Objective: To establish the methods for the determination of four genotoxic impurities namely methyl chloride, ethyl chloride, acetamide and 4-chloro-1-butanol in the specification for N2-(2-(dimethylamino) ethyl)-N2-methyl-N5-(4-(1-methyl-1H-indol-3-yl) pyrimidin-2-yl)-6-(2,2,2- trifluoroethoxy) pyridine-2,3,5-triamine (AST 2815), the key intermediate of furmonertinib mesilate, which reduced the residual risk in final product as an in-process control. Methods: The gas chromatography-hydrogen flame ionization detection (GC-FID) method was established for the simultaneous determination of methyl chloride, ethyl chloride and acetamide in the key intermediate AST 2815 of furmonertinib mesilate and gas chromatography-tandem mass spectrometry(GC-MS/MS) method for the determination of 4-chloro-1-butanol in AST 2815. Results: Four impurities indicated good linearity between peak areas and concentration in the range of 5.246-104.9, 5.228-104.6, 2.034-40.68 and 0.016 05-0.321 1 μg·mL-1, respectively, and the r values were all above 0.999. The LOQ of methyl chloride, ethyl chloride, acetamide and 4-chloro-1-butanol was calculated as 0.016%, 0.016%, 0.041%, 0.000 054% and the LOD was 0.005 2%, 0.005 2%, 0.020% and 0.000 018%, respectively. The average recoveries (n=9) were 92.8%, 95.0%, 98.6% and 95.1% and the RSD (n=9) was 2.9%, 1.4%, 3.3% and 5.4%, respectively. The four genotoxic impurities were all not detected in samples from six different batches. Conclusion: The established methods are both simple, rapid, sensitive and accurate, which are applicable for quantification of these four genotoxic impurities in the key intermediate AST 2815. The article can also be referenced for trace analysis of these four genotoxic impurities in other drug substances and drug products.
WU Yang, ZHANG Qiang, XU Qi, LIANG Chun-qing, HUANG Yi-wen
. Determination of four genotoxic impurities in intermediate of furmonertinib mesilate*[J]. Chinese Journal of Pharmaceutical Analysis, 2022
, 42(7)
: 1170
-1177
.
DOI: 10.16155/j.0254-1793.2022.07.09
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