Stability indicating UPLC-MS/MS method for quantification and identification of cefepime and its degradants in API

Jabeen Bangalore Venkatappa Suma   

Open Access   

Published:  Jan 03, 2023

DOI: 10.7324/JAPS.2023.118104
Abstract

An analytical method was developed and validated for determining stability studies of the drug cefepime (CFP) by Ultra Performance Liquid Chromatography - Tandem Mass Spectrometer (UPLC-MS/MS). In this research, Ultra Performance Liquid Chromatography (UPLC) C18 ethylene hybrid column was used. About 0.2% formic acid in the water and acetonitrile (ACN), in 20:80 v/v ratios, was used as the mobile phase with a 0.15 ml/minute flow rate. In multiple reaction monitoring modes, positive electrospray ionization (ESI) was used. The chromatogram of standard Cefepime (CFP) was found to have a retention time of 0.82 ± 0.02 minutes. The degradation of CFP was tested under different stress conditions and the method was validated to meet the International Conference on Harmonization of Technical Requirement for Registration of Pharmaceuticals for Human Use guidelines. The retention time of the forced degraded solutions of CFP was found to be 0.76, 0.83, 0.81, and 0.82 minutes for forced acidic, oxidation, thermal, and neutral conditions, respectively. The MS/MS spectra for CFP at 179.15 and 241.33 ± 0.06 in different stress conditions (except basic) with retention times at 0.90 ± 0.02 and 0.84 ± 0.10 minutes indicate Cefepime degradant 1 (CD1) and Cefepime degradant 2 (CD2), respectively. The MS/MS spectra for CFP basic degradant (CD1) in the basic medium were obtained at an m/z ratio of 179.15. The research findings conclude that CFP was unstable with partial degradations in all conditions, and complete degradation in basic medium.


Keyword:     Cefepime fragmentation ICH guidelines liquid chromatography mass spectrometry


Citation:

Jabeen, Suma BV. Stability indicating UPLC-MS/MS method for quantification and identification of cefepime and its degradants in API. J Appl Pharm Sci, 2023. https://doi.org/10.7324/JAPS.2023.118104

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

Abd El Aziz Shama SA, Sharkawy AS El, Mobarez EA, Nassar SH. A simultaneous, validated RP-HPLC method for determination of eight cephalosporins in pharmaceutical formulations. Sys Rev Pharm, 2021; 12(3):646-53. Available via https://www.sysrevpharm.org/articles/ a-simultaneous-validated-rphplc-method-for-determination-of-eight-cephalosporins-in-pharmaceutical-formulations.pdf

Al Kamaly O. Review on characterization, properties, and analytical methods of cefepime. Int J Anal Chem, 2022; 6909528; doi:10.1155/2022/6909528 https://doi.org/10.1155/2022/6909528

Bajaj S, Singla D, Sakhuja, N. Stability testing of pharmaceutical products. J App Pharm Sci, 2012; 2(3):129-38; doi:10.73690952824/ JAPS.2012.2322

Bjergum MW, Barreto EF, Scheetz MH, Rule AD, Jannetto PJ. Stability and validation of a high-throughput LC-MS/MS method for the quantification of cefepime, meropenem, and piperacillin and tazobactam in serum. J Appl Lab Med, 2021; 6(5):1202-12; doi:10.1093/jalm/jfab036 https://doi.org/10.1093/jalm/jfab036

Connors KA, Amidon GL, Stella VJ. Chemical stability of pharmaceuticals. In: A handbook for pharmacists. 2nd edition, John Wiley & Sons, Inc, New York, NY, 1986.

