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image of Head Space GC-MS/MS Method for Quantification of Five Nitrosoamine-Genotoxic Impurities in Metformin HCl

Abstract

Background

N-nitrosamines have recently been discovered in metformin hydrochloride and other generic drugs. To quantify the five N-nitrosamines in metformin hydrochloride, we devised sensitive and reliable multiple reactions monitoring mode-based GC-MS/MS technique, particularly, N-nitrosodiethy amine (NDEA), N-nitroso ethyl isopropylamine (NEIPA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodipropylamine (NDPA), as well as N-nitrosodibutylamine (NDBA).

Objective

To develop a sensitive, precise, and accurate MRM mode based GC-MS/MS method for the quantification of five N-nitrosamines in metformin hydrochloride and valídate as per ICH guidelines.

Methods

The settings for mass spectrometry and gas chromatography were optimized. With the linearity, sensitivity, specificity, accuracy, and precision of the parameter, the procedure was as per the recommendation of ICH: International Council for Harmonization guidelines.

Results

N-nitrosamines in metformin hydrochloride had detection and quantification limits of 0.001 ppm and 0.004 ppm, correspondingly. The obtained results were within the sensitivity limitations issued by the US Food and Drug Administration. The calibration curve's regression coefficients for five N-nitrosamines were over 0.99, demonstrating the process's good linearity. The retrievals of N-nitrosamines in metformin hydrochloride between 97.1 – 127.4%. The RSD (Relative Standard Deviation) was lower than 10% for both inter-day and intra-day precision studies.

Conclusion

The proposed method exhibited a rapid analysis capability, high accuracy, sensitivity, and precision, making it a trustworthy method for monitoring N-nitrosamines in metformin hydrochloride.

