非洛地平及其片剂的杂质研究
Analysis and evaluation of the impurity of felodipine and its tablets
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摘要:
系统研究非洛地平及其片剂的杂质, 完善质量标准对有关物质的控制。采用HPLC-DAD、UPLC-MS、IR和NMR等方法对非洛地平及其片剂中的杂质进行分离、鉴定, 并利用斑马鱼模式动物分析杂质的毒性。由非洛地平以及片剂中分离鉴定了3种杂质, 分别为杂质1 (2, 6-二甲基-4-(2, 3-二氯苯基)-1, 4-二氢-3, 5-吡啶二甲酸二甲酯), 杂质2 (2, 6-二甲基-4-(2, 3-二氯苯基)-3, 5-吡啶二甲酸甲乙酯) 和杂质3 (2, 6-二甲基-4-(2, 3-二氯苯基)-1, 4-二氢-3, 5-吡啶二甲酸二乙酯)。斑马鱼模式动物分析4种化合物的致畸作用依次为: 杂质3 ≥ 非洛地平 > 杂质1 > 杂质2; 致死作用依次为: 杂质2 = 杂质3 > 非洛地平 ≥ 杂质1。本研究确证了非洛地平的3种杂质, 并对杂质进行了毒性研究, 提出了标准修订建议, 为生产过程中杂质的控制提供了有力的数据支持。
Abstract:The paper reports the systematic study on felodipine and its impurities in tablets, to improve its quality standards for the control of the related substances. HPLC-DAD, UPLC-MS, IR and NMR methods were used for the isolation of felodipine and its impurities in tablets, their identification and the zebrafish animal model was used for the analysis of the toxic impurities. In felodipine material and its tablets, three impurities are isolated and identified. They are impurity 1 dimethyl 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5- dicarboxylate, impurity 2 ethyl methyl 4-(2, 3-dichlorophenyl)-2, 6-dimethylpyridine-3, 5-dicarboxylate and impurity 3 diethyl 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate, separately. The result of zebrafish animal model analysis showed that the teratogenic effects of four compounds were: impurity 3 ≥ felodipine > impurity 1 > impurity 2, lethal effects were as follows: impurity 2 = impurity 3 > felodipine ≥ impurity 1. This study confirmed the toxicity of three impurities in felodipine. According to the results, the paper suggested the amendments to the standard of the medicine and provided the support to the control of impurities in the manufacturing process.
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