FORCED DEGRADATION STUDIES OF NILOTINIB HYDROCHLORIDE: ISOLATION, IDENTIFICATION & CHARACTERIZATION OF IMPURITIES
Abstract
Nilotinib hydrochloride is a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia was subjected to forced degradation studies and the samples were analyzed by utilizing the LCMS compatible HPLC methods. Nilotinib Hydrochloride was subjected to thermal, hydrolytic, oxidative, acidic, basic and photolytic degradation conditions as per the regulatory guidelines. The drug was degraded in oxidative, basic and acidic environments and stable in photolytic and thermal conditions. The main degradation impurity components produced through the forced degradation study were isolated for the identification and quantification in presence of these impurities in the stability studies of drug substances as well as drug products. The identified degradation components were separated by mass assisted auto-purification technique and subjected for the characterization by NMR (13C-NMR, 1H-NMR, HMBC and HSQC), HRMS and FT-IR experimentations. Degradation products obtained from oxidative, basic and acidic environments were isolated and identified by the advanced techniques as acid degradation product (DP-1) with molecular mass of 306.11 g/mol, empirical formula C17H14N4O2 with name as 4-methyl-3- (4 -(pyridine -3-yl) pyrimidin -2 -ylamino) benzoic acid. Base degradation product (DP-2) has molecular weight of 241.08 g/mol, molecular formula C11H10F3N3 with name as 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline.Oxidative degradation product (DP-3) has molecular weight of 545.18 g/mol, molecular formula C28H22F3N7O2 with name as 3-(2-(2-methyl-5-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenylcarbamoyl) phenylamino)pyrimidin-4-yl)pyridine1-oxide.
Keywords:
Nilotinib Hydrochloride, Forced degradation studies, Isolation, Characterization, NMR spectroscopy, High resolution mass spectroscopy.DOI
https://doi.org/10.25004/IJPSDR.2020.120516References
Kantarjian HM, Talpaz M. Definition of the accelerated phase of chronic myelogenous leukemia. J Clin Oncol. 1988; 6(1): 180-2.
DeRemer DL, Ustun C, Natarajan K. Nilotinib: a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous Leukaemia. Clinical Therapeutics. 2008; 30(11): 1956–75.
Kantarjian H, Giles F, Wunderle L, Bhalla K, et al. Nilotinib in Imatinib-resistant CML and Philadelphia chromosomepositive all. The New England Journal of Medicine. 2006; 354(24):2542–51.
Manley PW, Drueckes P, et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta. 2010;1804:445-53.
Weisberg E, Manley P, Mestan J, Cowan JS, Ray A, Griffin JD. AMN107 (nilotinib): A novel and selective inhibitor of BCR-ABL. Br J Cancer. 2006; 94:1765-9.
Kivikko M, Lehtonen L. Nilotinib Hydrochloride: a new inodilatory drug for the treatment of decompensated heart failure. Current Pharmaceutical Design. 2005; 11(4): 435-55.
Prenen H, Guetens G, et al. Cellular uptake of the tyrosine kinase inhibitors imatinib and AMN107 in gastrointestinal stromal tumor cell lines. Pharmacology. 2006; 77:11-6.
Singh S, Bakshi M. Guidance on conduct of stress tests to determine inherent stability of drugs. Pharmaceutical Technology Online. 2000;24: 1–14.
ICH harmonized tripartite guideline; Photostability testing of new drug substances and products Q1B; 1996.
Ramu I, Manikya Sastry T, Satyaveni S. Development and validation of Stability indicating HPLC method for the determination of Nilotinib hydrochloride in bulk and pharmaceutical dosage form. International Journal of Pharmacy and Pharmaceutical Sciences. 2016;8(9):41-8.
Xiaohong W, Yong L, Cuilin P, Huichun X, Man P, Tianyou Z, Yoichiro I. Preparative isolation and purification of chemical constituents of belamcanda by MPLC, HSCCC and prep-HPLC. J Liq Chromatogr Relat Technol. 2011;34(4): 241–57.
Sivasankar B. Instrumental methods of analysis. Oxford University Press, 2012.
Frank AS. Infrared Spectroscopy. In: Handbook of Instrumental Techniques for Analytical Chemistry. New Jersey, 1997.
Alsante KM, Hatajik TD, Lohr LL, Santafianos D, Sharp TR. Solving impurity/degradation problems: case studies. pp:380, In; handbook of Isolation and Characterization of impurities in Pharmaceutical, Ahuja S, Alsante editors, Academics Press, New York. 2003.
Nathan V M, Matthew A Wa, John A J, Barbara P K, Mosbah M K, Elizabeth H J. Preparative HPLC Method for the Purification of Sulforaphane and Sulforaphane Nitrile from Brassica oleracea. J Agric Food Chem 2001;49(4):1867-72.
ICH guidelines, Q1A (R2): Stability Testing of New Drug Substances and Products (revision2), International Conference on Harmonization.
Boccardi G. Oxidative susceptibility testing,: 220. In; pharmaceutical Stress testing-Predicting Drug Degradation; Baertschi SW, editors, Taylor and Francis, New York. 2005.
Ragine M. FDA Perspectives: scientific considerations of forced degradation studies in ANDA submissions. Pharmaceutical Technology. 2012; 36:73-80.
Manjusha ND, Priyanka AP, Sanjay DS, Priyanka SS. Review on Advance applications of FTIR Spectroscopy. Intl. J. Pharm. Sci. Rev. & Res. 2011;7(2): 29.
Ranjit S, Rehman Z. Current trends in forced degradation study for pharmaceutical product development. Journal of pharmaceutical and educational research. 2012; 2:54-63.
Brummer H. How to approach a forced degradation study. Life Sci Technol Bull. 2011;31:1–4.
Reynolds DW, Facchine KL, et al. Available guidance and best practices for conducting forced degradation studies. Pharm Technol. 2002;26(2):48–56.
Stability testing of new drug substances and products Q1A (R2), ICH Harmonised Tripartite Guideline, ICH, Geneva, Switzerland, (2003).
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