Generic placeholder image

Current Pharmaceutical Analysis


ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

Research Article

Determination of Two Potential Genotoxic Impurities in Crisaborole API by UPLC-MS/MS

Author(s): Mengmeng Zhang and Qiaogen Zou*

Volume 19, Issue 6, 2023

Published on: 27 June, 2023

Page: [511 - 520] Pages: 10

DOI: 10.2174/1573412919666230609152143

Price: $65


Background: Atopic dermatitis (AD) is an allergic skin disease that can be inherited. Crisaborole is a specific drug developed to deal with this disease. The compounds of 4-(4- Bromo-3-formyl-phenoxy)-benzonitrile and 4-(4-(4-bromo-3-formylphenoxy)-3- formylphenoxy) benzonitrile are the representative impurities in the synthesis of Crisaborole active pharmaceutical in gradient (API). Owing to the genotoxic impurities that could lead to cancer and gene mutations, it is necessary to develop a simple, efficient, sensitive, and accurate method to detect these impurities. In this study, the 4-(4-Bromo-3-formyl-phenoxy)-benzonitrile and 4-(4-(4- bromo-3-formylphenoxy)-3-formylphenoxy)benzo- nitrile present in Crisaborole API were detected using UPLC-MS/MS.

Methods: The separation was made on a ZORBAX Eclipse XDB-Pheny column (4.6 mm ×75mm, 3.5 μm) with the mobile phase of acetonitrile solution containing 0.1% trifluoroacetic acid (A) and water containing 0.1% formic acid (B) in gradient elution mode. Quantification was performed using positive ion electrospray ionization (ESI), and the contents of two compounds were determined using the multiple reaction monitoring (MRM) modes.

Results: The quantitative analytical method was fully validated with respect to linearity (r > 0.9998), sensitivity, precision, accuracy (the average recovery of two impurities was 84.1% to 90.7%), and robustness.

Conclusion: Three batches of samples were detected by UPLC-MS/MS, indicating that the proposed approach was applicable for the quality evaluation of Crisaborole.

Keywords: UPLC-MS/MS, Crisaborole, genotoxic impurities, quality control, quantitative analysis, 4-(4-Bromo-3-formylphenoxy)- benzonitrile, 4-(4-(4-bromo-3-formylphenoxy)-3- formylphenoxy)benzonitrile.

