顶空气相色谱法测定selexipag中6种有机溶剂残留量
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摘要
建立顶空气相色谱法,测定selexipag中甲醇、乙醇、丙酮、二氯甲烷、四氢呋喃和甲苯的残留量,为其质量控制提供试验依据。色谱柱为Kromat PC-624(V)(30.0 m×0.32 mm,1.8μm)毛细管柱,采用程序升温模式:初始柱温40℃,维持5 min,以20℃/min升至180℃,维持5 min;氢火焰离子化检测器(FID),进样口温度为200℃,检测器温度为250℃,分流比为20∶1。在该色谱条件下,6种残留溶剂均完全分离,峰面积与浓度呈良好线性关系(r=0.998 2~1.000);精密度、重复性、稳定性试验结果符合要求,各被测组分的平均回收率在96.67%~101.7%之间。该气相色谱法操作简单,准确度、灵敏度高,可用于检测selexipag原料药中残留的有机溶剂。
A headspace gas chromatography method was developed for the determination of six residual solvents including methanol, ethanol, acetone, dichloromethane, tetrahydrofuran and toluene residues in selexipag to provide the experimental basis for its quality control. The samples were separated on Kromat PC-624( V) silica capillary column( 30. 0 m × 0. 32 mm,1. 8 μm) using temperature programming. The column temperature was kept at 40 °C for 5 min initially,and then raised to 180 °C at the rate of 20 °C/min and subsequently sustained for 5 min. FID detector temperature was 250 °C and injection temperature was 200 °C. The split ratio was 20 ∶ 1.The six residual solvents are separated completely under the given chromatographic conditions with a good linearity( r = 0. 998 2-1. 000); the results of precision,repeatability and stability experiments met the requirement,and the mean recoveries of all solvents were in the range of 96. 67%-101. 7%. The analytical method is simple,accurate and sensitive,and it can be used for the determination of residual solvents in selexipag.
A headspace gas chromatography method was developed for the determination of six residual solvents including methanol, ethanol, acetone, dichloromethane, tetrahydrofuran and toluene residues in selexipag to provide the experimental basis for its quality control. The samples were separated on Kromat PC-624( V) silica capillary column( 30. 0 m × 0. 32 mm,1. 8 μm) using temperature programming. The column temperature was kept at 40 °C for 5 min initially,and then raised to 180 °C at the rate of 20 °C/min and subsequently sustained for 5 min. FID detector temperature was 250 °C and injection temperature was 200 °C. The split ratio was 20 ∶ 1.The six residual solvents are separated completely under the given chromatographic conditions with a good linearity( r = 0. 998 2-1. 000); the results of precision,repeatability and stability experiments met the requirement,and the mean recoveries of all solvents were in the range of 96. 67%-101. 7%. The analytical method is simple,accurate and sensitive,and it can be used for the determination of residual solvents in selexipag.
引文
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[11]Huang R,Zhang SJ,Huang LY.Determination of residual organic solvents in fenazinel dihydrochloride by headspace gas chromatography[J].J China Pharm Univ(中国药科大学学报),2008,39(2):183-184.
[2]Du C,Liu YX.Selexipag[J].Chin J Med Chem(中国药物化学杂志),2016,26(4):352.
[3]Xia XM.FDA approved Uptarvi(selexipag)tablets in the treatment of pulmonary arterial hypertension[J].J Guangdong Pharm Univ(广东药学院学报),2016,32(1):35.
[4]Wang H.Study on the synthesis of selexipag(Selexipag的工艺研究)[D].Shijiazhuang:Hebei University of Science and Technology,2017.
[5]Shang ZH,Wang H,Fang Q.Method for preparing selexipag:CN,201610357729.3[P].2016-06-20[2017-07-15].
[6]Chinese Pharmacopoeia Commission.Chinese Pharmacopoeia:part4[S].(中华人民共和国药典:四部),Beijing:China Medical Science Press,2015:105-109.
[7]Ito Y,Ishizuki K,Sekiguchi W,et al.Analysis of residual solvents in annatto extracts using a static headspace gas chromatography method[J].Ameri J Analy Chem,2012,3(9):638-645.
[8]Teglia CM,Montemurro M,Zan MMD,et al.Multiple responses optimization in the development of a headspace gas chromatography method for the determination of residual solvents in pharmaceuticals[J].J Pharm Anal,2015,5(5):296-306.
[9]Grodowska K,Parczewski A.Grouping of residual solvents present in pharmaceuticals using experimental planning and chemometric methods[J].Acta Poloniae Pharm,2013,70(2):191-203.
[10]Cheng C,Liu S,Mueller B J,et al.A generic static headspace gas chromatography method for determination of residual solvents in drug substance[J].J Chromatogr A,2010,1217(41):6413-6421.
[11]Huang R,Zhang SJ,Huang LY.Determination of residual organic solvents in fenazinel dihydrochloride by headspace gas chromatography[J].J China Pharm Univ(中国药科大学学报),2008,39(2):183-184.