利伐沙班中金属催化剂及ICH控制元素杂质测定方法的建立

李萍; 王帆; 陈万勤; 丁芳芳; 艾婕; 王建

doi:10.13748/j.cnki.issn1007-7693.20232763

利伐沙班中金属催化剂及ICH控制元素杂质测定方法的建立

Establishment for the Determination of Impurities in Metal Catalysts and ICH Control Elements in Rivaroxaban

摘要

摘要:
目的根据人用药品技术要求国际协调理事会(International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use，ICH) Q3D最新要求，建立同时测定利伐沙班中金属催化剂及控制元素杂质的分析方法。
方法应用微波消解-电感耦合等离子体-质谱法(microwave digestion-inductively coupled plasma-mass spectrometry，MD-ICP-MS)，通过系列实验建立简便、快速的微波消解样品前处理方法，采用2 mL 15.1 mol·L⁻¹硝酸的微波消解体系，无需预消解，样品经消解后无需赶酸，直接定容即可进ICP-MS分析，无基质干扰。以钪(Sc)、铟(In)、锗(Ge)、铋(Bi)为内标，等离子功率1549 W，载气流量1.08 L·min⁻¹。
结果 8种元素杂质线性均良好(r 均>0.999)，检测限为0.001~0.059 ng·mL⁻¹，各浓度点平均回收率为80%~100% (n=3)，仪器精密度均<2%(n=6)。不同厂家的利伐沙班中金属催化剂及ICH控制元素杂质含量均符合ICH要求。
结论该方法速度快、干扰少、灵敏度高，可实现利伐沙班中元素杂质的准确定量测定，并简化了微波消解样品前处理方法，提高了检验效率，节省了检验成本，可推广应用到相似性质类别药品的微波消解样品前处理。

Abstract:
OBJECTIVE To develop a method for simultaneous determination of impurities in metal catalysts and control elements in rivaroxaban according to the latest requirements of International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH) Q3D.
METHODS Using microwave digestion-inductively coupled plasma-mass spectrometry(MD-ICP-MS), a simple and rapid method for sample pretreatment of microwave digestion was established through a series of experiments. The microwave digestion system of 2 mL 15.1 mol·L⁻¹ nitric acid was used without pre-digestion. After digestion, the sample could be directly analyzed by ICP-MS without acid removal and no matrix interference. Sc, In, Ge and Bi as the internal standard. Plasma power was set at 1549 W and carrier gas was set at 1.08 L·min⁻¹.
RESULTS The linear relationship of the eight element impurities was good(r>0.999). Detection limits were 0.001−0.059 ng·mL⁻¹. The average recovery of each concentration point was 80%−100%(n=3). The instruction precision were <2%(n=6). The contents of impurities in metal catalysts and ICH Control elements in rivaroxaban from different manufacturers comply with ICH requirement.
CONCLUSION The method has the advantages of high speed, less interference and high sensitivity, and can be used for accurate and quantitative determination of elemental impurities in rivaroxaban. The sample pretreatment method of microwave digestion is simplified, the test efficiency is improved, and the test cost is saved. It can be widely applied to the sample pretreatment of similar drugs.

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