咪达唑仑原料药及其注射液中醛基类基因毒性杂质测定与含量比较  

Determination and Comparative Analysis of Aldehyde Genotoxic Impurity in Midazolam Active Pharmaceutical Ingredients and Midazolam Injections

作　　者：匡鑫玉 程义 沈丹丹 徐琛 张伟 KUANG Xinyu;CHENG Yi;SHEN Dandan;XU Chen;ZHANG Wei(Chongqing Institute for Food and Drug Control·NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances,Chongqing,China 401121;College of Bioengineering,Chongqing University,Chongqing,China 400044;Chongqing Qijiang District Hospital,Chongqing,China 401420;Chongqing Technology and Business University Hospital,Chongqing,China 400067)

机构地区：[1]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 [2]重庆大学生物工程学院,重庆400044 [3]重庆市綦江区人民医院,重庆401420 [4]重庆工商大学校医院,重庆400067

出　　处：《中国药业》2024年第17期1-5,共5页China Pharmaceuticals

基　　金：国家药品监督管理局监管科学重点项目[RS2024H006];重庆市药品科研项目[渝药监〔2023〕24号]。

摘　　要：目的建立测定咪达唑仑原料药及注射液中醛基类基因毒性杂质M 1-[4-氯-2-(2-氟苯甲酰基)苯基]-2-甲基-1H-咪唑-5-甲醛(简称杂质M)含量的超高效液相色谱串联质谱法,比较我国3家生产企业咪达唑仑原料药及注射液、参比制剂中杂质M的含量。方法色谱柱为Acquity UPLC BEH-C18柱(100 mm×2.1 mm,1.7µm),流动相为含0.1%甲酸的0.01 mol/L甲酸铵水溶液-含0.1%甲酸的乙腈(梯度洗脱),流速为0.4 mL/min,柱温为40℃,进样量为5µL。采用电喷雾电离子源、正离子、多反应监测模式检测,毛细管电压为3.5 kV,脱溶剂温度为350℃,锥孔气流速为60 L/h,脱溶剂气流速为600 L/h。结果杂质M的质量浓度在0.46~9.16 ng/mL(r=0.9992,n=7)和28.62~1144.77 ng/mL(r=0.9953,n=7)范围内与峰面积线性关系良好;检测限为0.03 ng/mL,定量限为0.13 ng/mL;平均加样回收率为98.53%,RSD为4.53%(n=6)。国内3家生产企业的咪达唑仑注射液中杂质M的含量均显著高于原料药(P<0.05);未通过一致性评价的厂家A生产的咪达唑仑注射液中杂质M的含量最高,且显著高于参比制剂(P<0.05)。结论该方法灵敏度高、重复性好,可用于咪达唑仑注射液中杂质M的质量控制。建议未通过一致性评价的生产企业尽快开展一致性评价研究,优化制剂生产工艺,并基于风险评估制订杂质控制策略。Objective To establish an ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method for the content determination of 1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-2-methyl-1H-imidazole-5-carbaldehyde(aldehyde-based genotoxic impurity M,referred to as impurity M)in midazolam active pharmaceutical ingredients(API)and midazolam injections,and to compare the content of impurity M in midazolam API and midazolam injections from three Chinese manufacturers,and reference preparations.Methods The chromatographic column was Acquity UPLC BEH-C18 column(100 mm×2.1 mm,1.7µm),the mobile phase was 0.01 mol/L aqueous ammonium formate-acetonitrile containing 0.1%formic acid(gradient elution),the flow rate was 0.4 mL/min,the column temperature was 40℃,and the injection volume was 5µL.The electrospray ion source(ESI)was adopted with positive ion detection and multiple reactionmonitoring(MRM)mode,the capillary voltage was 3.5 kV,the temperature of desolvent was 350℃,the gas flow of the cone hole was 60 L/h,and the flow of the desolvent was 600 L/h.Results The linear ranges of impurity M were 0.46-9.16 ng/mL(r=0.9992,n=7)and 28.62-1144.77 ng/mL(r=0.9953,n=7).The limit of detection was 0.03 ng/mL,and the limit of quantification was 0.13 ng/mL.The average recovery of impurity M was 98.53%with an RSD of 4.53%(n=6).The contents of impurity M in the Midazolam Injection from three domestic manufacturers were significantly higher than those in the midazolam API(P<0.05),and the content of impurity M in the Midazolam Injection produced by manufacturer A,which did not pass the consistency evaluation,was the highest and significantly higher than that in the reference preparation(P<0.05).Conclusion This method has high sensitivity and good repeatability,which can be used for quality control of impurity M in Midazolam Injection.It is recommended that manufacturers that have not passed consistency evaluation conduct consistency evaluation research as soon as possible,optimize preparation production processes,and formu

关 键 词：超高效液相色谱串联质谱法 咪达唑仑 基因毒性杂质 含量测定 风险评估 

分 类 号：R927.2[医药卫生—药学] R971.43