Cosa G. Photodegradation and photosensitization in pharmaceutical products: assessing drug phototoxicity. Pure Appl Chem, 2004; 76(2):263-75; doi:10.1351/pac200476020263 https://doi.org/10.1351/pac200476020263

De Borba B, Hurum DC, Rohrer JS. Determination of cefepime and related compounds using HPLC with UV detection. Application Note, 2008. Available via https://www.chromatographyonline.com/view/ determination-cefepime-and-related compounds-using-hplc-uv-detection-1

Deidda R, Orlandini S, Hubert P, Hubert C. Risk-based approach for method development in pharmaceutical quality control context: a critical review. J Pharm Biomed Anal, 2018; 161:110-21; doi:10.1016/j. jpba.2018.07.050 https://doi.org/10.1016/j.jpba.2018.07.050

Dos Anjos MV, Possa E, da Silva Fonseca G, Bergoza L, dos Santos PR, Moura E Silva S, Tasso L. Development and validation of an LC- ESI-QTOF-MS method to measure cefepime in the plasma and peritoneal fluid of rats using microdialysis: application in a pilot pharmacokinetic study. Biomed Chromatogr, 2022; 36(11):e5470; doi:10.1002/bmc.5470 https://doi.org/10.1002/bmc.5470

El-Beltagy HE, Amin AS, El-Balkeny MN, Madkour SA. Simultaneous determination of cefepime, cefotaxime and ceftriaxone in pharmaceutical formulation by HPLC method. IOSR J Pharm Biol Sci, 2019; 14:81-7; doi:10.9790/3008-1401038187

El-Dars F, Elshater NS, Abd Elaziz SM. Analytical determination of cefepime residues in rabbit' muscles, liver and kidney using HPLC. Curr Sci Int, 2019; 4:699-706; doi:10.36632/csi/2019.8.4.10 https://doi.org/10.36632/csi/2019.8.4.10

Fage D, Deprez G, Fontaine B, Wolff F, Cotton F. Simultaneous determination of 8 beta-lactams and linezolid by an ultra-performance liquid chromatography method with UV detection and cross-validation with a commercial immunoassay for the quantification of linezolid. Talanta, 2021; 221:121641. https://doi.org/10.1016/j.talanta.2020.121641

Glish GL, Burinsky DJ. Hybrid mass spectrometers for tandem mass spectrometry. J Am Soc Mass Spectrom, 2008; 19(2):161-72. https://doi.org/10.1016/j.jasms.2007.11.013

ICH. ICH Q1A (R2) stability testing of new drug substances and products. In: International Conference on Harmonization, IFPMA, Geneva, Switzerland, 2003.

Isla A, Arzuaga A, Maynar J, Gascón AR, Solinís MA, Corral E, Pedraz JL. Determination of ceftazidime and cefepime in plasma and dialysate-ultrafiltrate from patients undergoing continuous veno-venous hemodiafiltration by HPLC. J Pharm Biomed Anal, 2005; 39(5): 996-1005. https://doi.org/10.1016/j.jpba.2005.05.027

Jabeen, Suma BV. Newly validated stability-indicating ultra-performance liquid chromatography-tandem mass spectrometry method for the estimation of ceftaroline fosamil by using a quadrupole mass detector. J Appl Pharm Sci, 2022; 12(6):215-23; doi:10.7324/JAPS.2022.120621 https://doi.org/10.7324/JAPS.2022.120621

Jagadeesh Kumar V, Badarinadh Gupta P, Pavan Kumar KSR, Prasada Rao KVV, Rao KR, Prasanna SJ, Kumar Sharma H, Mukkanti K. Identification and characterization of new degradation products of cefepime dihydrochloride monohydrate drug substance during stress stability studies. Anal Sci, 2010; 26(10):1081-6; doi:10.2116/analsci.26.1081 https://doi.org/10.2116/analsci.26.1081

Jiang M, Wang L, Ji R. Biotic and abiotic degradation of four cephalosporin antibiotics in a lake surface water and sediment. Chemosphere, 2010; 80(11), 1399-405. https://doi.org/10.1016/j.chemosphere.2010.05.048

Jiménez Palacios FJ, Callejón Mochón M, Jiménez Sánchez JC, Bello López MÁ, Guiráum Pérez A. Validation of an HPLC method for determination of cefepime (a fourth-generation cephalosporin). Determination in human serum, cerebrospinal fluid, and urine. Pharmacokinetic profiles. Chromatographia, 2005; 62, 355-61. https://doi.org/10.1365/s10337-005-0603-y

