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目的:基于高效液相色谱-离子阱质谱串联技术(HPLC-MS/MS)对原料药氨氯地平中未知杂质进行在线结构鉴定。方法:以甲酸铵水溶液-甲醇为流动相,经Waters X-Bridge C18柱(150 mm×4.6 mm,5μm)分离,通过ESI离子阱质谱获得相关色谱与一级与二级质谱谱图。结果:首先通过对氨氯地平主化合物及已知杂质的质谱裂解行为进行研究,提出了以二氢吡啶环为中心的retro-Diels-Alder(RDA)裂解机理。在此基础上,将未知杂质的质谱裂解谱图与已知化合物的相应谱图比较,基于质谱裂解的异同判断结构的异同,从而鉴定各未知杂质的结构。3个未知杂质分别为二甲酯式氨氯地平、甲酯异丙酯式氨氯地平、异丙酯乙酯式氨氯地平。结论:本研究提出了一条基于HPLC-MS/MS在线鉴定药物中未知杂质的研究思路与策略,对其他药物中杂质的研究同样具有借鉴作用。
OBJECTIVE: To identify the unknown structure of the unknown impurity in amlodipine based on high performance liquid chromatography-ion trap mass spectrometry (HPLC-MS / MS). Methods: Aqueous ammonium formate with methanol as mobile phase was separated on a Waters X-Bridge C18 column (150 mm × 4.6 mm, 5 μm). The related chromatograms, first-order and second-order spectra were obtained by ESI ion trap mass spectrometry. Results: The retro-Diels-Alder (RDA) cleavage mechanism centered on the dihydropyridyl ring was first proposed by mass spectrometric cleavage of the major amlodipine compound and its known impurities. On this basis, comparing the spectra of the unknown impurities with the corresponding spectra of the known compounds, the similarities and differences of the structures are judged based on the similarities and differences of the mass spectrometry cleavage to identify the structures of the unknown impurities. Three unknown impurities were dimethyl ester of amlodipine, isopropyl ester of amlodipine, isopropyl ester of amlodipine. Conclusion: This study presents an online method for identifying unknown impurities in pharmaceuticals based on HPLC-MS / MS. It also provides a reference for the study of impurities in other drugs.