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

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.