« Previous
Gupta, D. Atopic dermatitis. Med. Clin. North Am., 2015, 99(6), 1269-1285, xii.
[] [PMID: 26476252]
Frazier, W.; Bhardwaj, N. Atopic dermatitis: Diagnosis and treatment. Am. Fam. Physician, 2020, 101(10), 590-598.
[PMID: 32412211]
Mandlik, D.S.; Mandlik, S.K. Atopic dermatitis: New insight into the etiology, pathogenesis, diagnosis and novel treatment strategies. Immunopharmacol. Immunotoxicol., 2021, 43(2), 105-125.
[] [PMID: 33645388]
Paller, A.S.; Tom, W.L.; Lebwohl, M.G.; Blumenthal, R.L.; Boguniewicz, M.; Call, R.S.; Eichenfield, L.F.; Forsha, D.W.; Rees, W.C.; Simpson, E.L.; Spellman, M.C.; Stein Gold, L.F.; Zaenglein, A.L.; Hughes, M.H.; Zane, L.T.; Hebert, A.A. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J. Am. Acad. Dermatol., 2016, 75(3), 494-503.e6.
[] [PMID: 27417017]
McDowell, L.; Olin, B. Crisaborole: A novel nonsteroidal topical treatment for atopic dermatitis. J. Pharm. Technol., 2019, 35(4), 172-178.
[] [PMID: 34861031]
Cheape, A.C.; Murrell, D.F. 2% Crisaborole topical ointment for the treatment of mild-to-moderate atopic dermatitis. Expert Rev. Clin. Immunol., 2017, 13(5), 415-423.
[] [PMID: 28290219]
Jarnagin, K.; Chanda, S.; Coronado, D.; Ciaravino, V.; Zane, L.T.; Guttman-Yassky, E.; Lebwohl, M.G. Crisaborole topical ointment, 2%: A nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis. J. Drugs Dermatol., 2016, 15(4), 390-396.
[PMID: 27050693]
Schlessinger, J.; Shepard, J.S.; Gower, R.; Su, J.C.; Lynde, C.; Cha, A.; Ports, W.C.; Purohit, V.; Takiya, L.; Werth, J.L.; Zang, C.; Vlahos, B. Safety, effectiveness, and pharmacokinetics of crisaborole in infants aged 3 to < 24 months with mild-to-moderate atopic dermatitis: A phase IV open-label study (CrisADe CARE 1). Am. J. Clin. Dermatol., 2020, 21(2), 275-284.
[] [PMID: 32212104]
Al-Sabti, B.; Harbali, J. Development and validation of an analytical method for quantitative determination of three potentially genotoxic impurities in vildagliptin drug material using HPLC‐MS. J. Sep. Sci., 2021, 44(13), 2587-2595.
[] [PMID: 33934507]
Szekely, G.; Amores de Sousa, M.C.; Gil, M.; Castelo, F.F.; Heggie, W. Genotoxic impurities in pharmaceutical manufacturing: Sources, regulations, and mitigation. Chem. Rev., 2015, 115(16), 8182-8229.
[] [PMID: 26252800]
Moorthy, M.K.; Ali, S.M.; Reddy, G.V.S. Development and validation of LC–QTOF–MS/MS method for the identification and determination of low levels of a genotoxic impurity, 4,6‐dichloro‐5‐nitro‐2‐(propylthio)pyrimidine in ticagrelor API. Biomed. Chromatogr., 2022, 36(4), e5336.
[] [PMID: 35023200]
Grigori, K.; Loukas, Y.L. Malenović A.; Samara, V.; Kalaskani, A.; Dimovasili, E.; Kalovidouri, M.; Dotsikas, Y. Chemometrically assisted development and validation of LC–MS/MS method for the analysis of potential genotoxic impurities in meropenem active pharmaceutical ingredient. J. Pharm. Biomed. Anal., 2017, 145, 307-314.
[] [PMID: 28709127]
Seeley, M.R.; Tonner-Navarro, L.E.; Beck, B.D.; Deskin, R.; Feron, V.J.; Johanson, G.; Bolt, H.M. Procedures for health risk assessment in Europe. Regul. Toxicol. Pharmacol., 2001, 34(2), 153-169.
[] [PMID: 11603958]
Guidelines for industry. Genotoxic and carcinogenic impurities in drug substances and products: recommended approaches. U.S. Department of Health and Human Services Food and Drug; US Food and Drug Administration, 2008.
Questions and answers on the 'Guideline on the limits of genotoxic impurities'; The European Agency for the Evaluation of Medicinal Products, EMEA Safety Working Party, 2010.
Guideline on the Limits of Genotoxic Impurities. The European Agency for the Evaluation of Medicinal Products; Committee for Medicinal Products, 2006.
