The anticancer drug ibrutinib was subjected to stress degradation studies under the ICH-prescribed hydrolytic, photolytic, oxidative and thermal stress conditions, and its degradation behavior was studied. A significant degradation was noted for the drug under acidic/alkaline hydrolytic, acid/alkaline photolytic, and oxidative conditions. The UPLC-UV/PDA studies revealed the generation of six degradation products (I–VI), and these were adequately resolved from the drug under the developed chromatographic conditions over a Kinetex® C18 (100 mm×4.6 mm; 2.6 μm) column employing isocratic elution method. Detection wavelength was selected as 289 nm. The UPLC-UV/PDA method conditions were extrapolated to UPLC-MS/TOF studies. All the six degradation products were found to be ionized in the total ion chromatogram, and the products could be identified and characterized from their mass spectral data. The possible degradation route of ibrutinib leading to generation of various products was also postulated.
DeeksED. Ibrutinib: A review in chronic lymphocytic leukaemia. Drugs2017; 77: 225–236.
2.
KapoorASinghPBeniwalS, et al.Ibrutinib: A comprehensive review of a promising drug. Clin Cancer Investig J2016; 5: 203–207.
3.
MolicaSMatutesETamC,et al.Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on. Hematol Oncol2020; 38: 129–136.
4.
CinarMHamedaniFMoZ, et al.Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by ibrutinib induces apoptosis. Leuk Res2013; 37: 1271–1277.
5.
VeeraraghavanSViswanadhaSThappaliS, et al.Simultaneous quantification of lenalidomide, ibrutinib and its active metabolite PCI-45227 in rat plasma by LC–MS/MS: Application to a pharmacokinetic study. J Pharm Biomed Anal2015; 107: 151–158.
6.
BeauvaisDGoossensJFBoyleE, et al.Development and validation of an UHPLC-MS/MS method for simultaneous quantification of ibrutinib and its dihydrodiol-metabolite in human cerebrospinal fluid. J Chromatogr B2018; 1093–1094: 158–166.
7.
RoodJJMDormansPJAvan HarenMJ, et al.Bioanalysis of ibrutinib, and its dihydrodiol-and glutathione cycle metabolites by liquid chromatography-tandem mass spectrometry. J Chromatogr B2018; 1090: 14–21.
8.
RoodJJMvan HoppeSSchinkelAH, et al.Liquid chromatography-tandem mass spectrometric assay for the simultaneous determination of the irreversible BTK inhibitor ibrutinib and its dihydrodiol-metabolite in plasma and its application in mouse pharmacokinetic studies. J Pharm Biomed Anal2016; 118: 123–131.
9.
YasuTMomoKYasuiH,et al.Simple determination of plasma ibrutinib concentration using high performance liquid chromatography. Biomed Chromatogr2019; 33: e4435.
10.
WeiLMXuZXLvPF, et al.A simple HPLC method for the determination of ibrutinib in rabbit plasma and its application to a pharmacokinetic study. Lat Am J Pharm2016; 35: 130–134.
11.
HepsebahNJRKumarAA. Bioanalytical method development and validation of ibrutinib in biological matrices by LC-MS/MS. Int J Pharm Pharm Sci2019; 11: 22–26.
12.
IqbalMShakeelFAnwerT. Simple and sensitive UPLC-MS/MS method for high-throughput analysis of ibrutinib in rat plasma: Optimization by Box-Behnken experimental design. J AOAC Int2016; 99: 618–625.
13.
DuPGuanYAnZ, et al.A selective and robust UPLC-MS/MS method for the simultaneous quantitative determination of anlotinib, ceritinib and ibrutinib in rat plasma and its application to a pharmacokinetic study. Analyst2019; 144: 5462–5471.
14.
SanthoshillendulaDhandempallyPShirishaV, et al.A new simple method development and validation of ibrutinib in bulk and pharmaceutical dosage form by RP-HPLC. Int J Pharm Biol Sci2019; 9: 36–46.
15.
UppalaVDivyaNCharishmaE, et al.Validated stability-indicating RP-HPLC method for determination of ibrutinib. Indo Am J Pharm Sci2016; 3: 324–330.
16.
MuneerSAhadHABonnothCK. A novel stability indicating analytical development and validation of a RP-HPLC assay method for the quantification of ibrutinib in bulk and its formulation. J Pharm Res2017; 11: 712–718.
17.
FouadMHelvensteinMBlankertB. Ultra high performance liquid chromatography method for the determination of two recently FDA approved TKIs in human plasma using diode array detection. J Anal Methods Chem2015; 2015: 215128.
