| 引用本文: | 徐桂连,姜博海,韩春晖.磷酸苯丙哌林合成过程中氯化物中间体的潜在基因毒性危害评估及其残留水平检测[J].中国现代应用药学,2025,42(8):69-73. |
| xuguilian,jiang bohai,hanchunhui.Hazard assessment and determination of the chloride intermediate, a potential genotoxic impurity, in the synthesis of benproperine phosphate[J].Chin J Mod Appl Pharm(中国现代应用药学),2025,42(8):69-73. |
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| 摘要: |
| 目的:评估磷酸苯丙哌林合成过程中氯化物中间体的基因毒性危害,建立氯化物中间体残留检测方法。方法:采用毒性预测软件对氯化物中间体进行危害评估及基因毒性杂质分类,并计算了氯化物中间体的残留控制限度。以DB-17 MS为色谱柱,起始温度为50 ℃,维持1 min,然后以25℃·min-1升至220 ℃,维持1 min,最后以10 ℃·min-1升至280 ℃,维持2 min；载气为氦气,流速为1.0 mL·min-1,进样量1 μL,Sim正离子模式,以m/z 260.5为定量离子,外标法定量。结果:基于氯化物中间体具有氯代烷烃警示结构,Toxtree、Derek Nexus和Sarah Nexus均提示其存在致突变风险。建立的GC-MS检测方法,氯化物中间体在1.054~10.54 ng·mL-1浓度范围内线性关系良好,平均回收率(n=9)为95 %,精密度RSD%值为2.41%(n=6),10个连续批次磷酸苯丙哌林原料药中均检出氯化物中间体。结论:氯化物中间体属于3类潜在基因毒性杂质,建立的残留检测方法稳定、可靠,可用于磷酸苯丙哌林原料药中氯化物中间体残留水平监测。 |
| 关键词: 磷酸苯丙哌林 基因毒性杂质 氯化物中间体 GC-MS |
| DOI：10.13748/j.cnki.issn1007-7693.20240138 |
| 分类号: |
| 基金项目:2023大连市青年科技之星项目 |
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| Hazard assessment and determination of the chloride intermediate, a potential genotoxic impurity, in the synthesis of benproperine phosphate |
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xuguilian, jiang bohai, hanchunhui
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dalian institute for drug control
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| Abstract: |
| ABSTRACT: OBJECTIVE To evaluate the genotoxicity of the chloride intermediate and establish a method for determination of chloride intermediate residue. METHODS Hazard assessment and genotoxic impurity classification of the chloride intermediate were carried out by toxicity prediction software, and the residue control limit of the chloride intermediate was calculated. Using DB-17MS as the column, the initial temperature was 50 ℃ for 1 min, then raised to 220 ℃ at a speed of 25 ℃·min -1 remaining 1min, and finally raised to 280 ℃ at a speed of 10 ℃·min -1 remaining 2min. The carrier gas was helium, the flow rate was 1.0 mL·min-1, the sample volume was 1 μL, SIM positive ion mode was adopted, and m/z 260.5 was the quantitative ion, qualitified by the external reference method. RESULTS Based on gen.aliphatic halogens sructure, Toxtree、Derek Nexus and Sarah Nexus were suggested that the Chloride intermediate was mutagenic. The established detection method showed a good linear relationship in the concentration range of 1.054~10.54 ng·mL-1, the average recovery (n=9)was 95% and the RSD of repeatability test was 2.41%(n=6). CONCLUSION The Chloride intermediate belongs to the class 3 of genotoxic potential impurities, and the established detection method is stable and reliable, which can be used to monitor the content of the chloride intermediate in benproperine phosphate API. |
| Key words: benproperine phosphate genotoxic impurity the chloride intermediate GC-MS |
