(Quantitative)structure-activity relationship to assess genotoxicity of parecoxib sodium-related substances
Objective:Based on the synthesis process,the impurities that may be generated during the production process of parecoxib sodium active pharmaceutical ingredient were sorted out to evaluate the mutagenicity and carcinogenicity of the relevant substances and determined in the categories of relevant substances.This study provided a basis for the optimization of the drug production process and the quality control of the final product.Methods:The genotoxicity of 51 related substances in parecoxib sodium was evaluated by a database.According to the risk assessment results,the genotoxicity was classified and the corresponding acceptable limits were formulated on the basis of ICH M7 guidelines.Results:Among the 51 relevant substances sorted out,9 were positive in the comprehensive assessment,which needed to be controlled according to genotoxic impurities;37 in the comprehensive assessment results were negative and regarded as non-genotoxic impurities;5 predictions were also ambiguous and uncertain whether they were genotoxic.Conclusion:In order to ensure the quality and safety of drugs,the maximum limit of relevant substances assessed as positive by(Quantitative)structure-activity relationship[(Q)SAR]should not exceed 18 ppm,and it is suggested that scientific and reasonable quality control methods should be established for nine potentially genotoxic impurities with warning structures in parecoxib sodium.
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