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Drug Res (Stuttg) 2023; 73(08): 431-440
DOI: 10.1055/a-2081-4232
Review

Nitrosamine Impurities in Herbal Formulations: A Review of Risks and Mitigation Strategies

Nunavath Raja Shekhar
1   Department of Pharmaceutical Analysis, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
,
Krishnaveni Nagappan
1   Department of Pharmaceutical Analysis, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
,
Madhu Tanya Singh
2   Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
,
S. P. Dhanabal
3   Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
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Abstract

Nitrosamines are a class of chemical compounds that have been found to be impurities in a variety of pharmaceutical products. These impurities have raised concerns due to their potential carcinogenic effects. Recent studies have identified nitrosamines as impurities in a number of pharmaceutical products including angiotensin II receptor blockers (ARBs) and proton pump inhibitors (PPIs). The presence of nitrosamines in these products has led to recalls and market withdrawals. In addition to pharmaceuticals, nitrosamines have also been found in some herbal medicines particularly those containing traditional Chinese medicinal ingredients. The presence of nitrosamines in herbal formulations poses a significant risk to public health and highlights the need for quality control and regulations in the herbal drug industry. The present review article aims to discuss nitrosamine impurities (NMI) prominent causes, risks and scientific strategies for preventing NMI in herbal formulations. The primary objective of this study is to examine the origins of nitrosamine contamination in herbal formulations, the risks associated with these contaminants, and the methods for reducing them. The significance of thorough testing and examination before releasing herbal products to the public is also emphasized. In conclusion, the presence of nitrosamines is not limited to pharmaceutical products and poses a significant threat to the safety of herbal drugs as well. Adequate testing and extensive research are crucial for producing and distributing herbal medicines to the general population.

Key words

carcinogenicity - herbal formulations - nitrosamine impurities - quality control - synthetic phyto active constituents


Publication History

Received: 03 February 2023

Accepted: 14 April 2023

Article published online:
24 July 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Beard JC, Swager TM.. An Organic Chemist’s Guide to N-Nitrosamines: Their Structure, Reactivity, and Role as Contaminants. J Org Chem 2021; 86: 2037-57
    CrossrefPubMedSearch in Google Scholar
  • 2 Li K, Ricker K, Tsai FC.. Estimated cancer risks associated with nitrosamine contamination in commonly used medications. Int J Environ Res Public Health 2021; 18: 9465
    CrossrefPubMedSearch in Google Scholar
  • 3 Cintya H, Silalahi J, de Lux Putra E.. Analysis of nitrosamines in processed meat products in Medan city by liquid chromatography-mass spectrometry. J Med Sci 2019; 7: 1382-87
    CrossrefPubMedSearch in Google Scholar
  • 4 Niklas AA, Herrmann SS, Pedersen M.. The occurrence of volatile and non-volatile N-nitrosamines in cured meat products from the Danish market. J Food Chem 2022; 378: 132046
    CrossrefPubMedSearch in Google Scholar
  • 5 Abdullah ATM, Khan TA, Sharif M.. Determination of dietary exposure and extraction efficiency of nitrosamine from cooked meat. Curr Res Food Sci 2022; 5: 491-97
    CrossrefPubMedSearch in Google Scholar
  • 6 Wu Y, Qin L, Chen J.. Nitrite, biogenic amines and volatile N-nitrosamines in commercial Chinese traditional fermented fish products. Food Addit Contam Part B Surveill 2022; 15: 10-19
    CrossrefPubMedSearch in Google Scholar
  • 7 Jireš J, Douša M.. Nitrites as precursors of N-nitrosation in pharmaceutical samples – A trace level analysis. J Pharm Biomed Anal 2022; 213: 114677
    CrossrefPubMedSearch in Google Scholar
  • 8 Mayer A, Rindelaub J, Miskelly GM.. Nitrosamine formation from the reaction of methamphetamine with gaseous nitrous acid. Drug Test Anal 2022; 14: 474-480
    CrossrefPubMedSearch in Google Scholar
  • 9 Borths CJ, Burns M, Curran T.. Nitrosamine Reactivity: A Survey of Reactions and Purge Processes. Org Process Res Dev 2021; 25: 1788-1801
    CrossrefPubMedSearch in Google Scholar
  • 10 Chan TH, Tsoi MF, Yung Cheung BM.. Cancer Risk of Angiotensin II Receptor Blocker Valsartan: A Population-based Study. J Cardiovasc Pharmacol 2022; 79: 577-82
    CrossrefPubMedSearch in Google Scholar
  • 11 Thresher A, Foster R, Ponting DJ.. Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data. Regul Toxicol Pharmacol 2020; 116: 104749
    CrossrefPubMedSearch in Google Scholar
  • 12 Nagendla NK, Shaik H, Balasubramanyam S.. Development, Validation, and Estimation of Measurement Uncertainty for the Quantitative Determination of Nitrosamines in Sartan Drugs Using LC-APCI-MS/MS. SSRN Electronic Journal 2022;
    CrossrefPubMedSearch in Google Scholar
  • 13 Vogel M, Norwig J.. Analysis of Genotoxic N-Nitrosamines in Active Pharmaceutical Ingredients and Market Authorized Products in Low Abundance by Means of Liquid Chromatography – Tandem Mass Spectrometry. SSRN Electronic Journal 2022;
    CrossrefPubMedSearch in Google Scholar
  • 14 Jung JW, Kim UJ, Yu WJ.. Probabilistic cancer risk assessment for dietary intake of seven nitrosamine chemicals in Korea. Human and Ecological Risk Assessment 2021; 28: 1-12
    CrossrefPubMedSearch in Google Scholar
  • 15 Schmidtsdorff S, Neumann J, Schmidt AH.. Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development. Arch Pharm (Weinheim) 2022; 355: 1-10
    CrossrefPubMedSearch in Google Scholar
  • 16 Boltres B.. Evaluating Nitrosamines from Elastomers in Pharmaceutical Primary Packaging. J Pharm Sci Technol 2022; 76: 136-150
    CrossrefPubMedSearch in Google Scholar
  • 17 Fritzsche M, Blom G, Keitel J.. NDMA analytics in metformin products: Comparison of methods and pitfalls. European Journal of Pharmaceutical Sciences 2022; 168: 106026
    CrossrefPubMedSearch in Google Scholar
  • 18 Robles H.. Nitrosamines. Encyclopaedia of Toxicology 2005; 249-250
    CrossrefPubMedSearch in Google Scholar
  • 19 Ruepp R, Frötschl R, Bream R.. The EU Response to the Presence of Nitrosamine Impurities in Medicines. Front Med (Lausanne) 2021; 8: 782536
    CrossrefPubMedSearch in Google Scholar
  • 20 Dobariya U, Chauhan N, Patel H.. Nitrosamine Impurities: Origin, Control and Regulatory Recommendations. International Journal of Drug Regulatory Affairs 2021; 9: 77-80 10.22270/ijdra.v9i2.472
    CrossrefPubMedSearch in Google Scholar
  • 21 Roberts SW, Lennard A, Mohan G.. Meeting Report: N-Nitrosamine Impurity Control Strategies in the Pharmaceutical and Biotechnology Industries. AAPS J 2021; 2394
    CrossrefPubMedSearch in Google Scholar
  • 22 Wachtel-Galor S, Benzie IFF.. Herbal medicine: An introduction to its history, usage, regulation, current trends, and research needs. Second. Herbal Medicine: Biomolecular and Clinical Aspects; 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2011: Chapter 1.
