Research Article
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Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures

Year 2024, Volume: 7 Issue: 2, 55 - 66, 01.03.2024

Fadime Canbolat Ahmet Aydın

https://doi.org/10.19127/bshealthscience.1377252

Abstract

Nitrosamines have been classified as potent genotoxic agents for humans by the International Agency for Research on Cancer. Our study aimed to determine the levels of nitrosamine impurities that could be formed in the content of drugs under different temperature conditions during their shelf life using chromatographic analysis. Eleven drugs in pharmacies were subjected to long-term exposure at two different temperatures. Twelve nitrosamine impurities of all samples were performed using LC-MS/MS. When the impurity levels of the analyzed drugs were examined, no nitrosamine impurity was detected in any drugs. Our study revealed that if no impurity was detected under storage conditions, there was no impurity formation even when the temperature was increased. When impurity formation is effectively prevented during the manufacturing stage, the risk of impurity occurrence during the shelf-life of drugs belonging to the same group is estimated to be low.

Keywords

Drug Impurity LC-MS/MS Nitrosamine Toxicology

References

  • Abe Y, Yamamoto E, Yoshida H, Usui A, Tomita N, Kanno H, Masada S, Yokoo H, Tsuji G, Uchiyama N, Hakamatsuka T, Demizu Y, Izutsu K, Goda Y, Okuda H. 2020. Temperature-dependent formation of N-nitrosodimethylamine during the storage of ranitidine reagent powders and tablets. Chem Pharma Bullet, 68(10): 1008-1012. doi: 10.1248/cpb.c20-00431
  • Bharate SS. 2021. Critical analysis of drug product recalls due to nitrosamine impurities. J Med Chem, 64(6): 2923-2936. doi.org/10.1021/acs.jmedchem.0c02120
  • Chidella KS, Dasari VB, Anireddy J. 2021. Ultra-sensitive LC-MS/MS method for the trace level quantification of six potential genotoxic nitrosamine impurities in telmisartan. American J Analytical Chem, 12(6): 227-240. doi: 10.4236/ajac.2021.126014.
  • EMA. 2021. Assessment report on nitrosamine impurities in human medicinal products. European Medicines Agency EMA/369136/2020, Amsterdam, The Netherlands https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf 2021.
  • Golob N, Peterlin S, Roškar R. 2023. NDMA formation due to active ingredient degradation and nitrite traces in drug product. J Pharma Sci, 112 (5): 1277-1286. doi: 10.1016/j.xphs.2023.03.007
  • Hao G, Hu R, Wang X, Gao P, Wang L, Jiang M, Xin L, Tan G, Zhao Y, Sun F, Chu D, Lv J, You J, Huang F. Song X. 2023. N-Nitrosodimethylamine formation in metformin hydrochloride sustained-release tablets: Effects of metformin and hypromellose used in drug product formulation. J Pharma Biomed Analy, 222, 1-7. doi: 10.1016/j.jpba.2022.115066, 1-7.
  • Hu J, Christison T, Rohrer J. 2021. Determination of dimethylamine and nitrite in pharmaceuticals by ion chromatography to assess the likelihood of nitrosamine formation. Heliyon, 7(2): 1-8. doi: 10.1016/j.heliyon.2021.e06179.
  • Kao YT, Wang SF, Wu MH, Her SH, Yang YH, Lee CH, Lee HF, Lee AR, Chang LC, Pao LH. 2022. A substructure-based screening approach to uncover N-nitrosamines in drug substances. J Food Drug Analy, 30(1): 150-162. doi.org/10.38212/2224-6614.3400.
  • Lapo MIF. 2021. Risk assessment and mitigation of the presence of nitrosamine impurities in medicines (Doctoral dissertation), Pharmaceutical Engineering University of Lisbon, http://hdl.handle.net/10451/54117.
  • Li K, Ricker K, Tsai FC, Hsieh CJ, Osborne G, Sun M., Marder ME, Elmore S, Schmitz R, Sandy MS. 2021. Estimated cancer risks associated with nitrosamine contamination in commonly used medications. Inter J Environ Res Pub Health, 18(18): 2-13. doi:10.3390/ijerph18189465.
  • Mavis ME, Gursu GG, Cagatay NU. 2023. Development of a sensitive LC-APCI-MS/MS method for simultaneous determination of eleven nitrosamines in valsartan and irbesartan with a simple extraction approach. J Chromatography B, 1216 (123593): 1-13. doi: 10.1016/j.jchromb.2023.123593.
