抗凝药利伐沙班的制备与表征

Preparation and characterization of rivaroxaban as an anticoagulant

以抗凝药利伐沙班晶型Ⅰ为基础,通过重结晶的方法对其进行多晶型的制备,确定了两种晶型Ⅱ(药用晶型)、五种晶型Ⅳ的制备方法。采用X射线粉末衍射(PXRD)、差示扫描量热仪(DSC)、元素分析(EA)、质谱(MS)和红外光谱(IR)等现代分析手段对制备的晶型进行了定性并且通过扫描电子显微镜(SEM)观察了不同晶型的形貌。结果表明,本方法所制备的晶型Ⅱ和Ⅳ的PXRD与DSC分析结果与国内外专利一致,EA、MS和IR的检测结果符合利伐沙班的化学结构,由SEM可知晶型Ⅰ呈片层状,晶型Ⅱ呈线状,晶型Ⅳ呈条状。综上,与国内外专利相比,本研究制备晶型Ⅱ和Ⅳ的方法可靠,所需试剂易得,实验条件易实现,制备过程简捷。本研究为利伐沙班的生产应用提供了新的参考。

The preparation of polymorphic forms of rivaroxaban was carried out using a recrystallization method based on that for crystal form-Ⅰ.Preparation methods were developed for two crystal forms-Ⅱ(medicinal crystal form)and five crystal forms-Ⅳand the crystals were then characterized.The crystalline form was identified by applying modern analytical means including X-ray powder diffraction(PXRD),differential scanning calorimetry(DSC),element analysis(EA),mass spectrometry(MS),and infrared spectrum(IR),and the morphology of different crystal forms was observed by scanning electron microscopy(SEM).The results show that the PXRD and DSC characteristics of prepared crystal forms-II and IV are consistent with those described in patents at home and abroad,and the test results with EA,MS and IR are in accordance with the chemical structure of rivaroxaban.The crystal form-I is lamellar,the crystal form-II is linear and crystalline form-IV is striped as determined by SEM.In summary,the methods for preparing crystal form-II and form-IV are reliable,the required reagents are easily available,the experimental conditions are easy to implement and the preparation process is simple.Our study provides a new reference for the production and application of rivaroxaban.