气相色谱法测定奥希替尼中溶剂残留量
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摘要
目的建立一种毛细管气相色谱法,同时测定原料药奥希替尼中5种残留溶剂乙醇、乙腈、乙酸乙酯、二氯甲烷、1,4-二氧六环的含量。方法以Thermo TG-5MS毛细管柱(30 m×0.32 mm,0.25μm)为色谱柱,以氮气为载气,程序升温:起始柱温为30℃,保持10 min,之后以15℃·min~(-1)的速率升至150℃,保持4 min。采用直接进样法,进样体积为1μL。结果 5种有机溶剂在建立的色谱条件下分离度较高,且在质量浓度10.00～200.00 mg·L~(-1)内线性关系良好(r≥0.999 5),乙醇、乙腈、乙酸乙酯、二氯甲烷和1,4-二氧六环的检测限质量浓度分别为0.68、1.23、2.81、1.81和2.93μg·mL~(-1),定量限质量浓度分别为1.68、3.76、9.48、3.38和9.54 mg·L~(-1),平均回收率分别为100.4%、101.2%、102.7%、103.0%、101.2%,RSD分别为2.31%、3.53%、3.61%、4.71%、2.47%。利用该方法对3批奥希替尼样品中的残留溶剂进行检查,结果显示,乙醇的残留量分别为0.059%、0.064%和0.060%,乙酸乙酯的残留量分别为0.263%、0.260%、0.267%,乙腈、二氯甲烷和1,4-二氧六环未被检测出。结论该色谱方法可用于测定原料药奥希替尼中5种有机溶剂的含量。
Objective To establish a capillary gas chromatography method to detect the contents of 5 kinds of residual solvents in osimertinib,including ethanol,acetonitrile,ethyl acetate,dichloromethane and 1,4-Dioxane.Methods The gas chromatography method was performed on a Thermo TG-5 MS capillary column(30 m×0.32 mm,0.25 μm).The hydrogen flame ionization detector was used as the detector.Temperature-programmed mode:the initial column temperature was 30 ℃ for 10 min,then it was increased to 150 ℃ at a rate of 15 ℃·min~(-1),stayed for 4 min.Nitrogen was used as the carrier gas,methanol was used as the internal standard.Results The limit of quantitation of ethanol,acetonitrile,ethyl acetate,dichloromethane and 1,4-dioxane were 1.68,3.76,9.48,3.38 and 9.54 mg·L~(-1) separately,the limit of detection of ethanol,acetonitrile,ethyl acetate,dichloromethane and 1,4-dioxane were 0.68,1.23,2.81,1.81 and 2.93 mg·L~(-1) separately.Ethanol,acetonitrile,ethyl acetate,dichloromethane and 1,4-dioxane were well separated by gas chromatography,and the linearities were quite good from 2 to 200 mg·L~(-1)(r≥0.9995).The average recoveries were 100.4%,101.2%,102.7%,103.0% and 101.2%.RSD were 2.31%,3.53%,3.61%,4.71% and 2.47%.The residual contents of ethanol in the 3 batches of samples were 0.059%,0.064% and 0.060%,separately.The residual contents of ethyl acetate were 0.263%,0.260% and 0.267%,separately.Acetonitrile,dichloromethane and 1,4-dioxane were not detected.Conclusion The chromatograph method could be used to detect the contents of 5 kinds of residual solvents in osimertinib.
