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Current Pharmaceutical Analysis

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

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Research Article

Potential Impurities of Tigecycline: Synthesis, Isolation, Characterization and In Vitro Pharmacological Evaluation

Author(s): Selliamman Palaniyandi Nallusamy Sharavanan, Chidambaram Subramanian Venkatesan, Singaram Sathiyanarayanan and Senthamaraikannan Kabilan*

Volume 16, Issue 6, 2020

Page: [730 - 742] Pages: 13

DOI: 10.2174/1573412915666190225160030

Price: $65

Abstract

Background: Tigecycline is a known antibiotic in the tetracycline family and a chemical analog of minocycline. It may be used for the treatment against drug-resistant bacteria.

Methods: HPLC method was used for related substance analysis. The degraded impurities during the process were isolated and characterized by IR, HRMS (High Resolution Mass Spectrometry) and NMR spectral analysis.

Result: Four impurities of tigecycline, a broad spectrum antibacterial agent, were identified, synthesized and characterized. The in vitro biological evaluation of the isolated compounds showed significant antimicrobial and antioxidant properties to that of tigecycline. Apart from these, the tigecycline drug substance showed significant degradation under oxidation conditions.

Conclusion: The extensive investigational data confirm the structure of the four impurities. The specification limit for these impurities is applied based on the toxicological data. The antimicrobial activity revealed that the impurity 4 shows excellent activity towards both Gram-positive and Gram-negative bacteria when compared with tigecycline. The results obtained for DPPH (2,2-diphenyl-1- picrylhydrazyl) antioxidant activity concluded that the impurity 2 and the impurity 3 showed good antioxidant properties when compared with tigecycline. There was no activity observed on fungi for both isolated degradants as well as tigecycline.

Keywords: Tigecycline, potential impurities, NMR, in vitro antimicrobial, antioxidant activity, ICH.

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[1]
Rose, W.E.; Rybak, M.J. Tigecycline: first of a new class of antimicrobial agents. Pharmacotherapy, 2006, 26(8), 1099-1110.
[http://dx.doi.org/10.1592/phco.26.8.1099] [PMID: 16863487]
[2]
Kasbekar, N. Tigecycline: a new glycylcycline antimicrobial agent. Am. J. Health Syst. Pharm., 2006, 63(13), 1235-1243.
[http://dx.doi.org/10.2146/ajhp050487] [PMID: 16790575]
[3]
Nguyen, F.; Starosta, A.L.; Arenz, S.; Sohmen, D.; Dönhöfer, A.; Wilson, D.N. Tetracycline antibiotics and resistance mechanisms. Biol. Chem., 2014, 395(5), 559-575.
[http://dx.doi.org/10.1515/hsz-2013-0292] [PMID: 24497223]
[4]
Christine, M.S.; Keith, A.R.; Larry, H.D. A Novel Broad-Spectrum Antimicrobial: Pharmacology and Mechanism of Action Christine. Ann. Pharmacother., 2007, 41, 965-972.
[http://dx.doi.org/10.1345/aph.1H543]
[5]
Kaewpoowat, Q.; Ostrosky-Zeichner, L. Tigecycline : a critical safety review. Expert Opin. Drug Saf., 2015, 14(2), 335-342.
[http://dx.doi.org/10.1517/14740338.2015.997206] [PMID: 25539800]
[6]
Skrtić, M.; Sriskanthadevan, S.; Jhas, B.; Gebbia, M.; Wang, X.; Wang, Z.; Hurren, R.; Jitkova, Y.; Gronda, M.; Maclean, N.; Lai, C.K.; Eberhard, Y.; Bartoszko, J.; Spagnuolo, P.; Rutledge, A.C.; Datti, A.; Ketela, T.; Moffat, J.; Robinson, B.H.; Cameron, J.H.; Wrana, J.; Eaves, C.J.; Minden, M.D.; Wang, J.C.; Dick, J.E.; Humphries, K.; Nislow, C.; Giaever, G.; Schimmer, A.D. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell, 2011, 20(5), 674-688.
[http://dx.doi.org/10.1016/j.ccr.2011.10.015] [PMID: 22094260]
[7]
Guidance for Industry on Abbreviated New Drug Applications: Impurities in Drug Substances; Availability. Fed. Regist., 2009, 74, 34359-34360.
[8]
Guidance for industry Q3A (R2), Impurities in new drug substances, Proceedings of the International Conference on Harmonization (ICH) Guidelines. Geneva, 2006.
[9]
International Conference on Harmonization; revised guidance on Q3A impurities in new drug Substances; Availability. Notice. Fed. Regist, 2003.
[10]
Siddiqui, M.R.; AlOthman, Z.A.; Rahman, N. Analytical techniques in pharmaceutical analysis. a review. Arab. J. Chem., 2017, 10, S1409-S1421.
[http://dx.doi.org/10.1016/j.arabjc.2013.04.016]
[11]
AlOthman, Z.A.; Rahman, N.; Siddiqui, M.R. Review on pharmaceutical impurities, stability studies and degradation products. Rev. Adv. Sci. Eng., 2013, 2, 155-166.
[http://dx.doi.org/10.1166/rase.2013.1039]
[12]
Rahman, N.; Azmi, S.N.H.; Wu, H.F. The importance of impurity analysis in pharmaceutical products: an integrated approach. Accredit. Qual. Assur., 2006, 11, 69-74.
[http://dx.doi.org/10.1007/s00769-006-0095-y]
[13]
Okada, Y.; Okada, M. Scavenging effect of soluble proteins in broad beans on free radicals and active oxygen species. J. Agric. Food Chem., 1998, 46(2), 401-406.
[http://dx.doi.org/10.1021/jf970470l] [PMID: 10554253]
[14]
Marcocci, L.; Maguire, J.J.; Droy-Lefaix, M.T.; Packer, L. The nitric oxide-scavenging properties of Ginkgo biloba extract EGb 761. Biochem. Biophys. Res. Commun., 1994, 201(2), 748-755.
[http://dx.doi.org/10.1006/bbrc.1994.1764] [PMID: 8003011]
[15]
Marcocci, L.; Packer, L.; Droy-Lefaix, M.T.; Sekaki, A.; Gardès-Albert, M. Antioxidant action of Ginkgo biloba extract EGb 761. Methods Enzymol., 1994, 234, 462-475.
[http://dx.doi.org/10.1016/0076-6879(94)34117-6] [PMID: 7808320]
[16]
Green, L.C.; Wagner, D.A.; Glogowski, J.; Skipper, P.L.; Wishnok, J.S.; Tannenbaum, S.R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal. Biochem., 1982, 126(1), 131-138.
[http://dx.doi.org/10.1016/0003-2697(82)90118-X] [PMID: 7181105]
[17]
Ramabharathi, V.; Apparao, A.V.N.; Rajitha, G. Phytochemical investigation and evaluation of antibacterial and antioxidant activities of leaf-bud exudate of Tarennaasiatica (L.) Kuntze ex K. Schum. Indian J. Nat. Prod. Resour., 2014, 5(1), 48-51.
[18]
Gu, J.; Cai, P.; Gong, Y.; Ruppen, M.E.; Storz, T. Facile conversion of tetracycline antibiotics to 4,11a-bridged derivatives via oxidative mannich cyclization. J. Antibiot. (Tokyo), 2010, 63(12), 693-698.
[http://dx.doi.org/10.1038/ja.2010.119] [PMID: 20978515]

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