气相色谱法测定替格瑞洛原料药中6种残留溶剂
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摘要
目的:建立替格瑞洛原料药中6种残留溶剂的测定方法。方法:采用气相色谱法检测替格瑞洛原料药中甲醇、乙醇、乙腈、乙酸乙酯、异辛烷、乙酸。色谱条件为DB-624(30 m×0.320 mm×1.8 mm)毛细管柱;载气采用高纯氮气,流速为1 m L/min;检测器为氢火焰离子化检测器,检测器温度为250℃(空气流速),进样口温度为200℃;程序升温,分流比20∶1。结果:6种有机溶剂在各自的检测质量范围内线性关系良好(r=0.998 31~0.999 99),平均回收率为91.49%~100.48%(RSD=2.85%~7.17%,n=9);甲醇、乙醇、乙腈、乙酸乙酯、异辛烷、乙酸的定量限分别为7.92、7.89、6.29、0.90、0.23、4.20 mg/L,检测限分别为1.98、0.99、0.79、0.22、0.08、1.05 mg/L。用该方法测定3批次替格瑞洛原料药,只有乙酸乙酯和异辛烷被检出但均符合标准,其他残留溶剂未检测到。结论:该方法操作简便、稳定、重复性好,可用于替格瑞洛原料药中上述6种残留溶剂的测定。
Aim: To develop a method for the content determination of residual solvents in ticagrelor raw material including methanol,ethanol,acetonitrile,ethyl acetate,isooctane,and acetic acid. Methods: Capillary gas chromatography was adopted. The determination was performed on DB-624( 30 m × 0. 320 mm × 1. 8 mm) capillary column,a flame ionization detector( FID) and the external standard method were used for the separation and quantitative analysis. The condition was that the injector temperature was 200 ℃,the FID temperature was 250 ℃ and the residual organic solvents were determined by the split injection mode. Results: The good linear range of the 6 kinds of residual solvents had been obtained( r = 0. 998 31-0. 999 99) with average recoveries of 91. 49%-100. 48%( RSD = 2. 85%-7. 17%,n = 9). The limits of quantification of the 6 kinds of residual solvents were 7. 92,7. 89,6. 29,0. 90,0. 23 and 4. 20 mg/L; the detection limits were 1. 98,0. 99,0. 79,0. 22,0. 08 and 1. 05 mg/L. The proposed method was successfully applied to analyze the residual organic solvent in the real sample of ticagrelor raw material,and the results showed that only ethyl acetate and isooctane were detected in the samples. Conclusion: The method is rapid,stable and repeatable for the content determination of the6 kinds of residual solvents in ticagrelor raw material.
Aim: To develop a method for the content determination of residual solvents in ticagrelor raw material including methanol,ethanol,acetonitrile,ethyl acetate,isooctane,and acetic acid. Methods: Capillary gas chromatography was adopted. The determination was performed on DB-624( 30 m × 0. 320 mm × 1. 8 mm) capillary column,a flame ionization detector( FID) and the external standard method were used for the separation and quantitative analysis. The condition was that the injector temperature was 200 ℃,the FID temperature was 250 ℃ and the residual organic solvents were determined by the split injection mode. Results: The good linear range of the 6 kinds of residual solvents had been obtained( r = 0. 998 31-0. 999 99) with average recoveries of 91. 49%-100. 48%( RSD = 2. 85%-7. 17%,n = 9). The limits of quantification of the 6 kinds of residual solvents were 7. 92,7. 89,6. 29,0. 90,0. 23 and 4. 20 mg/L; the detection limits were 1. 98,0. 99,0. 79,0. 22,0. 08 and 1. 05 mg/L. The proposed method was successfully applied to analyze the residual organic solvent in the real sample of ticagrelor raw material,and the results showed that only ethyl acetate and isooctane were detected in the samples. Conclusion: The method is rapid,stable and repeatable for the content determination of the6 kinds of residual solvents in ticagrelor raw material.
