首页|盐酸布比卡因注射液中基因毒性杂质含量测定与来源分析

盐酸布比卡因注射液中基因毒性杂质含量测定与来源分析

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目的 建立测定盐酸布比卡因注射液中基因毒性杂质 2，6-二甲基苯胺(杂质F)含量的高效液相色谱法，探讨杂质F的产生原因。方法 色谱柱为Xbridge Shield RP18 柱(250 mm×4。6 mm，5 μm)，流动相为[0。05mol/L磷酸盐缓冲液(pH8。0)-乙腈(65∶35，V/V)]-乙腈(梯度洗脱)，流速为 1。0 mL/min，检测波长为 240 nm，柱温为 30℃，进样量为 10 μL。从原料药合成工艺、辅料、制剂生产工艺、制剂所用原料药 4 个方面，抽取 5 家生产企业 94 批样品进行杂质F的检测和对比，分析基因毒性杂质F的产生原因。结果 杂质F的质量浓度在 0。15～3 μg/mL范围内与峰面积线性关系良好(r = 1。000 0，n = 5);精密度、重复性试验结果的RSD分别为 0。42%(n=6)和 9。27%(n=6);加样回收率为 99。41%，RSD为 2。06%(n=9)。生产企业B，D，F，G的 85批样品中均未检出杂质F;企业E的 9批样品中均检出杂质F，检出量分别为 0。0004%，0。0004%，0。0004%，0。000 6%，0。000 5%，0。000 5%，0。000 4%，0。000 4%，0。000 3%。结论 该方法专属性强、重复性好、精密度高，可为杂质F的定量检测和制剂的质量控制提供参考。建议各制剂生产企业重视基因毒性杂质F的质量控制，尽快建立企业的内控标准，同时对原料药进行严格的入库质控，从源头控制杂质F的引入风险。
Content Determination and Source Analysis of Genotoxic Impurity in Bupivacaine Hydrochloride Injection
Objective To establish a high-performance liquid chromatography(HPLC)method for the content determination of genotoxic impurity 2,6-dimethylaniline(impurity F)in Bupivacaine Hydrochloride Injection,and to investigate the source of impurity F.Methods The chromatography column was Xbridge Shield RP18 column(250 mm×4.6 mm,5 μm),the mobile phase was[0.05 mol/L phosphate buffer(pH = 8.0)-acetonitrile(65∶35,V/V)]-acetonitrile(gradient elution),the flow rate was 1.0 mL/min,the detection wavelength was 240 nm,the column temperature was 30℃,and the injection volume was 10 μL.The content of impurity F in 94 batches of samples from five manufacturers was detected and compared from the aspects of active pharmaceutical ingredients(API),synthesis process,excipients,preparation production process,and API used in preparation,and the source of genotoxic impurity F was analyzed.Results The linear range of impurity F was 0.15-3 μg/mL(r= 1.000 0,n= 5).The RSDs of precision and repeatability test results were 0.42%(n = 6)and 9.27%(n = 6),respectively.The recovery rate of impurity F was 99.41%with an RSD of 2.06%(n = 9).Impurity F was not detected in 85 batches of samples from manufacturers B,D,F,and G,while that was detected in nine batches of samples from manufacturer E,with contents of 0.000 4%,0.000 4%,0.000 4%,0.000 6%,0.000 5%,0.000 5%,0.000 4%,0.000 4%,and 0.000 3%,respectively.Conclusion This method has strong specificity,good repeatability,and high precision,which can provide a reference for the quantitative detection of impurity F and the quality control of preparations.It is recommended that all manufacturers should pay attention to controlling the content of genotoxic impurity F,establish internal control standards as soon as possible,and strictly control the quality of purchased API in the warehouse to control the introduction risk of impurity F from the source.

Bupivacaine Hydrochloride InjectionHPLC2,6-dimethylanilineproduction process

周冰捷、王非梦、李超、罗立骏、徐登、冯琴、梁静

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重庆市食品药品检验检测研究院·国家药品监督管理局麻醉精神药品质量监测重点实验室,重庆 401121

西南大学药学院,重庆 400716

盐酸布比卡因注射液 高效液相色谱法 2,6-二甲基苯胺 生产工艺

重庆市技术创新与应用发展专项面上项目

CSTB2022TIAD-GPX0071

2024

10.3969/j.issn.1006-4931.2024.09.004

中国药业
重庆市食品药品监督管理局

中国药业

CSTPCD
影响因子：1.369
ISSN：1006-4931
年,卷(期)：2024.33(9)
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