手性固定相HPLC法测定替格瑞洛片中替格瑞洛异构体含量
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摘要
目的:建立以手性填料色谱柱为固定相的高效液相色谱法,同时测定替格瑞洛片中替格瑞洛对映异构体和非对映异构体的含量。方法:采用CHIRALPAK IA(250 mm×4.6 mm,5μm)色谱柱;以正己烷-甲醇-乙醇-醋酸(800∶100∶100∶1)为流动相,流速为0.8 mL·min~(-1);柱温为30℃;检测波长为255 nm。结果:在该色谱条件下,替格瑞洛片中替格瑞洛及其各异构体之间分离度均大于1.5;替格瑞洛及其各异构体在所测定的浓度范围内线性良好,检测限均为0.1μg·mL~(-1),定量限为0.2~0.4μg·mL~(-1);供试品溶液在18 h内稳定;方法精密度和耐用性良好。结论:本方法专属性强,灵敏度高,可满足生产中替格瑞洛片异构体含量检测的要求。
Objective: To establish a method of high performance liquidchromatography(HPLC) with chiral stationary phase for the detection of ticagrelor enantiomer and diastereomers in ticagrelor tablets. Methods:The experiments were performed on a CHIRALPAK IA(250 mm × 4. 6 mm,5 μm) column at 30 ℃ with the mobile phase of n-hexane-methanol-ethanol-acetic acid(800∶ 100∶ 100 ∶ 1) at a flow rate of 0. 8 mL·min~(-1). The detection wavelength was set at 255 nm. Results: All the resolutions between ticagrelor and the enantiomer,and between the enantiomer and the diastereomers were greater than 1. 5. The calibration curves of ticagrelor and the isomers showed good linear relationships over the detection range with correction coefficients more than 0. 999. The limits of detection(LODs) of ticagrelor and the isomers were 0. 1 μg·mL~(-1),and the limits of quantitation(LOQs)of ticagrelor and the isomers were 0. 2 ~ 0. 4 μg·mL~(-1). The sample solutions were stable within 18 hours. The method had a good precision and robustness. Conclusion: The method is specific and sensitive,which meets the detecting demand of ticagrelor enantiomer and diastereomers in ticagrelor tablets.
Objective: To establish a method of high performance liquidchromatography(HPLC) with chiral stationary phase for the detection of ticagrelor enantiomer and diastereomers in ticagrelor tablets. Methods:The experiments were performed on a CHIRALPAK IA(250 mm × 4. 6 mm,5 μm) column at 30 ℃ with the mobile phase of n-hexane-methanol-ethanol-acetic acid(800∶ 100∶ 100 ∶ 1) at a flow rate of 0. 8 mL·min~(-1). The detection wavelength was set at 255 nm. Results: All the resolutions between ticagrelor and the enantiomer,and between the enantiomer and the diastereomers were greater than 1. 5. The calibration curves of ticagrelor and the isomers showed good linear relationships over the detection range with correction coefficients more than 0. 999. The limits of detection(LODs) of ticagrelor and the isomers were 0. 1 μg·mL~(-1),and the limits of quantitation(LOQs)of ticagrelor and the isomers were 0. 2 ~ 0. 4 μg·mL~(-1). The sample solutions were stable within 18 hours. The method had a good precision and robustness. Conclusion: The method is specific and sensitive,which meets the detecting demand of ticagrelor enantiomer and diastereomers in ticagrelor tablets.
引文
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[11]TENG R,OLIVER S,HAYES MA,et al.Absorption,distribution,metabolismand excretion of ticagrelor in healthy subjects[J].Drug Metab Dispos,2010,38(9):1514-1521.
[12]STEG PG,HARRINGTON RA,EMANUELSSON H,et al.Stent thrombosis with ticagrelor versus clopidogrelinpatients with acute coronary syndromes:an analysis from the prospective,randomized PLATO trial[J].Circulation,2013,128(10):1055-1065.
[13]陈艳,袁晋清.替格瑞洛临床应用新进展[J].心血管病学进展,2016,37(3):235-239.
[14]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):994-997.
[15]陈莉莉,岑均达.替卡格雷合成路线图解[J].中国医药工业杂志,2011,42(2):146-151.
[2]何晓清,徐建国,吴泰志,等.替卡格雷Dimroth重排杂质的研究[J].中国药物化学杂志,2015,25(2):129-131.
[3]FDA.FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes[EB/OL].[2011-10-16].http://www.fda.gov/News Events/Newsroom/Press Announcements/ucm263964.htm.
[4]PHILIPPE GS,STEFAN J,HARRINGTON RA,et al.Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention[J].Coron Heart Dis,2010,122(21):2131-2141.
[5]凤凰网.治疗ASC患者的新选择-倍林达中国上市获批准[EB/OL].http://gz.ifeng.com/yangsheng/jiankangsudi/detail_2012_11/30/456315_0.shtml.
[6]李慕鹏,熊艳,陈小平.抗血小板药物替格瑞洛药代药效动力学及遗传药理学研究进展[J].中国临床药理学与治疗学,2014,19(2):214-222.
[7]DEEKS ED.Ticagrelor:a review of its use in the management of acute coronary syndromes[J].Drugs,2011,71(7):909-933.
[8]Astra Zeneca.Brilique(ticagrelor)[EB/OL].[2013-01-10].http://www.astrazeneca.com/Medicines/Car-diovascular/Product/Brilinta-Brilique.
[9]刘美,刘梅林.新型抗血小板药替卡格雷[J].中国新药杂志,2012,21(15):1703-1707.
[10]杨昭毅,向倩,周颖,等.新型抗血小板药物替格瑞洛临床应用分析[J].中国新药杂志,2015,24(2):235-240.
[11]TENG R,OLIVER S,HAYES MA,et al.Absorption,distribution,metabolismand excretion of ticagrelor in healthy subjects[J].Drug Metab Dispos,2010,38(9):1514-1521.
[12]STEG PG,HARRINGTON RA,EMANUELSSON H,et al.Stent thrombosis with ticagrelor versus clopidogrelinpatients with acute coronary syndromes:an analysis from the prospective,randomized PLATO trial[J].Circulation,2013,128(10):1055-1065.
[13]陈艳,袁晋清.替格瑞洛临床应用新进展[J].心血管病学进展,2016,37(3):235-239.
[14]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):994-997.
[15]陈莉莉,岑均达.替卡格雷合成路线图解[J].中国医药工业杂志,2011,42(2):146-151.