Kalyani L, Rao CVN. Stability indicating RP-HPLC method development and validation of cefepime and amikacin in pure and pharmaceutical dosage forms. Braz J Pharm Sci, 2018; 54(3):1-9; doi:10.1590/s2175-97902018000317258 https://doi.org/10.1590/s2175-97902018000317258

Kommana R, Kannabattula G, Gurrala S, Yeradesi VR, Durga PA. Quantification and stress degradation studies of cefepime/Tazobactam in dry injection form by an RP-HPLC method. Braz J Pharm Sci, 2014; 50(4):895-902; doi:10.1590/S1984-82502014000400025 https://doi.org/10.1590/S1984-82502014000400025

Lemke TL, Williams DA, Roche VF, Zito SW. Foye's principles of medicinal chemistry. 6th edition, Lippincott Williams & Wilkins, Philadelphia, PA, 2002.

Liu Y, Zhang J, Hu C. Validated LC-MS/MS method for simultaneous analysis of 21 cephalosporins in zebrafish for a drug toxicity study. Anal Biochem, 2018; 558:28-34. https://doi.org/10.1016/j.ab.2018.08.001

Mameli M, Vezzelli A, Verze' S, Biondi S, Motta P, Greco A, Michi M, Breda M. Liquid chromatography-tandem mass spectrometry for the simultaneous quantitation of enmetazobactam and cefepime in human plasma. J Pharm Biomed Anal, 2019; 174:655-62; doi:10.1016/j.jpba.2019.06.041 https://doi.org/10.1016/j.jpba.2019.06.041

Moorthy GS, Vedar C, Zane NR, Downes KJ, Prodell JL, DiLiberto MA, Zuppa AF. Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: application to pediatric pharmacokinetic study. J Pharm Biomed Anal, 2020; 179:113002. https://doi.org/10.1016/j.jpba.2019.113002

Nemutlu E, Kir S, Katlan D, Beksaç MS. Simultaneous multiresponse optimization of an HPLC method to separate seven cephalosporins in plasma and amniotic fluid: application to validation and quantification of cefepime, cefixime and cefoperazone. Talanta, 2009; 80(1):117-26. https://doi.org/10.1016/j.talanta.2009.06.034

Niessen WMA. Applications: small molecules. In: Liquid chromatography -mass chromatography. 3rd edition, Taylor & Francis, Boca Raton, London, NY, pp 385-6, 2010.

Niessen W, Ricardo CA. Fragmentation of antimicrobial compounds. In: Interpretation of MS-MS mass spectra of drugs and pesticide. 1st edition, John Wiley & Sons, Inc, Hoboken, NJ, pp 269-73, 2017.

Ocaña González JA, Jiménez Palacios FJ, Callejón Mochón M, Barragán De La Rosa FJ. Simultaneous determination of cefepime and grepafloxacin in human urine by high-performance liquid chromatography. J Pharm Biomed Anal, 2004; 36(1):117-23; doi:10.1016/j.jpba.2004.05.002 https://doi.org/10.1016/j.jpba.2004.05.002

Ohmori T, Suzuki A, Niwa T, Ushikoshi H, Shirai K, Yoshida S, Ogura S, Itoh Y. Simultaneous determination of eight β-lactam antibiotics in human serum by liquid chromatography-tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci, 2011; 879(15-16), 1038-42. https://doi.org/10.1016/j.jchromb.2011.03.001

Quadri SS, Sonwane LV, Poul BN, Kamshette SN. Review on stability indicating assay methods (SIAMs). PharmaTutor, 2014; 2(8):16- 31. Available via http://www.pharmatutorjournal.com/index.php/pt/article/ view/152

Rehm S, Rentsch KM. HILIC LC-MS/MS method for the quantification of cefepime, imipenem and meropenem. J Pharm Biomed Anal, 2020; 186:113289. https://doi.org/10.1016/j.jpba.2020.113289

Rodrigues DF, Salgado HRN. Development and validation of a green analytical method of RP-HPLC for quantification of cefepime hydrochloride in pharmaceutical dosage form: simple, sensitive and economic. Curr Pharm Anal, 2016; 12(4):306-14. https://doi.org/10.2174/1573412912666151221210921

Patil KR, Naik SK, Zope VS, Chavan RP, Yeole RD. Lc-Ms/ Ms method for the simultaneous determination of cefepime and tazobactam in dog plasma. Drug Anal Res, 2018; 2(1):36-45; doi:10.22456/2527- 2616.84357 https://doi.org/10.22456/2527-2616.84357

Sahu PK, Ramisetti NR, Cecchi T, Swain S, Patro CS, Panda J. An overview of experimental designs in HPLC method development and validation. J Pharm Biomed Anal, 2018; 147:590-611; doi:10.1016/j. jpba.2017.05.006 https://doi.org/10.1016/j.jpba.2017.05.006

Seraisso P, Lanot T, Baklouti S, Mané C, Ruiz S, Lavit M, De Riols P, Garrigues J-C, Gandia P. Evaluation of 4 quantification methods for monitoring 16 antibiotics and 1 beta-lactamase inhibitor in human serum by high-performance liquid chromatography with tandem mass spectrometry detection. J Pharm Biomed Anal, 2022; 219:114900; doi:10.1016/j. jpba.2022.114900 https://doi.org/10.1016/j.jpba.2022.114900

Shrestha B, Bhuyan NR, Sinha BN. Simultaneous determination of cefepime and tazobactam in injectables by ultra-high performance liquid chromatography method. Pharm Methods, 2014; 5(1):20-6; doi:10.5530/ phm.2014.1.4 https://doi.org/10.5530/phm.2014.1.4

Siddiqui MR, Malick T, Reddy KD, Negi PS, Yadav JS, Bhatnagar A, Chaudhary M, Singh R. High performance liquid chromatographic method for simultaneous determination of cefepime and sulbactam in pharmaceutical formulation (supime) and biological samples. Int J Pharm, 2010; 6(3):271-7. https://doi.org/10.3923/ijp.2010.271.277

Sun H, Xing H, Tian X, Zhang X, Yang J, Wang P. UPLC-MS/MS method for simultaneous determination of 14 antimicrobials in human plasma and cerebrospinal fluid: application to therapeutic drug monitoring. J Anal Methods Chem, 2022; 2022:7048605; doi:10.1155/2022/7048605 https://doi.org/10.1155/2022/7048605

Sundara Raj B, Punitha ISR, Krishnan S. Stability studies of cefepime hydrochloride by stability indicating RP-HPLC method. Int J Pharm Sci Nanotechnol, 2013; 6(3):2181-6; doi:10.37285/ijpsn.2013.6.3.10 https://doi.org/10.37285/ijpsn.2013.6.3.10

Sunitha N, Sindhura L, Thangabalan B, Babu S. Development and validation of RP-HPLC method for simultaneous estimation of cefepime and tazobactam in injection formulation. Asian J Pharm Anal, 2013; 3(4):131-7.

Van Vooren S, Verstraete AG. A sensitive and high-throughput quantitative liquid chromatography high-resolution mass spectrometry method for therapeutic drug monitoring of 10 β-lactam antibiotics, linezolid and two β-lactamase inhibitors in human plasma. Biomedical Chromatogr, 2021; 35(7):e5092; doi:10.1002/bmc.5092 https://doi.org/10.1002/bmc.5092

Waterman KC, Adami RC, Alsante KM, Antipas AS, Arenson DR, Carrier R, Hong J, Landis MS, Lombardo F, Shah JC, Shalaev E, Smith SW, Wang H. Hydrolysis in pharmaceutical formulations. Pharm Dev Technol, 2002; 7(2):113-46; doi:10.1081/PDT-120003494 https://doi.org/10.1081/PDT-120003494

Zander J, Maier B, Suhr A, Zoller M, Frey L, Teupser D, Vogeser M. Quantification of piperacillin, tazobactam, cefepime, meropenem, ciprofloxacin and linezolid in serum using an isotope dilution UHPLC-MS/ MS method with semi-automated sample preparation. Clin Chem Lab Med, 2015; 53(5):781-91; doi:10.1515/cclm-2014-0746 https://doi.org/10.1515/cclm-2014-0746

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