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Detection of Two Genotoxic Impurities in Drug Substance and Preparation of Imatinib Mesylate by LC–MS/MS

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Abstract

As a potential DNA damaging substance, genotoxic impurities have been concerned by regulatory authorities in various countries. Two genotoxic impurities were found in imatinib mesylate which was a classical small molecule inhibitor of tyrosine kinase, and the analysis method has never been reported. A LC–MS/MS method was developed for the analysis of two genotoxic impurity materials: N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine (IMA) and N-(2-methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine (IMN). The HPLC method utilized an ACQUITY UPLC HSS T3 C18 (150 × 2.1 mm, 1.7 μm) maintained at 40 °C. The mobile phase consisted of 0.02 M ammonium formate buffer (pH 3.4) and acetonitrile (containing 0.05% formic acid) in gradient elution mode. Detection was performed by triple quadrupole mass spectrometry fitted with ESI probe functioning in the positive ion mode and the following m/z 278/106 and 308/262 were used as qualifier and quantifier transitions. Flow rate was 0.4 mL min−1. The validation data demonstrated that the method had high sensitivity and selectivity. A linear calibration curve (correlation coefficient, r > 0.998) was obtained at the concentration range of 0.02–35.27 and 0.02–28.86 ng mL−1, respectively. The LOD of IMA in drug substances, tablets, and capsules were 0.0039, 0.0043, and 0.0044 ng mL−1, and LOD of IMN were 0.0034, 0.0035, and 0.0036 ng mL−1, respectively. Precision and accuracy were within the acceptable limit. The drug substances, tablets, and capsules from three manufacturers were used for inspection and all samples met the requirements. The developed LC–MS/MS method is robust and can be applied to detect the genotoxic impurities in imatinib mesylate.

Graphic Abstract

Mixed solution of Imatinib, IMA and IMN. A new LC-MS/MS method was developed for the analysis of two genotoxic impurities materials: N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine and N-(2-methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine (IMN)

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Acknowledgements

This work was supported by the Foundation and Advanced Research Project of Chongqing Science and Technology Bureau (cstc2018jscx-mszd0280, cstc2017shms-xdny0033) and the National Major Scientific and Technological Special Project of the Ministry of Science and Technology of China (2017ZX09101001).

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Authors and Affiliations

  1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China

    Dong Wang, Jing Wang & Jianhua Wang

  2. Chemistry Laboratory, Chongqing Institute for Food and Drug Control, Chongqing, 401121, China

    Lijun Luo, Jing Liang, Deng Xu, Haixia Feng & Linggao Zeng

  3. NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing, 401121, China

    Lijun Luo, Jing Liang, Deng Xu, Haixia Feng & Linggao Zeng

  4. Southwest Pharmacological Limited Company, Chongqing, 400715, China

    Yue Peng

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  1. Dong Wang
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Wang, D., Luo, L., Peng, Y. et al. Detection of Two Genotoxic Impurities in Drug Substance and Preparation of Imatinib Mesylate by LC–MS/MS. Chromatographia 83, 821–828 (2020). https://doi.org/10.1007/s10337-020-03903-1

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