Validation of the specificity of ICP-MS methods by ICH Q2 (R2) through spiking experiments cannot characterize the multi-atomic interference of complex high matrix samples, may affecting the method accuracy and reliability of results. This study demonstrates this issue by investigating the elemental impurities in lanthanum carbonate raw materials and use isotope ratio analysis to overcome this limitation to establishing an accurate ICP-MS method for 24 elemental impurities (listed in ICH Q3D). An Agilent 7900 ICP–MS was used with an automatic sampler for sample determination in He mode. The isotope ratio of elemental impurities in the spiked sample was analyzed to characterize polyatomic interference and select the exclusive mass number of elemental impurities. While the recovery rate of most elemental impurities met the requirements, that of selenium (default measurement mass number 78Se) exceeded the standard in the matric sample. The isotope ratio of Se (78Se/82Se) was much higher than the theoretical value, indicating that the response intensity of m/z 78 was formed by the combination of 78Se and other mass-to-charge ratio, such as LaOH2+ formed by the large amount of La in the matrix. Therefore, 82 was chosen as the mass number for Se. The validation results indicate the method has strong specificity, high accuracy, and is simple and feasible. This study provide technical support for the control of elemental impurities in lanthanum carbonate and isotope ratios can be used as a supplementary means of spiked recovery rate.

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