采用GC-MS法监控磷酸奥司他韦原料中两种带磺酸酯基因毒警示结构杂质的残留量  

Determination of Two Sulfonate Impurities with Alerting Structure in Oseltamivir Phosphate by GC-MS

作　　者：刘欣颖 周淼 折娜娜 许红霞 张文龙 郭鑫 谌宗永 马昂 王明娟 LIU Xinying;ZHOU Miao;SHE Nana;XU Hongxia;ZHANG Wenlong;GUO Xin;SHEN Zongyong;MA Ang;WANG Mingjuan(Beijing Sun-novo Pharmaceutical Research Co.,Ltd,Beijing 102200,China)

机构地区：[1]北京阳光诺和药物研究股份有限公司,北京102200

出　　处：《药品评价》2023年第8期938-942,共5页Drug Evaluation

基　　金：国家药品监督管理局化学药品杂质谱研究重点实验室开放课题(NMPA-KLIPCD-2020-06);北京市科委、中关村管委会专项课题(Z211100003421042)。

摘　　要：目的建立一种能够检测磷酸奥司他韦原料中甲磺酸甲酯、甲磺酸乙酯残留量的方法。方法应用GC-MS法,采用VF-624 MS毛细管柱(0.32 mm×30 m,1.8μm),升温程序:60℃维持2 min,以10℃/min升温至140℃,维持2 min,再以20℃/min升温至260℃,维持10 min。进样口温度为200℃;载气为氦气,流量1.5 mL/min;分流比10∶1;直接进样,进样体积1μL;质谱检测器参数:采用EI离子源,电压为70 eV,离子源温度:230℃;气相色谱-质谱接口温度为250℃;溶剂延迟时间2.5 min,采用选择离子检测模式(SIM):甲磺酸甲酯和甲磺酸乙酯的检测离子分别为m/z 80和79。结果空白溶剂和磷酸奥司他韦对甲磺酸甲酯和甲磺酸乙酯的检测无干扰;甲磺酸甲酯、甲磺酸乙酯的检测限分别为0.063μg/mL和0.062μg/mL,定量限均为0.21μg/mL(相当于2.1 ppm,两种杂质的限度均为10 ppm,总量限度为33.3 ppm);甲磺酸甲酯和甲磺酸乙酯重复性结果的RSD分别为7.3%和3.7%(n=6),中间精密度结果的RSD均为9.1%(n=12);对照品溶液和加标供试品溶液在室温下放置,24 h之内稳定;甲磺酸甲酯和甲磺酸乙酯在0.2~2.1μg/mL范围内(相当于2~21 ppm)峰面积与浓度均呈良好的线性关系(r>0.990);加样回收率分别介于87.3%~101.3%和84.9%~102.8%范围。结论该方法的专属性、灵敏度、准确性及线性等指标均符合规定,能够用于磷酸奥司他韦原料中甲磺酸甲酯和甲磺酸乙酯残留量的准确监控。Objective To establish a method for determination of methyl mesylate and ethyl mesylate with alerting structure residue in oseltamivir phosphate drug substance.Methods The GC-MS method was applied,using VF-624 MS column(0.32 mm×30 m,1.8μm)with a gradient heating procedure:maintain at 60℃for 2 min,rise to 140℃at a rate of 10℃/min and maintain for 2 min,then rise to 260℃at a rate of 20℃/min and maintain for 10 min.Injector temperature was set at 200℃.Helium was used as the carrier gas at a flow rate of 1.5 mL/min.The split ratio was 10∶1 and 1μL of test solutions and reference solutions were injected directly.MS conditions were as follows:EI ion source,voltage set at 70 eV,ion source temperature and GC-MS interface temperature were maintained at 230℃and 250℃,respectively.Solvent delay time was 2.5 min,The selective ion monitor(SIM)detection mode was adopted and m/z 80 and 79 were used for determination of methyl mesylate and ethyl mesylate,respectively.Results No interference was observed from blank solvent or oseltamivir phosphate.The limits of quantification for methyl mesylate and ethyl mesylate were both 0.21μg/mL corresponding to 2.1 ppm,lower than their individual limit(10 ppm),and their detection limits were 0.063μg/mL and 0.062μg/mL,respectively.Precision at 100%spiked concentration of methyl mesylate and ethyl mesylate were 7.3%and 3.7%(n=6),respectively.The RSDs for methyl mesylate and ethyl mesylate results obtained in intermediate precision were both 9.1%(n=12).The reference solution and 100%spiked test solution were stable for 12 h at room temperature.In the range of 0.2~2.1μg/mL(corresponding to 2~21 ppm),the peak areas of methyl mesylate and ethyl mesylate both showed linear response with their concentrations(r>0.990).Their individual spiked recoveries were between 87.3%~101.3%and 84.9%~102.8%.Conclusion This method was proved to be specific,accurate,sensitive,and showed linear response in the range covering the proposed limit,demonstrating its suitability for trace control o

关 键 词：药物污染 磷酸奥司他韦 磺酸酯 基因毒杂质 警示结构 GC-MS 风险评估 

分 类 号：R927.1[医药卫生—药学]