18.
ReddyMRMishraKSureshR. Development and validation of a liquid chromatographic method for the determination of selected anticancer drugs in bulk and pharmaceutical formulations. Int J Pharma Res Health Sci2018; 6: 2303–2307.
19.
BinduGHAnnapurnaMM. A sensitive stability indicating RP-HPLC method for the determination of ibrutinib – an anti-cancer drug. Res J Pharm Tech2018; 11: 4587–4591.
20.
KapavarapuSGolkondaRChintalaR. Validation of stability indicating RP-HPLC method for the assay of ibrutinib in pharmaceutical dosage form. Anal Chem2016; 16: 7–19.
21.
KonduruNGundlaRKatariNK, et al.Development and validation of a stability-indicating method for ibrutinib: Identification and separation of degradation products, known and genotoxic impurities using RP-HPLC/PDA and QDa mass detectors. Anal Chem Lett2019; 10: 113–136.
22.
PrasadSSMohanGKBabuAN. A quality by design approach for development of simple and robust reversed phase stability indicating HPLC method for estimation of ibrutinib and its impurities. AnalMethods2019; 12: 1434–1445.
23.
ICH. Stability testing of new drug substances and products Q1A (R2). In: International Conference on Harmonisation, 06 February, 2003, Geneva: IFPMA.
24.
VajjhaSBommuluriVRumallaCS, et al.Degradation studies of ibrutinib under stress conditions: Characterization and structural elucidation of novel degradants. J Pharm Biomed Anal2019; 172: 9–17.
25.
MehtaLNavedTGroverP, et al.LC and LC-MS/MS studies for identification and characterization of new degradation products of ibrutinib and elucidation of their degradation pathway. J Pharm Biomed Anal2021; 194: 113768.
26.
ICH. Guidelines on Photostability Testing of New Drug Substances and Products. In: Proceeding of International Conference on Harmonisation, 06 November, 1996, Geneva: IFPMA.
27.
KoshyKTLachJL. Stability of aqueous solutions of n-acetyl p-aminophenol. J Pharm Sci1961; 50: 113–118.
28.
Al-RimaviFKharoafM. Analysis of chloramphenicol and its related compound 2-amino-1-(4-nitrophenyl)propane-1,3-diol by reversed-phase high-performance liquid chromatography with UV detection. Chromatogr Res Int2011; 2011: Article ID 482308.
29.
UsuiYSatoKTanakaM. Catalytic dihydroxylation of olefins with hydrogen peroxide: An organic-solvent- and metal-free system. Angew Chem Int Ed2003; 42: 5623–5625.
30.
GriffithJCJonesKMPiconS, et al.Alkene syn dihydroxylation with malonoyl peroxides. J Am Chem Soc2010; 132: 14409–14411.
31.
Terent’evAOBoyarinovaKANikishinGI. Oxidation of alkenes with hydrogen peroxide, catalyzed by boron trifluoride. synthesis of vicinal methoxyalkanols. Russ J Gen Chem2008; 78: 592–596.
32.
SharkeyWHMochelWE. Mechanism of the photoöxidation of amides. J Am Chem So1959; 81: 3000–3005.
33.
YoshidaHYuzawaHAokiaM, et al.Photocatalytic hydroxylation of aromatic ring by using water as an oxidant. Chem Commun2008; 38: 4634–4636.
34.
YamadaMKarlinKDFukuzimiS. One-step selective hydroxylation of benzene to phenol with hydrogen peroxide catalysed by copper complexes incorporated into mesoporous silica–alumina. Chem Sci2016; 7: 2856–2863.
35.
LahaSGuthyRG. Oxidation of aniline and other primary aromatic amines by manganese dioxide. Environ Sci Technol1990; 24: 363–373.
36.
WangJHeJZhiC, et al.Highly efficient synthesis of azos catalyzed by the common metal copper through oxidative coupling reactions. RSC Adv2014; 32: 16607–16611.
37.
HartauerKJArbuthnotGNBaertschiSW, et al.Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets: Identification and control of an oxidative degradation product. Pharm Dev Technol2000; 5: 303–310.
38.
QinXFrechP. Liquid chromatography/mass spectrometry (LC/MS) identification of photooxidative degradates of crystalline and amorphous MK-912. J Pharm Sci2001; 90: 833–844.
39.
ZhaoZZQinXZWuA,et al.Novel rearrangements of an N-oxide degradate formed from oxidation of a morpholine acetal substance P antagonist. J Pharm Sci2004; 93: 1957–1961.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
