运用高分辨LC-PDA-QTOF-MS联用强降解研究方法调查盐酸帕罗西汀片中未知杂质峰  

Investigation of an unknown impurity in paroxetine hydrochloride tablets by LC-PDA-QTOF-MS in tandem with forced degradation studies

作　　者：周丽萍[1] 吕倩倩 郑乐伟 钟雪妮 万恒 李敏 林金生 ZHOU Li-ping;LÜQian-qian;ZHENG Le-wei;ZHONG Xue-ni;WAN Heng;LI Min;LIN Jin-sheng(Taizhou Vocational&Technical Institute,Medicinal&Pharmaceutical Technology College,Taizhou 318000,China;Zhejiang Huahai Pharmaceuticals Co.,Ltd.,Center of Excellence for Modern Analytical Technologies(CEMAT),Linhai 317024,China;College of Pharmaceutical Sciences,Zhejiang University,866 Yuhangtang Road,West Lake District,Hangzhou 310030,China;Zhejiang Huahai Pharmaceuticals Co.,Ltd,Drug Products Plant,Analytical Department of Non-sterile Drug Products,Linhai 317024,China)

机构地区：[1]台州职业技术学院医药与制药工程学院,台州318000 [2]浙江华海药业股份有限公司高等分析技术中心,临海317024 [3]浙江大学药学院西湖区余杭塘路866号,杭州310058 [4]浙江华海药业股份有限公司制剂分厂非无菌成品检测室,临海317024

出　　处：《药物分析杂志》2022年第9期1608-1617,共10页Chinese Journal of Pharmaceutical Analysis

基　　金：浙江省教育厅高等学校访问工程师校企合作项目(FG2020223);台州市科技计划项目(1901gy22)。

摘　　要：目的:采用高分辨LC-PDA-QTOF-MS联用强降解方法对盐酸帕罗西汀片检测过程中的未知峰进行调查,确定该未知杂质的结构及产生的根本原因,制定出该未知峰控制策略。方法:在LC-MS研究中,目标杂质(RRT 0.55杂质)与主成分帕罗西汀可以完全分离。通过高分辨LC-PDA-QTOF-MS方法确定目标杂质的紫外吸收光谱及一级、二级高分辨质谱数据,并与药物活性成分帕罗西汀进行比较,推测出目标杂质的可能结构,并根据基于目标杂质结构进行的强制降解研究,证明该杂质的产生机理,并提出它的控制措施。结果:通过LC-PDA-QTOF-MS试验结果,推测目标杂质为药物活性成分帕罗西汀与处方中的乳糖发生Maillard反应产生的杂质,并且通过试验确认,目标杂质在盐酸帕罗西汀片分析溶液制备过程中,配制溶液pH选择不当造成的。通过控制样品制备过程中稀释液的pH,并优化了样品溶液制备过程,此杂质的含量明显下降,并低于最终产品的报告限度(≤0.05%)。结论:盐酸帕罗西汀片中RRT 0.55未知杂质的产生大部分源于分析方法本身,不是产品中的真实杂质;通过优化分析方法过程中稀释液的pH,可以控制该未知峰的产生,从而准确分析盐酸帕罗西汀片的质量。Objective: To identify the structure and root cause of the unknown impurity in paroxetine hydrochloride tablet by LC-PDA-QTOF-MS. To prove the mechanism by forced degradation studies. To propose an effective control strategy to control the unknow impurity.Methods: The RRT 0.55 impurity that affected qualityof the final product of paroxetine hydrochloride tablets were well separated from the main peak by optimizing the LC-MS chromatography conditions. The structure of RRT 0.55 impurity was confirmed by LC-MS/MS and UV absorption spectra by comparing the differences between those of paroxetine and RRT 0.55 impurity. The fragment peaks and generation pathway were analyzed. Structure of this impurity and the formation mechanism was verified with the structure-based forced studies. Results: The RRT 0.55 impurity was identified as a paroxetine-lactose adduct by LC-PDA-QTOF-MS/MS which was generated by the Maillard reaction between paroxetine with lactose. By optimizing the pH of the diluent in the sample preparation procedure of paroxetine hydrochloride tablets, this impurity was significantly decreased to lower than the reported limit in the final product(≤0.05%). Conclusion: The unknown RRT 0.55 impurity in paroxetine hydrochloride tablets is mainly resulted from the solution degradation in the process of sample preparation and it is not the true impurity in paroxetine hydrochloride tablets. By optimizing the pH of the diluent in the sample preparation procedure of paroxetine hydrochloride tablet, generation of this unknown peak can be controlled, and the true level of this unknown impurity can be determined in the modified method.

关 键 词：盐酸帕罗西汀 MAILLARD反应 乳糖 溶液降解 液相色谱-质谱联用 帕罗西汀-乳糖加合物 

分 类 号：R917[医药卫生—药物分析学]