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Isolation, Identification and Characterization of Gefitinib Novel Degradation Products by NMR and HRMS, Method Development and Validation by UPLC
Corresponding Author(s) : Hima Bindu Gandham
Asian Journal of Chemistry,
Vol. 33 No. 8 (2021): Vol 33 Issue 8, 2021
Abstract
Gefitinib (GFT) sold under the brand name Iressa, is a medication used to treat certain type of breast, lung and other cancers, Gefitinib was subject to stress degradation under acidic, basic, peroxide mediated oxidation, photolytic and thermal degradation. The stress degradation was performed according to ICH guidelines Q1A(R2) and the drug was inert under thermal and photolytic conditions. One degradant is identified in acid hydrolysis referred as 7-methoxy-6-(3-morpholinopropoxy) quinazolin-4(3H)-one (GFT-DP1) and two degradants were formed in peroxide mediated hydrolysis referred as 4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-1-oxidoquinazolin-6-yl)oxy)-propyl)morpholine-4-oxide (GFT-DP2) and 4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-propyl)-morpholine-4-oxide (GFT-DP3). In present study, all the novel three degradation product structures were confirmed by HRMS and 1D (1H, 13C) and 2D (COSY, HSQC and HMBC) based on 1D and 2D NMR data proton and carbon chemical shift values assigned exactly for all degradation products. A stability indicating RP-UPLC method was developed and validated with shorter run time and this method was validated in terms of linearity, specificity, accuracy, LOD and LOQ.
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- M.J. Wieduwilt and M. M. Moasser, Cell Mol. Life Sci., 65, 1566 (2008); https://doi.org/10.1007/s00018-008-7440-8
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- ICH, Stability Testing of New Drug Substances and Products Q1A(R2), In: International Conference on Harmonisation, IFPMA, Geneva (2003).
- WHO, Draft Stability Testing of Active Pharmaceutical Ingredients and Pharmaceutical Products, World Health Organization, Geneva (2007).
- CPMP, Note for Guidance on Stability Testing: Stability Testing of Existing Active Substances and Related Finished Products, Committee for Proprietary Medicinal Products, EMEA: London (2002).
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- A. Sreedevi, A. Lakshmana Rao and L. Kalyani, Int. J. Pharm. Chem. Biol. Sci., 3, 1305 (2013)
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References
M.J. Wieduwilt and M. M. Moasser, Cell Mol. Life Sci., 65, 1566 (2008); https://doi.org/10.1007/s00018-008-7440-8
Z. Du and C.M. Lovly, Mol. Cancer, 17, 58 (2018); https://doi.org/10.1186/s12943-018-0782-4
G. Giaccone, Clin. Cancer Res., 10, 4233S (2004); https://doi.org/10.1158/1078-0432.CCR-040005
Y. Sako, S. Minoghchi and T. Yanagida, Nat. Cell Biol., 2, 168 (2000); https://doi.org/10.1038/35004044
ICH, Stability Testing of New Drug Substances and Products Q1A(R2), In: International Conference on Harmonisation, IFPMA, Geneva (2003).
WHO, Draft Stability Testing of Active Pharmaceutical Ingredients and Pharmaceutical Products, World Health Organization, Geneva (2007).
CPMP, Note for Guidance on Stability Testing: Stability Testing of Existing Active Substances and Related Finished Products, Committee for Proprietary Medicinal Products, EMEA: London (2002).
M. Bakshi and S. Singh, J. Pharm. Biomed. Anal., 28, 1011 (2002); https://doi.org/10.1016/S0731-7085(02)00047-X
A. Sreedevi, A. Lakshmana Rao and L. Kalyani, Int. J. Pharm. Chem. Biol. Sci., 3, 1305 (2013)
P.V.V. Satyanarayana and M. Murali, Int. J. Res. Pharm. Chem., 1, 2231 (2011).
S.K. Savale, Hygeia J. Drug Med., 10, 1 (2018); https://doi.org/10.15254/H.J.D.Med.10.2018.172
M. Zhao, C. Hartke, A. Jimeno, J. Li, P. He, Y. Zabelina, M. Hidalgo and S.D. Baker, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 819, 73 (2005); https://doi.org/10.1016/j.jchromb.2005.01.027
N.A.G. Lankheet, M.J.X. Hillebrand, H. Rosing, J.H.M. Schellens, J.H. Beijnen and A.D.R. Huitema, Biomed. Chromatogr., 27, 466 (2013); https://doi.org/10.1002/bmc.2814
P.P. Reddy, V.M. Balram and G.K. Mohan, Int. J. Chem. Res., 2, 6 (2012).
P. Kallepalli and M.M. Annapurna, Res. J. Pharm. Technol., 11, 3647 (2018); https://doi.org/10.5958/0974-360X.2018.00672.8