(定量)构效关系预测利伐沙班有机杂质遗传毒性

(Quantitative)Structure-activity Relationships to Predict the Genotoxicity of Rivaroxaban Organic Impurities

目的通过对利伐沙班原料中有机杂质进行遗传毒性预测,并以杂质遗传毒性进行分类,为实际生产中质量保障体系的建立提供依据。方法分析利伐沙班的合成工艺,结合实际生产中有可能采用的生产工艺,推测有机杂质,按照国际认可的指导原则,采用基于专家规则和基于统计学规则的2个互补的(定量)构效关系评估[(quantitative)structure-activity relationships,(Q)SAR]预测软件,对18个有机杂质进行遗传毒性预测分析,并依据预测结果按照其致突变性和致癌性进行分类。结果在18个有机杂质中,需要按遗传毒性杂质控制的杂质有5个,可以按非遗传毒性杂质控制的杂质有13个。结论采用(Q)SAR评估有关物质的遗传毒性,可实现快速确定杂质毒性特征的目的。预测结果提示利伐沙班应针对具有遗传毒性警示结构的5个杂质建立有效的质量控制体系。

OBJECTIVE To predict the genotoxicity of organic impurities in materials of rivaroxaban and classify the genotoxicity,so as to provide a basis for the establishment of quality assurance system in actual production.METHODS The synthetic process of rivaroxaban was analyzed,and the possible organic impurities were speculated based on the production process that possible used in actual production.According to the internationally recognized guidelines,two complementary(quantitative)structure-activity relationships[(Q)SAR]prediction software based on expert knowledge rules and statistical rules were used to predict 18 organic compounds.The genotoxicity of impurities was predicted and classified according to their mutagenicity and carcinogenicity.RESULTS The 18 organic impurities,5 were required to be controlled as genotoxic impurities and 13 as non-genotoxic impurities.CONCLUSION(Q)SAR can be used to evaluate the genotoxicity of related substances,which can quickly predict the characteristics of impurities.The prediction results indicate that rivaroxaban should establish effective quality control system for five impurities with warning structure of genotoxicity.