引文
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[6]冯光玲,丁文娟,伊星璐,等.毛细管气相色谱法测定坎底沙坦酯原料药中8种有机溶剂残留量[J].中国药房,2014,25(9):845
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[10]张静,徐三能.顶空气相色谱法测定比阿培南的有机溶剂残留量[J].安徽医药,2011,15(1):36
[11]贺成,卢建秋,张伟.顶空毛细管气相色谱法测定盐酸莫西沙星中残留溶剂的含量[J].中国药品标准,2013,14(1):18
[12]宋国申,姜建国,张西如.顶空毛细管气相色谱法测定罗库溴铵中的残留溶剂[J].中国现代应用药学杂志,2009,26(10):849
[13]黄珊,杨本霞.顶空毛细管气相色谱法测定阿托伐他汀钙原料药中残留溶剂的含量[J].中国药房,2013,24(44):4206
[14]廖世峰,蔺宇,张海波,等.新型抗凝血药替格瑞洛的合成[J].海峡药学,2015,27(4):249
[15]李小东,廖祥伟,蒲道俊,等.替格瑞洛的合成工艺改进[J].合成化学,2016,24(11):994
[16]曾志旋,曹胜华,陈林,等.替格瑞洛的合成工艺改进[J].化学研究与应用,2015,27(3):374
[2]王曼曼,高娜,李清娟,等.犬血浆中替格瑞洛及活性代谢产物的LC-MS/MS法测定[J].中国医药工业杂志,2014,45(11):1050
[3]林志坚,郭淮莲,孙凯,等.阿司匹林与氯吡格雷对小鼠血小板P-选择素抑制作用的比较[J].中国神经精神疾病杂志,2013,39(3):170
[4]LI HY,GUO JC,CARLSON GF,et al.Pharmacodynamic,pharmacokinetics,and safety of ticagrelor in Chinesc patients with stable coronary artery disease[J].Br J Clin Pharmacol,2016,82(2):352
[5]陈佳彬.阿司匹林、氯吡格雷抵抗及替格瑞洛研究进展[D].重庆:重庆医科大学,2014.
[6]冯光玲,丁文娟,伊星璐,等.毛细管气相色谱法测定坎底沙坦酯原料药中8种有机溶剂残留量[J].中国药房,2014,25(9):845
[7]陆烨,夏宇沁,昌军,等.毛细管气相色谱法测定13种有机溶剂残留[J].复旦学报(医学版),2013,40(2):222
[8]陈宁,陈朝艳.顶空气相色谱法测定头孢替坦二钠中的残留溶剂[J].中国抗生素杂志,2011,36(11):849
[9]胡慧廉.顶空气相色谱法测定氟尼辛葡甲胺原料药中有机溶剂残留量[J].色谱,2012,30(1):99
[10]张静,徐三能.顶空气相色谱法测定比阿培南的有机溶剂残留量[J].安徽医药,2011,15(1):36
[11]贺成,卢建秋,张伟.顶空毛细管气相色谱法测定盐酸莫西沙星中残留溶剂的含量[J].中国药品标准,2013,14(1):18
[12]宋国申,姜建国,张西如.顶空毛细管气相色谱法测定罗库溴铵中的残留溶剂[J].中国现代应用药学杂志,2009,26(10):849
[13]黄珊,杨本霞.顶空毛细管气相色谱法测定阿托伐他汀钙原料药中残留溶剂的含量[J].中国药房,2013,24(44):4206
[14]廖世峰,蔺宇,张海波,等.新型抗凝血药替格瑞洛的合成[J].海峡药学,2015,27(4):249
[15]李小东,廖祥伟,蒲道俊,等.替格瑞洛的合成工艺改进[J].合成化学,2016,24(11):994
[16]曾志旋,曹胜华,陈林,等.替格瑞洛的合成工艺改进[J].化学研究与应用,2015,27(3):374