Corrigan, D.K.; Whitcombe, M.J.; McCrossen, S.; Piletsky, S. Reichardt’s dye and its reactions with the alkylating agents 4-chloro-1-butanol, ethyl methanesulfonate, 1-bromobutane and Fast Red B - a potentially useful reagent for the detection of genotoxic impurities in pharmaceuticals. J. Pharm. Pharmacol., 2010, 61(4), 533-537.
[] [PMID: 19298702]
ICH Harmonised Guideline for Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7 In: International Council For Harmonisation Of Technicalrequirements For Pharmaceuticals For Human Use (ich); , 2017.
Venugopal, N.; Vijaya, B.R.A.; Gangadhar, R.K.; Madhavi, V.; Madhavi, G. Method development and validation study for quantitative determination of 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride a genotoxic impurity in pantoprazole active pharmaceutical ingredient (API) by LC/MS/MS. J. Pharm. Biomed. Anal., 2012, 70, 592-597.
[] [PMID: 22749172]
Xia, Y.Y.; Zou, Q.G.; Yang, Y.F.; Sun, Q.; Han, C.Q. Determination of impurities in perampanel bulk drugs by high- performance liquid chromatography and gas chromatography. Curr. Pharm. Anal., 2021, 17(7), 873-884.
ICH Harmonised Impurities : Guideline for Residual Solvents Q3C(R8). In: International Council for Harmonisation of Technical; ICH Expert Working Group, 2021.
Miller, E.C.; Miller, J.A. Mechanisms of chemical carcinogenesis. Cancer, 1981, 47(S5), 1055-1064.
[<1055:AID-CNCR2820471302>3.0.CO;2-3] [PMID: 7016297]
Miller, E.C.; Miller, J.A. Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer, 1981, 47(10), 2327-2345.
[<2327:AID-CNCR2820471003>3.0.CO;2-Z] [PMID: 7272889]
Benigni, R.; Bossa, C. Mechanisms of chemical carcinogenicity and mutagenicity: A review with implications for predictive toxicology. Chem. Rev., 2011, 111(4), 2507-2536.
[] [PMID: 21265518]
Chen, L.; Zhang, W.; Hu, S. Determination of genotoxic epoxide at trace level in drug substance by direct injection GC/MS. J. Pharm. Biomed. Anal., 2017, 146, 103-108.
[] [PMID: 28873359]
Kalauz, A.; Kapui, I. Determination of potentially genotoxic impurities in crotamiton active pharmaceutical ingredient by gas chromatography. J. Pharm. Biomed. Anal., 2022, 210, 114544.
[] [PMID: 34968997]
Lakka, N.S.; Kuppan, C.; Ravinathan, P.; Palakurthi, A.K. Development and validation of liquid chromatography–tandem mass spectrometry method for the estimation of a potential genotoxic impurity 2‐(2‐chloroethoxy)ethanol in hydroxyzine. Biomed. Chromatogr., 2022, 36(5), e5325.
[] [PMID: 34993972]
Al-Sabti, B.; Harbali, J. HPLC–MS analysis of four potential genotoxic impurities in alogliptin pharmaceutical materials. J. AOAC Int., 2022, 105(2), 362-369.
[] [PMID: 34849990]
Gao, P.; Zou, Q.G. Simple and rapid LC-MS/MS method for determination of perampanel in human plasma and application to bioequivalence study. Curr. Pharm. Anal., 2022, 18(10)
Cui, Y.; Li, Y.; Fan, L.; An, J.; Wang, X.; Fu, R.; Dong, Z. UPLC-MS/MS method for the determination of Lenvatinib in rat plasma and its application to drug-drug interaction studies. J. Pharm. Biomed. Anal., 2021, 206, 114360.
[] [PMID: 34508926]
Wang, R.; Zhu, Z.; Qiu, X.; Bai, L.; Guo, W.; Zuo, L.; Zhao, T.; Shan, G. Determination of epoxide impurity in sarpogrelate hydrochloride intermediate by UHPLC and column-switching liquid chromatography. J. Pharm. Biomed. Anal., 2019, 174, 57-62.
[] [PMID: 31154094]
Wang, T.; Yang, H.; Yang, J.; Guo, N.; Wu, G.; Xu, X.; An, M. Quantitative determination of four potential genotoxic impurities in the active pharmaceutical ingredients in TSD-1 using UPLC-MS/MS. Molecules, 2022, 27(13), 4129.
[] [PMID: 35807373]
Li, S.; Dong, L.; Tang, K.; Lan, Z.; Liu, R.; Wang, Y.; Wang, R.; Lin, H. Simultaneous and trace level quantification of two potential genotoxic impurities in valsartan drug substance using UPLC-MS/MS. J. Pharm. Biomed. Anal., 2022, 212, 114630.
[] [PMID: 35158183]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy