QUANTITATIVE DETERMINATION OF METHYL-4-CHLOROBUTYRATE, A POTENTIAL GENOTOXIC IMPURITY, CONTENT IN MOXIFLOXACIN HCL BY GC-EI-MS
DOI:
https://doi.org/10.22159/ijap.2024v16i5.51551Keywords:
Fluoroquinolone, Moxifloxacin, Methyl-4-Chlorobutyrate, Genotoxic impurity, Quality control, GC-EI-MSAbstract
Objective: Methyl-4-Chlorobutyrate (M4CB), a genotoxic impurity, was identified in the active pharmacological components of the fourth-generation fluoroquinolone, moxifloxacin (MXFN). There has not yet been a report on the analysis of the M4CB impurity content in the MXFN molecule. Consequently, a Gas Chromatography-Electron Ionization-Mass Spectrometry (GC-EI-MS) method was established that has the ability to identify and measure M4CB impurity content at ppm level.
Methods: The column exploited in M4CB impurity assay was a Dura Bond 624 (DB-624) type stationary column. Temperatures of 220 °C and 280 °C were consistently maintained at the injection and detection sites, respectively. The helium, as carrier gas, in split mode with ratio of 1:7 was used. The column's flow rate remained steady around 2.0 ml/min. The mass spectrometer was operated in Single Ion Monitoring (SIM) mode at m/z = 74.
Results: The impurity M4CB is generated during the manufacturing process of cyclopropanamine, which is an intermediary molecule in the manufacturing process of MXFN. This new GC-EI-MS approach can measure the M4CB at 0.9452 ppm in MXFN samples with a 500 mg/ml concentration following International Council for Harmonisation (ICH) standards. Very low quantification limits (0.9452 ppm), high linearity (range=0.945 ppm to 5.625 ppm; regression coefficient= 0.9999), and a reasonable recovery range (94.60-94.63%) were all provided by this new validated GC-EI-MS approach. Three batches were analysed for M4CB content by new GC-EI-MS approach and found that none of the batches contained M4CB impurity.
Conclusion: The GC-EI-MS approach has excellent applicability in the quality assurance testing of MXFN for M4CB content since it was adequate in terms of linearity, precision, sensitivity, accuracy, specificity, and robustness.
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References
Greenberg RG, Landersdorfer CB, Rivera Chaparro N, Harward M, Conrad T, Nakamura A. Population pharmacokinetics of moxifloxacin in children. Paediatr Drugs. 2022;24(2):163-73. doi: 10.1007/s40272-022-00493-3, PMID 35284983.
Obrink Hansen K, Hardlei TF, Brock B, Jensen Fangel S, Kragh Thomsen M, Petersen E. Moxifloxacin pharmacokinetic profile and efficacy evaluation in empiric treatment of community acquired pneumonia. Antimicrob Agents Chemother. 2015;59(4):2398-404. doi: 10.1128/AAC.04659-14, PMID 25666151.
Anon. Current management of acute bacterial rhinosinusitis and the role of moxifloxacin. Clin Infect Dis. 2005;41 Suppl 2:S167-76. doi: 10.1086/428057, PMID 15942883.
Chuchalin A, Zakharova M, Dokic D, Tokic M, Marschall HP, Petri T. Efficacy and safety of moxifloxacin in acute exacerbations of chronic bronchitis: a prospective multicenter observational study (Avanti). BMC Pulm Med. 2013;13:5. doi: 10.1186/1471-2466-13-5, PMID 23343427.
Wang H, Liu H, Lou M, Xu L, Zhang W, Jing L. Comprehensive clinical evaluation of moxifloxacin: a retrospective study. Med (Baltim). 2023;102(22):e33896. doi: 10.1097/MD.0000000000033896, PMID 37266643.
Szekely G, Amores de Sousa MC, Gil M, Castelo Ferreira F, Heggie W. Genotoxic Impurities in pharmaceutical manufacturing: sources regulations and mitigation. Chem Rev. 2015;115(16):8182-229. doi: 10.1021/cr300095f, PMID 26252800.
Reddy AV, Jaafar J, Umar K, Majid ZA, Aris AB, Talib J. Identification control strategies and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: a comprehensive review. J Sep Sci. 2015;38(5):764-79. doi: 10.1002/jssc.201401143, PMID 25556762.
Giordani A, Kobel W, Gally HU. Overall impact of the regulatory requirements for genotoxic impurities on the drug development process. Eur J Pharm Sci. 2011;43(1-2):1-15. doi: 10.1016/j.ejps.2011.03.004, PMID 21420491.
Alsante KM, Huynh Ba KC, Baertschi SW, Reed RA, Landis MS, Furness S. Recent trends in product development and regulatory issues on impurities in active pharmaceutical ingredient (API) and drug products. Part 2: safety considerations of impurities in pharmaceutical products and surveying the impurity landscape. AAPS PharmSciTech. 2014;15(1):237-51. doi: 10.1208/s12249-013-0061-z, PMID 24363207.
Lovsin Barle E, Winkler GC, Glowienke S, Elhajouji A, Nunic J, Martus HJ. Setting occupational exposure limits for genotoxic substances in the pharmaceutical industry. Toxicol Sci. 2016;151(1):2-9. doi: 10.1093/toxsci/kfw028, PMID 27207978.
