目的:研究吡嘧司特钾片中杂质Ⅱ(相对分子质量286.081 44)的分子结构和产生路径,为药品处方改进提供建议。方法:开展吡嘧司特钾与羧甲淀粉钠的相容性研究,以HPLC检查杂质含量、以UPLC-HRMS分析杂质结构。HPLC条件:采用岛津Intersil ODS-SP色谱柱(150 mm×4.6 mm,5 μm),以0.1%三氟乙酸的水溶液-乙腈(84∶16)为流动相,检测波长257 nm,柱温40 ℃;UPLC-Q-Orbitrap HRMS条件:超高效液相色谱采用Waters ACQUITY HSS T3柱(100 mm×2.1 mm,1.7 μm),以水-甲醇-冰醋酸 (90∶10∶0.2)为流动相,质谱采用HESI离子源、正负离子检测模式,碎片分析借助MsFrontier 7.0软件。结果:通过相容性试验和质谱分析,阐明了吡嘧司特钾与辅料羧甲淀粉钠中残留的氯乙酸间发生的“固-固”化学反应,是造成片剂中生成杂质Ⅱ的根本原因。结论:部分仿制药企业的吡嘧司特钾片处方中选择羧甲淀粉钠作辅料可能存在产生杂质Ⅱ的风险,建议企业优化片剂处方,降低因原辅料不相容带来的安全性风险。
Objective: To study the molecular structure and formation route of impurity II (accurate molecular weight 286.081 44) in pemirolast potassium tablets, and to provide suggestion for improvement of preparation formulation. Methods: The compatibility study between pemirolast potassium and carboxymethyl starch sodium (CMS) was performed by using HPLC to determine the impurity content and UPLC-HRMS to characterize the structure of the impurity. HPLC was applied with a Shimadzu Intersil ODS-SP column (150 mm×4.6 mm, 5 μm) and eluted with aqueous solution of 0.1% trifluoroacetic acid-acetonitrile (84∶16) under the condition of detection wavelength 257 nm and column temperature 40 ℃. UPLC was applied with a Waters ACQUITY HSS T3 column (100 mm×2.1 mm, 1.7 μm) and eluted with water-methanol-glacial acetic acid (90∶10∶0.2). MS was applied with HESI source and positive/negative ion modes. Fragment analysis was carried out by MsFrontier 7.0 software. Results: Through compatibility test and MS analysis, it was clarified that the solid-solid chemical reaction between API and the residual chloroacetic acid in the excipient carboxymethyl starch sodium was the cause of the formation of impurity Ⅱ in the tablets. Conclusion: The selection of CMS as an excipient in the prescription of pemirolast potassium tablets by some generic pharmaceutical companies probably causes the risk of formation of impurity Ⅱ. It is recommended that the manufacturers optimize the tablet prescriptions and reduce the safety risks caused by the drug-excipient incompatibility.
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