  • Monajjemzadeh F, Robertson TA. 2022. Influencing factors in N-nitrosodimethylamine (NDMA) impurity detection in ranitidine and possible reactivity of other histamine H2 receptor antagonists J Pharma Innovat, 17, 1053-1061. doi: 10.1007/s12247-021-09578-x.
  • Schlingemann J, Burns MJ, Ponting DJ, Avila CM, Romero NE, Jaywant MA, Graham FS, Ashworth IW, Stephanie S, Christoph S, Wilk A. 2023. The landscape of potential small and drug substance related nitrosamines in pharmaceuticals. J Pharmal Sci, 112 (5): 1287-1304.
  • Schmidtsdorff S, Schmidt AH. 2019. Simultaneous detection of nitrosamines and other sartan-related impurities in active pharmaceutical ingredients by supercritical fluid chromatography. J Pharma Biomed Analy, 174: 151-160. doi: 10.1016/j.jpba.2019.04.049.
  • Sung JH, Kwak IS, Park SK, Kim HI, Lim HS, Park HJ, Kim SH. 2010. Liquid chromatography-tandem mass spectrometry determination of N-nitrosamines released from rubber or elastomer teats and soothers. Food Additiv Contamin: Part A, 27 (12): 1745-1754. doi.org/10.1080/19440049.2010.508184.
  • Thresher A, Foster R, Ponting DJ, Stalford SA, Tennant RE, Thomas R. 2020. Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data. Regulatory Toxicol Pharma, 116 (104749): 4-10. doi: 10.1016/j.yrtph.2020.104749.
  • Tuesuwan B, Vongsutilers V. 2021. Nitrosamine contamination in pharmaceuticals: Threat, impact, and control. J Pharma Sci, 110(9): 3118-3128. doi.org/10.1016/j.xphs.2021.04.021.
  • USFDA. 2021. Information about nitrosamine impurities in medications. U.S. Food & Drug Administration (USFDA). https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications.
  • Vogel M, Norwig J. 2022. Analysis of genotoxic N-nitrosamines in active pharmaceutical ingredients and market authorized products in low abundance by means of liquid chromatography–tandem mass spectrometry. J Pharma Biomed Analy, 219 (114910): 1-10. doi: 10.1016/j.jpba.2022.114910.
  • Wohlfart J, Scherf-Clavel O, Kinzig M, Sorgel F, Holzgrabe U. 2021. The nitrosamine contamination of drugs, part 3: Quantification of 4-Methyl-1-nitrosopiperazine in rifampicin capsules by LC-MS/HRMS. J Pharma Biomed Analysis, 203 (114205): 1-6. doi: 10.1016/j.jpba.2021.114205.
  • Xu Q, Li Q, Belsky JL, Min D, Biba E, Gump E, Simpson JT. 2021. Development and validation of a single quadrupole LC/MS method for the trace analysis of six nitrosamine impurities in valsartan, 1-44. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3854535.
  • Yoon HJ, Kim JH, Seo GH, Park H. 2021. Risk of cancer following the use of N-nitrosodimethylamine (NDMA) contaminated ranitidine products: a nationwide cohort study in South Korea. J Clin Med, 10(1): 153, 1-18. doi: 10.3390/jcm10010153.

Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures

Year 2024, Volume: 7 Issue: 2, 55 - 66, 01.03.2024

Fadime Canbolat Ahmet Aydın

https://doi.org/10.19127/bshealthscience.1377252

Abstract

Nitrosamines have been classified as potent genotoxic agents for humans by the International Agency for Research on Cancer. Our study aimed to determine the levels of nitrosamine impurities that could be formed in the content of drugs under different temperature conditions during their shelf life using chromatographic analysis. Eleven drugs in pharmacies were subjected to long-term exposure at two different temperatures. Twelve nitrosamine impurities of all samples were performed using LC-MS/MS. When the impurity levels of the analyzed drugs were examined, no nitrosamine impurity was detected in any drugs. Our study revealed that if no impurity was detected under storage conditions, there was no impurity formation even when the temperature was increased. When impurity formation is effectively prevented during the manufacturing stage, the risk of impurity occurrence during the shelf-life of drugs belonging to the same group is estimated to be low.

Keywords

Drug Impurity LC-MS/MS Nitrosamine Toxicology

References

  • Abe Y, Yamamoto E, Yoshida H, Usui A, Tomita N, Kanno H, Masada S, Yokoo H, Tsuji G, Uchiyama N, Hakamatsuka T, Demizu Y, Izutsu K, Goda Y, Okuda H. 2020. Temperature-dependent formation of N-nitrosodimethylamine during the storage of ranitidine reagent powders and tablets. Chem Pharma Bullet, 68(10): 1008-1012. doi: 10.1248/cpb.c20-00431
  • Bharate SS. 2021. Critical analysis of drug product recalls due to nitrosamine impurities. J Med Chem, 64(6): 2923-2936. doi.org/10.1021/acs.jmedchem.0c02120
  • Chidella KS, Dasari VB, Anireddy J. 2021. Ultra-sensitive LC-MS/MS method for the trace level quantification of six potential genotoxic nitrosamine impurities in telmisartan. American J Analytical Chem, 12(6): 227-240. doi: 10.4236/ajac.2021.126014.
  • EMA. 2021. Assessment report on nitrosamine impurities in human medicinal products. European Medicines Agency EMA/369136/2020, Amsterdam, The Netherlands https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf 2021.
  • Golob N, Peterlin S, Roškar R. 2023. NDMA formation due to active ingredient degradation and nitrite traces in drug product. J Pharma Sci, 112 (5): 1277-1286. doi: 10.1016/j.xphs.2023.03.007
  • Hao G, Hu R, Wang X, Gao P, Wang L, Jiang M, Xin L, Tan G, Zhao Y, Sun F, Chu D, Lv J, You J, Huang F. Song X. 2023. N-Nitrosodimethylamine formation in metformin hydrochloride sustained-release tablets: Effects of metformin and hypromellose used in drug product formulation. J Pharma Biomed Analy, 222, 1-7. doi: 10.1016/j.jpba.2022.115066, 1-7.
  • Hu J, Christison T, Rohrer J. 2021. Determination of dimethylamine and nitrite in pharmaceuticals by ion chromatography to assess the likelihood of nitrosamine formation. Heliyon, 7(2): 1-8. doi: 10.1016/j.heliyon.2021.e06179.
  • Kao YT, Wang SF, Wu MH, Her SH, Yang YH, Lee CH, Lee HF, Lee AR, Chang LC, Pao LH. 2022. A substructure-based screening approach to uncover N-nitrosamines in drug substances. J Food Drug Analy, 30(1): 150-162. doi.org/10.38212/2224-6614.3400.
  • Lapo MIF. 2021. Risk assessment and mitigation of the presence of nitrosamine impurities in medicines (Doctoral dissertation), Pharmaceutical Engineering University of Lisbon, http://hdl.handle.net/10451/54117.
  • Li K, Ricker K, Tsai FC, Hsieh CJ, Osborne G, Sun M., Marder ME, Elmore S, Schmitz R, Sandy MS. 2021. Estimated cancer risks associated with nitrosamine contamination in commonly used medications. Inter J Environ Res Pub Health, 18(18): 2-13. doi:10.3390/ijerph18189465.
  • Mavis ME, Gursu GG, Cagatay NU. 2023. Development of a sensitive LC-APCI-MS/MS method for simultaneous determination of eleven nitrosamines in valsartan and irbesartan with a simple extraction approach. J Chromatography B, 1216 (123593): 1-13. doi: 10.1016/j.jchromb.2023.123593.
  • Monajjemzadeh F, Robertson TA. 2022. Influencing factors in N-nitrosodimethylamine (NDMA) impurity detection in ranitidine and possible reactivity of other histamine H2 receptor antagonists J Pharma Innovat, 17, 1053-1061. doi: 10.1007/s12247-021-09578-x.
  • Schlingemann J, Burns MJ, Ponting DJ, Avila CM, Romero NE, Jaywant MA, Graham FS, Ashworth IW, Stephanie S, Christoph S, Wilk A. 2023. The landscape of potential small and drug substance related nitrosamines in pharmaceuticals. J Pharmal Sci, 112 (5): 1287-1304.
  • Schmidtsdorff S, Schmidt AH. 2019. Simultaneous detection of nitrosamines and other sartan-related impurities in active pharmaceutical ingredients by supercritical fluid chromatography. J Pharma Biomed Analy, 174: 151-160. doi: 10.1016/j.jpba.2019.04.049.
  • Sung JH, Kwak IS, Park SK, Kim HI, Lim HS, Park HJ, Kim SH. 2010. Liquid chromatography-tandem mass spectrometry determination of N-nitrosamines released from rubber or elastomer teats and soothers. Food Additiv Contamin: Part A, 27 (12): 1745-1754. doi.org/10.1080/19440049.2010.508184.
  • Thresher A, Foster R, Ponting DJ, Stalford SA, Tennant RE, Thomas R. 2020. Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data. Regulatory Toxicol Pharma, 116 (104749): 4-10. doi: 10.1016/j.yrtph.2020.104749.
  • Tuesuwan B, Vongsutilers V. 2021. Nitrosamine contamination in pharmaceuticals: Threat, impact, and control. J Pharma Sci, 110(9): 3118-3128. doi.org/10.1016/j.xphs.2021.04.021.
  • USFDA. 2021. Information about nitrosamine impurities in medications. U.S. Food & Drug Administration (USFDA). https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications.
  • Vogel M, Norwig J. 2022. Analysis of genotoxic N-nitrosamines in active pharmaceutical ingredients and market authorized products in low abundance by means of liquid chromatography–tandem mass spectrometry. J Pharma Biomed Analy, 219 (114910): 1-10. doi: 10.1016/j.jpba.2022.114910.
  • Wohlfart J, Scherf-Clavel O, Kinzig M, Sorgel F, Holzgrabe U. 2021. The nitrosamine contamination of drugs, part 3: Quantification of 4-Methyl-1-nitrosopiperazine in rifampicin capsules by LC-MS/HRMS. J Pharma Biomed Analysis, 203 (114205): 1-6. doi: 10.1016/j.jpba.2021.114205.
  • Xu Q, Li Q, Belsky JL, Min D, Biba E, Gump E, Simpson JT. 2021. Development and validation of a single quadrupole LC/MS method for the trace analysis of six nitrosamine impurities in valsartan, 1-44. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3854535.
  • Yoon HJ, Kim JH, Seo GH, Park H. 2021. Risk of cancer following the use of N-nitrosodimethylamine (NDMA) contaminated ranitidine products: a nationwide cohort study in South Korea. J Clin Med, 10(1): 153, 1-18. doi: 10.3390/jcm10010153.
There are 22 citations in total.

