Validation of Reverse Phase High-performance Liquid Chromatography Analytical Method for Osimertinib Mesylate and its Degradation Products for Osimertinib Mesylate Tablets
Abstract
The purpose of this study is to develop an accurate, simple, and fast reverse-phase high-performance liquid chromatographic (RP-HPLC) method and validate for analyzing organic impurities in osimertinib mesylate (OSM) tablets. The developed method separates and validated for chloro impurity, hydroxy impurity, methoxy impurity, des-acrylic acid impurity, N-oxide, OSM dimer and OSM. The separation of all these impurities were achieved on inert sustain C18 (4.6×250) mm, 3 μ column, The mobile phase consists of 0.1% formic acid with pH to 6.50 adjusted with ammonium hydroxide and acetonitrile delivered in gradient elution mode. The analytes were monitored at 268 nm. Stress studies were performed to evaluate the capability of stability-indicating of this method. The OSM was observed to be stable under thermal, photolytic and neutral conditions. However, it is labile under acidic, basic and oxidative conditions. All the degradants are well resolved form the principle peak OSM. All the major degradation products were isolated and characterized through UHPLC-IMS-Q-TOF-MS. The method was validated as per International Conference on Harmonization (ICH) guidelines, and the validation included specificity, limit of detection (LoD), limit of quantification (LoQ), linearity, accuracy, precision, robustness, and solution stability for isolated impurities and OSM. The method was developed for this drug product with the purpose of properly defining the quality specification of the drug product or drug substance. This method can be incorporated in the monographs of USP, EP/BP, IP etc.
Keywords:
Osimertinib Mesylate (OSM), Method development, Method Validation, HPLC etcDOI
https://doi.org/10.25004/IJPSDR.2022.140611References
Australian Product Information TAGRISSO™ (Osimertinib Mesylate) Tablets. Doc ID-003300940, v5.0, Page 1‐30.
AZD9291 Mesylate: Activated Sludge Respiration Inhibition Test. April 2015. Smithers Viscient (ESG) Ltd. Study Number 3200658
Zhang H. Osimertinib making a breakthrough in lung cancer targeted therapy. OncoTargets and therapy. 2016;9:5489. Available from: https://doi:10.2147/OTT.S114722
Song Z, Jin Y, Ge Y, Wang C, Zhang J, Tang Z, Peng J, Liu K, Li Y, Ma X. Synthesis and biological evaluation of azole-diphenylpyrimidine derivatives (AzDPPYs) as potent T790M mutant form of epidermal growth factor receptor inhibitors. Bioorganic & Medicinal Chemistry. 2016 Nov 1;24(21):5505-12. Available from: https:// doi.org/10.1016/j.bmc.2016.09.001
Qin X, Li Z, Yang L, Liu P, Hu L, Zeng C, Pan Z. Discovery of new [1, 4] dioxino [2, 3-f] quinazoline-based inhibitors of EGFR including the T790M/L858R mutant. Bioorganic & Medicinal Chemistry. 2016 Jul 1;24(13):2871-81. Available from: https://doi.org/10.1016/j. bmc.2016.01.003
Xiao Q, Qu R, Gao D, Yan Q, Tong L, Zhang W, Ding J, Xie H, Li Y. Discovery of 5-(methylthio) pyrimidine derivatives as L858R/ T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors. Bioorganic & Medicinal Chemistry. 2016 Jun 15;24(12):2673-80. Available from: https://doi.org/10.1016/j. bmc.2016.04.032
Gao H, Yang Z, Yang X, Rao Y. Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors. Bioorganic & Medicinal Chemistry. 2017 Sep 1;25(17):4553-9. Available from: https://doi. org/10.1016/j.bmc.2017.06.004
https://www.drugbank.ca/drugs/DB09330
Gollapalli R, Singh G, Blinder A, Brittin J, Sengupta A, Mondal B, Patel M, Pati B, Lee J, Ghode A, Kote M. Identification of an adduct impurity of an active pharmaceutical ingredient and a leachable in an ophthalmic drug product using LC-QTOF. Journal of Pharmaceutical Sciences. 2019 Oct 1;108(10):3187-93. Available from: https://doi. org/10.1016/j.xphs.2019.06.009
Tapkir N, Soni F, Sahu AK, Jadav T, Tekade RK, Sengupta P. A comprehensive review on assessment and key control strategies for impurities in drug development with a special emphasis on post-marketing surveillance. Journal of Pharmaceutical Innovation. 2021 Nov 27:1-20. Available from: https://doi.org/10.1007/s12247- 021-09607-9
World Health Organization. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. WHO Technical report series. 2009;953:87-123.