Aparna K, Rachel KV, Narayana Rao KM. A rapid sensitive and accurate LCMS method for the determination of mutagenic impurities in moxifloxacin HCl. Rasayan J Chem. 2023;16(3):1780-8. doi: 10.31788/RJC.2023.1638349.
Djurdjevic P, Ciric A, Djurdjevic A, Stankov MJ. Optimization of separation and determination of moxifloxacin and its related substances by RP-HPLC. J Pharm Biomed Anal. 2009;50(2):117-26. doi: 10.1016/j.jpba.2009.03.029, PMID 19464135.
Vankalapati KR, Algete P, Boodida S. A rapid RP-HPLC stability indicating method development and validation of moxifloxacin hydrochloride related substances in finished dosage forms. Biomed Chromatogr. 2021;35(11):e5192. doi: 10.1002/bmc.5192, PMID 34110029.
Wu CS, Jia ZX, Ning BM, Zhang JL, Wu S. Separation and identification of moxifloxacin impurities in drug substance by high-performance liquid chromatography coupled with ultraviolet detection and fourier transform ion cyclotron resonance mass spectrometry. Chin Chem Lett. 2012;23(10):1185-8. doi: 10.1016/j.cclet.2012.09.001.
Li J, Yuan Y, Fan R, Su Q, Wang S, Zhou T. A Simple LC/MS/MS method for the determination of moxifloxacin n-sulfate in rat plasma and its application in a pharmacokinetic study. J AOAC Int. 2015;98(4):921-6. doi: 10.5740/jaoacint.14-254, PMID 26268973.
Krone N, Hughes BA, Lavery GG, Stewart PM, Arlt W, Shackleton CH. Gas chromatography-mass spectrometry (GC/MS) remains a pre-eminent discovery tool in clinical steroid investigations even in the era of fast liquid chromatography-tandem mass spectrometry (LC/MS/MS). J Steroid Biochem Mol Biol. 2010;121(3-5):496-504. doi: 10.1016/j.jsbmb.2010.04.010, PMID 20417277.
Apridamayanti P, Pratiwi L, Sari R. Gas chromatography study of n-hexane and chloroform fractions of ethanol extract of Melastoma malabathricum l. Int J Pharm Pharm Sci. 2022;14(3):40-6. doi: 10.22159/ijpps.2022v14i3.43801.
Raja EF, Paul JJP. GAS chromatography mass spectroscopy analysis and prediction of bioactivities in the chloroform extract of halymenia dilatata zanardini (red algae) collected from mandapam tamil nadu india. Asian J Pharm Clin Res. 2021;14(12):60-3. doi: 10.22159/ajpcr.2021.v14i12.43068.
Madriwala B, Jays J. Analytical method development and validation for estimation of residual solvents in gliclazide using gas chromatography. Int J Curr Pharm Sci. 2022;14(4):68-73. doi: 10.22159/ijcpr.2022v14i4.1998.
Chen X, Gu X, Yang J, Jiang Z, Deng J. Gas chromatography mass spectrometry technology: application in the study of inflammatory mechanism in COVID-19 patients. Chromatographia. 2023;86(2):175-83. doi: 10.1007/s10337-022-04222-3, PMID 36718226.
Ganesh P, RajuChBV N, Suman G. Rama Devi d, Basavaiah K. Quantitative determination of methyl-4-chlorobutyrate in nucleoside reverse transcriptase inhibitors by GCMS using electron ionization. World J Pharm Pharm Sci. 2023;12(12):716-26. doi: 10.20959/wjpps202312-26108.
Marques Dos Santos M, Cheriaux C, Jia S, Thomas M, Gallard H, Croue JP. Genotoxic effects of chlorinated disinfection by products of 1,3-diphenylguanidine (DPG): cell based in vitro testing and formation potential during water disinfection. J Hazard Mater. 2022;436:129114. doi: 10.1016/j.jhazmat.2022.129114, PMID 35739694.
Wu B, Zhang Y, You Y, Liang Y. Genotoxicity of chlorinated hydrophobic organic compounds extracted from a source of drinking water. Ecotoxicology and Environmental Safety. 2023;267(15):115598. doi: 10.1016/j.ecoenv.2023.115598.
ICH Guidelines, Validation of analytical procedures technical requirements for registration of pharmaceuticals for human use: text and Methodology. Vol. Q2. Geneva, Switzerland; 2005. p. R1.
Sharma S, Goyal S, Chauhan K. A review on analytical method development and validation. Int J App Pharm. 2018;10(6):8-15. doi: 10.22159/ijap.2018v10i6.28279.
Pekamwar SS, Kalyankar TM, Tambe BV. Validated RP-HPLC method for simultaneous estimation of cefixime and moxifloxacin in combined pharmaceutical dosage form. Int J Pharm Pharm Sci. 2014;6(11):84-8.
ICH Guidelines, Assessment and control of DNA reactive (mutagenic) IMPURITIES in pharmaceuticals to limit potential carcinogenic risk. Vol. M7. Geneva, Switzerland; 2017. p. R1.
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