Details

Primary Language English
Subjects Pharmaceutical Toxicology
Journal Section Research Article
Authors

Fadime Canbolat 0000-0001-6759-7735

Ahmet Aydın 0000-0003-3499-6435

Early Pub Date December 7, 2023
Publication Date March 1, 2024
Submission Date October 17, 2023
Acceptance Date November 28, 2023
Published in Issue Year 2024 Volume: 7 Issue: 2

Cite

APA Canbolat, F., & Aydın, A. (2024). Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures. Black Sea Journal of Health Science, 7(2), 55-66. https://doi.org/10.19127/bshealthscience.1377252
AMA Canbolat F, Aydın A. Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures. BSJ Health Sci. March 2024;7(2):55-66. doi:10.19127/bshealthscience.1377252
Chicago Canbolat, Fadime, and Ahmet Aydın. “Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures”. Black Sea Journal of Health Science 7, no. 2 (March 2024): 55-66. https://doi.org/10.19127/bshealthscience.1377252.
EndNote Canbolat F, Aydın A (March 1, 2024) Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures. Black Sea Journal of Health Science 7 2 55–66.
IEEE F. Canbolat and A. Aydın, “Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures”, BSJ Health Sci., vol. 7, no. 2, pp. 55–66, 2024, doi: 10.19127/bshealthscience.1377252.
ISNAD Canbolat, Fadime - Aydın, Ahmet. “Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures”. Black Sea Journal of Health Science 7/2 (March 2024), 55-66. https://doi.org/10.19127/bshealthscience.1377252.
JAMA Canbolat F, Aydın A. Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures. BSJ Health Sci. 2024;7:55–66.
MLA Canbolat, Fadime and Ahmet Aydın. “Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures”. Black Sea Journal of Health Science, vol. 7, no. 2, 2024, pp. 55-66, doi:10.19127/bshealthscience.1377252.
Vancouver Canbolat F, Aydın A. Determination of Nitrosamines in Various Pharmaceuticals at Variable Temperatures. BSJ Health Sci. 2024;7(2):55-66.
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