Objective: To establish limits and method for assay determination of 17 elemental impurities (Al、Cd、Cr、Cu、Fe、Pb、Mn、Hg、Mo、Ni、Sn、Zn、As、Co、V、 Sb、 Li) in methylene blue API in terms of the latest requirement of ICH Q3D, along with quality specification of methylene blue in EP and USP. Methods: Samples were analyzed by inductively coupled plasma mass spectroscopy (ICP-MS) after microwave digestion. The measuring mode was collision mode with He as the collision gas. The RF power was 1 550 W and the plasma gas flow was 15.0 L·min-1. The carrier gas was 1.05 L·min-1. The temperature of atomizing chamber was 2 ℃. The acquiring mode was jumping peak mode and the analytical mode was KED mode. The quantitative method was standard curve calibration corrected by internal standard. Results: The results of analytical method validation indicated that response of nitric acid solution and reagent blank solution was far lower than that of 30% limit solution, which demonstrated there was no quantitative interference.All the calibration curves of elemental impurities showed good linearity in the test concentration range(25%-200% limit concentration, r>0.999). Limits of detection (LOD) were 0.002-1.507 μg·g-1 and limits of quantitation (LOQ) were 0.006-4.567 μg·g-1. The spike recoveries were 82.4%-111.7%. The RSD of repeatability and intermediate precision were 1.1%-4.1% and 1.5%-6.0%, respectively. All results of validation were complied with the requirements of USP <233> and USP<730>. The assays of 17 element impurities in 3 batches of samples were all lower than the 30% limit,which satisfied the requirement of control threshold for elemental impurities in ICH Q3D. Conclusion: The established method is simple in operation, rapid in analysis, sensitive, accurate and precise, which is applicable for the quality control of 17 elemental impurities in methylene blue APIs.
LI Hao, GUAN Qing-lei, ZHENG Wen-feng, MA Li-bo
. Assay determination of 17 elemental impurities in methylene blue APIs[J]. Chinese Journal of Pharmaceutical Analysis, 2022
, 42(11)
: 1954
-1960
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DOI: 10.16155/j.0254-1793.2022.11.12
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