation process.(3) In different system of solvents, temperatures and other conditions to explore for the purification process of ticagrelor FormⅡ: the ethyl acetate as the solvent, heating added hexane or petroleum ether to the solution as an anti-solvent after dissolving clear isothermal crystallization, filtration and drying to obtain pure FormⅡof ticagrelor. Compared to conventional technology, the key to innovation and new technology is isothermal crystallization process, in order to control the nucleation and growth of high purity FormⅡ. Meanwhile the stability of ticagrelor FormⅡ at high temperatures, high humidity and strong light and other environmental also have been studied.