Aquino I, Gutiérrez-Blanco E, Ocampo L, Gutiérrez L, Bernad-Bernad MJ, Sumano H. Anesthetic evaluation of a novel phospholipid-free 1% propofol microemulsion formulation in dogs. Veterinaria México. 2020 Jan 13;6(4):1-1.
Ali I, Naim L, Ghanem A, Aboul-Enein HY. Chiral separations of piperidine-2, 6-dione analogues on Chiralpak IA and Chiralpak IB columns by using HPLC. Talanta. 2006 Jun 15;69(4):1013-7. Available from: https://doi.org/10.1016/j.talanta.2005.12.004
Aboul-Enein HY, Ali I. Opt imizat ion strategies for HPLC enantioseparation of racemic drugs using polysaccharides and macrocyclic glycopeptide antibiotic chiral stationary phases. Il Farmaco. 2002 Jul 4;57(7):513-29. Available from: https://doi. org/10.1016/S0014-827X(02)01242-9
Aboul-Enein HY, Ali I. HPLC enantiomeric resolution of nebivolol on normal and reversed amylose based chiral phases. Die Pharmazie. 2001 Mar 1;56(3):214-6.
Thomas S, Shandilya S, Bharati A, Paul SK, Agarwal A, Mathela CS. Identification, characterization and quantification of new impurities by LC–ESI/MS/MS and LC–UV methods in rivastigmine tartrate active pharmaceutical ingredient. Journal of pharmaceutical and biomedical analysis. 2012 Jan 5;57:39-51. Available from: https:// doi.org/10.1016/j.jpba.2011.08.014
Bhutnar AD, Saple SR, Vaidya VV. Separation, Identification, Isolation and Characterization of Degradation Product of Osimertinib Tablets by UPLC-QTOF-MS/MS and NMR: Evaluation of In-Silico Safety Assessment for Osimertinib (OSM) and Degradation Product (DP). Advances in Biological Chemistry. 2021 Jan 13;11(1):15-29. Available from: https://DOI: 10.4236/abc.2021.111003
Saple SR, Bhutnar AD, Vaidya VV, Lohakare SS. Separation and Identification of Oxidative Degradation Products of Osimertinib Tablets by using HPLC, UPLC-QTOF-MS/MS and Evaluation of their in-silico Safety Assessment. World Journal of Research and Review. 2020;11(3). Available from: https://doi. org/10.31871/WJRR.
Bhutnar AD, Saple SR, Vaidya VV. Identification, Isolation and Characterization of Degradation Products (DPs) in Osimertinib Mesylate (OSM) Tablets by UHPLC-IMS-QTOF-MS, and NMR: Evaluation of Genotoxicity for OSM and DPs. Analytical Chemistry Letters. 2022 Jan 2;12(1):119-33. Available from: https://doi.org/ 10.1080/22297928.2021.2017796
Krishna Katta , Sivarao T , Mosesbabu J and Venugopala Rao D Trace Level Quantification of Genotoxic Impurity “3-Chloro-N-(2-((2- Dimethylamino) Ethyl) (Methyl) Amino)-4-Methoxy-5-((4-(1- Methyl-1hIndol-3-Yl) Pyrimidin-2-Yl) Amino) Phenyl) Propanamide” in Osimertinib Mesylate by UPLC-QDa Journal of Chemical and Pharmaceutical Research, 2019, 11(4):48-59.
Chakradhar T, Mondal S, Vanapalli GK. A new stability indicating RP-HPLC method for estimation of Osimertinib Mesylate. Journal of Drug Delivery and Therapeutics. 2019 Apr 15;9(2-s):391-5. Available from: https://doi.org/10.22270/jddt.v9i2-s.2733
Van Veelen A, van Geel R, de Beer Y, Dingemans AM, Stolk L, Ter Heine R, de Vries F, Croes S. Validation of an analytical method using HPLC–MS/MS to quantify osimertinib in human plasma and supplementary stability results. Biomedical Chromatography. 2020 Apr;34(4):e4771. Available from: https://doi.org/10.1002/ bmc.4771
Dong ST, Li Y, Yang HT, Wu Y, Li YJ, Ding CY, Meng L, Dong ZJ, Zhang Y. An accurate and effective method for measuring osimertinib by UPLC-TOF-MS and its pharmacokinetic study in rats. Molecules. 2018 Nov 6;23(11):2894. Available from: https://doi.org/10.3390/ molecules23112894
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