Objective To establish a capillary gas chromatography method to detect the contents of 5 kinds of residual solvents in osimertinib,including ethanol,acetonitrile,ethyl acetate,dichloromethane and 1,4-Dioxane.Methods The gas chromatography method was performed on a Thermo TG-5 MS capillary column(30 m×0.32 mm,0.25 μm).The hydrogen flame ionization detector was used as the detector.Temperature-programmed mode:the initial column temperature was 30 ℃ for 10 min,then it was increased to 150 ℃ at a rate of 15 ℃·min~(-1),stayed for 4 min.Nitrogen was used as the carrier gas,methanol was used as the internal standard.Results The limit of quantitation of ethanol,acetonitrile,ethyl acetate,dichloromethane and 1,4-dioxane were 1.68,3.76,9.48,3.38 and 9.54 mg·L~(-1) separately,the limit of detection of ethanol,acetonitrile,ethyl acetate,dichloromethane and 1,4-dioxane were 0.68,1.23,2.81,1.81 and 2.93 mg·L~(-1) separately.Ethanol,acetonitrile,ethyl acetate,dichloromethane and 1,4-dioxane were well separated by gas chromatography,and the linearities were quite good from 2 to 200 mg·L~(-1)(r≥0.9995).The average recoveries were 100.4%,101.2%,102.7%,103.0% and 101.2%.RSD were 2.31%,3.53%,3.61%,4.71% and 2.47%.The residual contents of ethanol in the 3 batches of samples were 0.059%,0.064% and 0.060%,separately.The residual contents of ethyl acetate were 0.263%,0.260% and 0.267%,separately.Acetonitrile,dichloromethane and 1,4-dioxane were not detected.Conclusion The chromatograph method could be used to detect the contents of 5 kinds of residual solvents in osimertinib.
引文
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[10] 余秋丽,黄琦,于秋洋,等.顶空毛细管气相色谱法测定帕瑞昔布钠中的残留溶剂含量[J].沈阳药科大学学报,2017,34(10):889-892.
[11] 汪小瑞,刘洁,李爽,等.顶空气相色谱法测定帕利哌酮中的溶剂残留量[J].沈阳药科大学学报,2015,32(10):786-789.
[12] 金晶晶,王嘉平,汪娟,等.顶空气相色谱法测定恩格列净原料药中10种溶剂的残留量[J].沈阳药科大学学报,2017,34(1):48-51.
[2] ZHU G,WANG X,WANG F,et al.New and convergent synthesis of osimertinib[J].Journal of Heterocyclic Chemistry,2017,54(5):2898-2901..
[3] DEARDEN S,BROWN H,JENKINS S,et al.EGFR T790M mutation testing within the osimertinib AURA Phase I study[J].Lung Cancer,2017,109:9-13.
[4] OZTAN A,FISCHER S,SCHORCK A B,et al.Emergence of EGFR G724S mutation in EGFR-mutant lung adenocarcinoma post progression on osimertinib[J].Lung Cancer,2017,111:84.
[5] MOK T S,WU Y L,AHN M J,et al.Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer[J].New England Journal of Medicine,2017,376(7):629.
[6] BALLARD P,YATES J W,YANG Z,et al.Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-Mutant NSCLC brain metastases models,and early evidence of clinical brain metastases activity[J].Clinical Cancer Research,2016,22(20):5130.
[7] 周海钧.ICH 药品注册的国际技术要求:质量部分[M].周海钧译.北京:人民卫生出版社,2006:126-151.
[8] 国家药典委员会.中华人民共和国药典:四部[M].北京:中国医药科技出版社,2015:106-110.
[9] 王巍,段蒙蒙,孙媛媛,等.毛细管气相色谱法测定依折麦布中溶剂残留量[J].沈阳药科大学学报,2016,33(12):954-957.
[10] 余秋丽,黄琦,于秋洋,等.顶空毛细管气相色谱法测定帕瑞昔布钠中的残留溶剂含量[J].沈阳药科大学学报,2017,34(10):889-892.
[11] 汪小瑞,刘洁,李爽,等.顶空气相色谱法测定帕利哌酮中的溶剂残留量[J].沈阳药科大学学报,2015,32(10):786-789.
[12] 金晶晶,王嘉平,汪娟,等.顶空气相色谱法测定恩格列净原料药中10种溶剂的残留量[J].沈阳药科大学学报,2017,34(1):48-51.