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2024-10-18
2024-11-26

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References

  1. Szekely G. Amores de Sousa M.C. Gil M. Castelo Ferreira F. Heggie W. Genotoxic impurities in pharmaceutical manufacturing: sources, regulations, and mitigation. Chem. Rev. 2015 115 16 8182 8229 10.1021/cr300095f 26252800
    [Google Scholar]
  2. Raman N.V.V.S.S. Prasad A.V.S.S. Ratnakar Reddy K. Strategies for the identification, control and determination of genotoxic impurities in drug substances: A pharmaceutical industry perspective. J. Pharm. Biomed. Anal. 2011 55 4 662 667 10.1016/j.jpba.2010.11.039 21193280
    [Google Scholar]
  3. Teasdale A. Elder D.P. Analytical control strategies for mutagenic impurities: Current challenges and future opportunities. Trends Analyt. Chem. 2014 103 2 28
    [Google Scholar]
  4. Rojas L.B.A. Gomes M.B. Metformin: An old but still the best treatment for type 2 diabetes. Diabetol. Metab. Syndr. 2013 5 1 6 10.1186/1758‑5996‑5‑6 23415113
    [Google Scholar]
  5. Nasri H. Rafieian-Kopaei M. Metformin: Current knowledge. J. Res. Med. Sci. 2014 19 7 658 664 25364368
    [Google Scholar]
  6. Umapathi P. Ayyappan J. Quine S.D. Quantitative determination of metformin hydrochloride in tablet formulation containing croscarmellose sodium as disintegrant by HPLC and UV spectrophotometry. Trop. J. Pharm. Res. 2012 11 1 107 116 10.4314/tjpr.v11i1.14
    [Google Scholar]
  7. Hassan S.S.M. Mahmoud W.H. Elmosallamy M.A.F. Othman A.H.M. Determination of metformin in pharmaceutical preparations using potentiometry, spectrofluorimetry and UV–visible spectrophotometry. Anal. Chim. Acta 1999 378 1-3 299 311 10.1016/S0003‑2670(98)00500‑5
    [Google Scholar]
  8. Hamdan I.I. Jaber A.K.B. Abushoffa A.M. Development and validation of a stability indicating capillary electrophoresis method for the determination of metformin hydrochloride in tablets. J. Pharm. Biomed. Anal. 2010 53 5 1254 1257 10.1016/j.jpba.2010.03.017 20395106
    [Google Scholar]
  9. Lakshmi K. Rajesh T. Sharma S. Simultaneous determination of Metformin and pioglitazone by reversed phase HPLC in pharmaceutical dosage forms. Int. J. Pharm. Pharm. Sci. 2009 1 162 166
    [Google Scholar]
  10. Kolte B.L. Raut B.B. Deo A.A. Bagool M.A. Shinde D.B. Simultaneous high-performance liquid chromatographic determination of pioglitazone and metformin in pharmaceutical-dosage form. J. Chromatogr. Sci. 2004 42 1 27 31 14965412
    [Google Scholar]
  11. Mohamed A.M.I. Mohamed F.A.F. Ahmed S. Mohamed Y.A.S. An efficient hydrophilic interaction liquid chromatographic method for the simultaneous determination of metformin and pioglitazone using high-purity silica column. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2015 997 16 22 10.1016/j.jchromb.2015.05.032 26079265
    [Google Scholar]
  12. Sharma R. Chaturvedi S.C. Sahoo P.K. Simultaneous estimation of metformin hydrochloride and pioglitazone hydrochloride by RPHPLC method from combined tablet dosage form. Indian J. Pharm. Sci. 2008 70 3 383 386 10.4103/0250‑474X.43010 20046754
    [Google Scholar]
  13. Vaingankar P.N. Amin P.D. Development and Validation of Stability-Indicating RP-HPLC Method for Simultaneous Determination of Metformin HCl and Glimepiride in Fixed-Dose Combination. Anal Chem Insights 2016 11 13 20 10.4137/ACI.S38137
    [Google Scholar]
  14. Marie A.A. Hammad S.F. Salim M.M. Elkhodary M.M. Kamal A.H. Deduction of the operable design space of RP-HPLC technique for the simultaneous estimation of metformin, pioglitazone, and glimepiride. Sci. Rep. 2023 13 1 4334 10.1038/s41598‑023‑30051‑x 36928591
    [Google Scholar]
  15. T H.K. D G.S. RP-HPLC method for simultaneous estimation of Metformin Hydrochloride and Canagliflozin in pharmaceutical formulation. Indian Drugs 2021 58 6 49 59 10.53879/id.58.06.10607
    [Google Scholar]
  16. EMA update on metformin diabetes medicines. 2019 Available from: https://www.ema.europa.eu/en/news/ema-update-metformin-diabetes-medicines
  17. Technical Fact Sheet—N Nitrosodimethylamine (NDMA). 2014 Available from: http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://nepis.epa.gov/Exe/ZyNET.exe/P100LTGG.TXT?ZyActionD=ZyDocument&Client=EPA&Index=2011+Thru+2015&Docs=&Query=&Time=&EndTime=&SearchMethod=1&TocRestrict=n&Toc=&TocEntry=&QField=&QFieldYear=&QFieldMonth=&QFieldDay=&IntQFieldOp=0&ExtQFieldOp=0&XmlQuery=&File=D%3A%5Czyfiles%5CIndex%20Data%5C11thru15%5CTxt%5C00000014%5CP100LTGG.txt&User=ANONYMOUS&Password=anonymous&SortMethod=h%7C-&MaximumDocuments=1&FuzzyDegree=0&ImageQuality=r75g8/r75g8/x150y150g16/i425&Display=hpfr&DefSeekPage=x&SearchBack=ZyActionL&Back=ZyActionS&BackDesc=Results%20page&MaximumPages=1&ZyEntry=1&SeekPage=x&ZyPURL
  18. Brendler S.Y. Tompa A. Hutter K.F. Preussmann R. Pool-Zobel B.L. In vivo and in vitro genotoxicity of several N -nitrosamines in extrahepatic tissues of the rat. Carcinogenesis 1992 13 12 2435 2441 10.1093/carcin/13.12.2435 1473254
    [Google Scholar]
  19. Vecchia C.L. DʼAvanzo B. Airoldi L. Braga C. Decarli A. Nitrosamine intake and gastric cancer risk. Eur. J. Cancer Prev. 1995 4 6 469 474 10.1097/00008469‑199512000‑00005 8580782
    [Google Scholar]
  20. Yang J. Marzan T.A. Ye W. Sommers C.D. Rodriguez J.D. Keire D.A. Quantitative LC-HRMS Analytical Procedures for the Analysis of N-Nitrosodimethylamine in Metformin. AAPS J. 2020 22 4 89 10.1208/s12248‑020‑00473‑w 32613429
    [Google Scholar]
  21. Tummala S.R. Amgoth K.P. Development of GC-MS/MS Method for Simultaneous Estimation of Four Nitrosoamine Genotoxic Impurities in Valsartan. Turk. J. Pharm. Sci. 2022 19 4 455 461 10.4274/tjps.galenos.2021.17702 36047600
    [Google Scholar]
  22. Zmysłowski A. Książek I. Szterk A. N-Nitrosodimethylamine Contamination in the Metformin Finished Products. Molecules 2020 25 22 5304 10.3390/molecules25225304 33202951
    [Google Scholar]
  23. Yüksel B. Şen N. Development and validation of a GC-FID method for determination of cocaine in illicit drug samples. Marmara Pharm. J. 2018 22 4 511 518
    [Google Scholar]
  24. Öncü T. Yüksel B. Binay E. Şen N. LC-MS/MS Investigation of nitrosamine impurities in certain Sartan group medicinal products available in Istanbul, Türkiye. Ann. Pharm. Fr. 2024 82 1 72 83 10.1016/j.pharma.2023.08.002 37567559
    [Google Scholar]
  25. ICH Harmonised Tripartite Guideline. Q2(R1): Validation of analytical procedures: Text and methodology. 2005 Available from: https://database.ich.org/sites/default/files/Q2%28R1%29%20Guideline.pdf
  26. Dasgupta S. Dhyani V. Vyas S. Churley M. Quantification of Nitrosamine Impurities in Metformin Using Agilent GC/MS/MS Instrumentation. 2020 Available from: https://www.agilent.com/cs/library/applications/application-nitrosamine-metformin-gc-ms-ms-5994-2419en-agilent.pdf
/content/journals/cpa/10.2174/0115734129332940240919113159
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Head Space GC-MS/MS Method for Quantification of Five Nitrosoamine-Genotoxic Impurities in Metformin HCl
Bentham Science Publishers ; https://doi.org/10.2174/0115734129332940240919113159
/content/journals/cpa/10.2174/0115734129332940240919113159
/content/journals/cpa/10.2174/0115734129332940240919113159
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  • Article Type:     Research Article
Keywords: N-nitrosodibutylamine (NDBA). genotoxic impurity ; N-nitrosodipropylamine (NDPA) ; Metformin hydrochloride ; N-nitroso ethyl isopropylamine (NEIPA) ; GC-MS/MS ; N-nitrosodiisopropylamine (NDIPA) ; N-nitrosodiethy amine (NDEA)

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