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目的:建立LC-MS法对甲磺酸伊马替尼原料中的3个磺酸酯基因毒杂质—甲磺酸甲酯(MMS)、甲磺酸乙酯(EMS)、甲磺酸异丙酯(IPMS)进行定量检测。方法:选用Agilent Poroshell 120 SB-C18色谱柱(2.7μm,4.6 mm×100 mm),以10mmol·L-1甲酸铵(含0.1%甲酸)为流动相A,甲醇为流动相B,梯度洗脱[0 min(80%A-20%B)→5 min(10%A-90%B)→10 min(10%A-90%B)→10.5 min(80%A-20%B)→18.5 min(80%A-20%B)],流速为0.4 m L·min-1。ESI正离子化SIM模式下对3种磺酸酯进行同时检测,雾化氮气压力0.3 MPa、温度300℃、流速10 L·min-1,毛细管电压3 k V,传输电压30 V。结果:MMS在10~100 ng·m L-1内线性关系良好(r=0.9988),定量限为10 ng·m L-1;EMS在5~50 ng·m L-1内线性关系良好(r=0.9992),定量限为5 ng·m L-1;IPMS在10~100 ng·m L-1内线性关系良好(r=0.9993),定量限为10 ng·m L-1。MMS、EMS、IPMS的回收率分别为99.86%、101.7%、103.8%。结论:经方法学验证,该法可用于甲磺酸伊马替尼中3个磺酸酯基因毒杂质的同时检测,能为质量控制提供参考。
OBJECTIVE: To establish an LC-MS method for the determination of three sulfonate genotoxic impurities (MMS, Ethyl methanesulfonate (EMS), Isopropyl mesylate Ester (IPMS) for quantitative detection. Methods: Agilent Poroshell 120 SB-C18 column (2.7 μm, 4.6 mm × 100 mm) was used as the mobile phase A with 10 mmol·L -1 ammonium formate (containing 0.1% formic acid) as mobile phase B and gradient elution [0 min (80% A-20% B) → 5 min (10% A-90% B) → 10 min (10% A-90% B) → 10.5 min min (80% A-20% B)] at a flow rate of 0.4 m L · min-1. ESI positive ionization SIM mode simultaneous detection of three sulfonate ester, atomization nitrogen pressure 0.3 MPa, temperature 300 ℃, flow rate 10 L · min-1, capillary voltage 3 k V, the transmission voltage 30 V. Results: The linearity of MMS was 10-100 ng · m L-1 (r = 0.9988), and the limit of quantification was 10 ng · m L-1. EMS showed good linearity within 5-50 ng · m L-1 r = 0.9992). The limit of quantification was 5 ng · m L-1. The linearity of IPMS in 10-100 ng · m L-1 was good (r = 0.9993) and the limit of quantification was 10 ng · m L-1. The recoveries of MMS, EMS and IPMS were 99.86%, 101.7% and 103.8% respectively. Conclusion: This method can be used for the simultaneous detection of 3 sulfonate genotoxicity in imatinib mesylate by the methodological validation, which can provide reference for quality control.