米格列奈及其3个异构体杂质的反相液相色谱分离及质谱碎裂分析
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摘要
建立了超高效反相液相色谱-高分辨质谱方法以实现米格列奈及其3种异构体杂质的分离,以ACQUITY UPLC HSS T3(100 mm×2.1 mm, 1.8μm)为色谱柱,以水-乙腈-正戊醇(75∶25∶1)(用甲酸调节pH至1.8)为流动相,流速为0.4 mL/min。根据Q Exactive四极杆/静电场轨道阱高分辨质谱的精确质量数及碎裂情况,发现了米格列奈及3种异构体存在碎片离子丰度的明显差异,确认其中两种为本次新发现的异构体杂质,并推断了米格列奈及3种异构体杂质可能的质谱裂解机理。经验证,该方法的灵敏度、重复性及线性均满足分析要求。在此基础上,对米格列奈异构体杂质的来源进行了探讨,发现异构体杂质1可在高温下降解产生,并对各企业的米格列奈钙原料样品进行了测定。
The separation of mitiglinide and its three isomer impurities was achieved by reversed-phase ultra-performance liquid chromatography-high resolution mass spectrometry. An ACQUITY UPLC HSS T3 column(100 mm×2.1 mm, 1.8 μm) was used as the stationary phase and water-acetonitrile-n-pentanol(75∶25∶1, v/v/v; formic acid was added to adjust pH to 1.8) was used as the mobile phase with a flow rate of 0.4 mL/min. According to the exact mass and high resolution mass spectrometry fragmentation(Q Exactive), significant differences were observed in the fragment ion abundance in the secondary mass spectra of mitiglinide and its three isomer impurities. Two of these isomer impurities were newly discovered. The possible fragmentation mechanisms of mitiglinide and its three isomer impurities were also deduced. The limit of detection of the developed method was 1 μg/L. The linearity of the developed method was good from the limit of quantitation(2 μg/L) to 10 000 μg/L with a correlation coefficient of 0.999 9. The relative standard deviation of the peak area was 2.0%. On the basis of these results, the sources of the mitiglinide isomer impurities were discussed. Isomer impurity 1 was degraded at high temperature, while isomer impurities 2 and 3 were determined to be synthetic impurities. In addition, samples of mitiglinide calcium raw materials were analyzed.
The separation of mitiglinide and its three isomer impurities was achieved by reversed-phase ultra-performance liquid chromatography-high resolution mass spectrometry. An ACQUITY UPLC HSS T3 column(100 mm×2.1 mm, 1.8 μm) was used as the stationary phase and water-acetonitrile-n-pentanol(75∶25∶1, v/v/v; formic acid was added to adjust pH to 1.8) was used as the mobile phase with a flow rate of 0.4 mL/min. According to the exact mass and high resolution mass spectrometry fragmentation(Q Exactive), significant differences were observed in the fragment ion abundance in the secondary mass spectra of mitiglinide and its three isomer impurities. Two of these isomer impurities were newly discovered. The possible fragmentation mechanisms of mitiglinide and its three isomer impurities were also deduced. The limit of detection of the developed method was 1 μg/L. The linearity of the developed method was good from the limit of quantitation(2 μg/L) to 10 000 μg/L with a correlation coefficient of 0.999 9. The relative standard deviation of the peak area was 2.0%. On the basis of these results, the sources of the mitiglinide isomer impurities were discussed. Isomer impurity 1 was degraded at high temperature, while isomer impurities 2 and 3 were determined to be synthetic impurities. In addition, samples of mitiglinide calcium raw materials were analyzed.
引文
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[5] Zeng T, Huo D Q, Zhou X M, et al. China Pharmaceuticals, 2013, 22(17): 28 曾檀, 霍丹群, 周祥敏, 等. 中国药业, 2013, 22(17): 28
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[14] Zheng Y B, Huang B F, Ren Y P. Chinese Journal of Chromatography, 2016, 34(7): 692 郑熠斌, 黄百芬, 任一平. 色谱, 2016, 34(7): 692
[15] Xu J H, Xue Y, Wang Y, et al. Chemistry and Bioengineering, 2017, 34(6): 65 徐静涵, 薛芸, 王彦, 等. 化学与生物工程, 2017, 34(6): 65
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[17] Wang D W, Wang X N, Feng M J, et al, Journal of Instrumental Analysis, 2014, 33(10): 1123 王东武, 王西宁, 丰梅君, 等. 分析测试学报, 2014, 33(10): 1123
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