    Search in Google Scholar
  • 23 Rafieian-Kopaei M, Sewell RDE.. The history and ups and downs of herbal medicines usage. J HerbMed Pharmacol 2014; 3: 1-3
    PubMedSearch in Google Scholar
  • 24 Ravi S, Bharadvaja N.. Market Analysis of Medicinal Plants in India. Curr Pharm Biotechnol 2019; 20: 1172-1180
    CrossrefPubMedSearch in Google Scholar
  • 25 Welz AN, Emberger-Klein A, Menrad K.. Why people use herbal medicine: Insights from a focus-group study in Germany. BMC Complement. Altern Med 2018; 18: 92
    CrossrefPubMedSearch in Google Scholar
  • 26 Prabhakar P, Mamoni B.. Technical problems, regulatory and market challenges in bringing herbal drug into mainstream of modern medicinal practices. Res J Biotechnol 2021; 16: 212-222
    PubMedSearch in Google Scholar
  • 27 Kostova I.. Synthetic and natural coumarins as cytotoxic agents. Curr Med Chem Anticancer Agents 2005; 5: 29-46
    CrossrefPubMedSearch in Google Scholar
  • 28 Girme A, Saste G, Balasubramaniam AK.. Assessment of Curcuma longa extract for adulteration with synthetic curcumin by analytical investigations. J Pharm Biomed Anal 2020; 191: 113603
    CrossrefPubMedSearch in Google Scholar
  • 29 Bienaymé H, Hulme C, Oddon G.. Maximizing synthetic efficiency: multi-component transformations lead the way. Chemistry – A European Journal 2000; 6: 3321-9 10.1002/1521-3765(20000915)6:18<3321: aid-chem3321>3.0.co;2-a
    CrossrefPubMedSearch in Google Scholar
  • 30 Fukaya K, Kodama K, Tanaka Y.. Synthesis of paclitaxel. Construction of the ABCD ring and formal synthesis. Org Lett 2015; 17: 2574-2577
    CrossrefPubMedSearch in Google Scholar
  • 31 Murphy MB, Kumar P, Bradley AM.. Synthesis and evaluation of etoposide and podophyllotoxin analogs against topoisomerase IIα and HCT-116 cells. Bioorg & Med Chem 2020; 28: 115773
    CrossrefPubMedSearch in Google Scholar
  • 32 Sun JS, Liu H, Guo XH.. The chemical synthesis of aryltetralin glycosides. Org Biomol Chem 2016; 14: 1188-1200
    CrossrefPubMedSearch in Google Scholar
  • 33 Huang X, Wang M. You Q. Synthesis, mechanisms of action, and toxicity of novel aminophosphonates derivatives conjugated irinotecan in vitro and in vivo as potent antitumor agents. Eur J Med Chem 2020; 189: 112067
    CrossrefPubMedSearch in Google Scholar
  • 34 Tan H, Wang G, Li J.. Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor. Bioorg & Med Chem 2015; 23: 118-125
    CrossrefPubMedSearch in Google Scholar
  • 35 Liu Q, Huang G, Liu M.. A Formal Synthesis of Camptothecin via a Photocatalytic Decarboxylative Radical Addition. Eur J Org Chem 2019; 2019: 6024-27
    CrossrefPubMedSearch in Google Scholar
  • 36 Miyazaki T, Yokoshima S, Simizu S.. Synthesis of (+)-vinblastine and its analogues. Org Lett 2007; 9: 4737-4730
    CrossrefPubMedSearch in Google Scholar
  • 37 Ishikawa H, Colby DA, Seto S.. Total synthesis of vinblastine, vincristine, related natural products, and key structural analogues. J Am Chem Soc 2009; 131: 4904-4916
    CrossrefPubMedSearch in Google Scholar
  • 38 Basmadjian C, Zhao Q, Bentouhami E.. Cancer wars: Natural products strike back. Front Chem 2014; 2: 20
    CrossrefPubMedSearch in Google Scholar
  • 39 Chen B, Liu X, Hu YJ.. Enantioselective total synthesis of (-)-colchicine, (+)-demecolcinone and metacolchicine: Determination of the absolute configurations of the latter two alkaloids. Chem Sci 2017; 8: 4961-4966
    CrossrefPubMedSearch in Google Scholar
  • 40 Su Z, Zhang Q, Zhao Q.. Synthesis and properties of sildenafil isostere. Arch Pharm (Weinheim) 2021; 354: 202100145
    CrossrefPubMedSearch in Google Scholar
  • 41 Xiao S, Shi XX, Xing J.. Synthesis of tadalafil (Cialis) from l-tryptophan. Tetrahedron Asymmetry 2009; 20: 2090-2096
    CrossrefPubMedSearch in Google Scholar
  • 42 Zhang J, Zhang C, Liu A.. Synthesis of Icariin-Zinc and its Protective Effect on Exercise Fatigue and Reproductive System Related Glands in Male Rats. Front Pharmacol 2021; 12: 611722
    CrossrefPubMedSearch in Google Scholar
  • 43 Ren Z, Lv M, Xu H.. Osthole: Synthesis, Structural Modifications, and Biological Properties. Mini Rev Med Chem 2022; 22: 2124-2137
    CrossrefPubMedSearch in Google Scholar
  • 44 Yücel NT, Kandemir Ü, Özkay ÜD.. 5-HT1A serotonergic, α-adrenergic and opioidergic receptors mediate the analgesic efficacy of vortioxetine in mice. Molecules 2021; 26: 3242
    CrossrefPubMedSearch in Google Scholar
  • 45 Jeffery JE, Kerrigan F, Miller TK.. Synthesis of sibutramine, a novel cyclo butyl alkylamine useful in the treatment of obesity, and its major human metabolites. J Chem Soc 1996; 1: 2583-89
    CrossrefPubMedSearch in Google Scholar
  • 46 Reddy GO, Sarma MR, Chandrasekhar B.. A study and identification of potential by-products of sibutramine. Org Pro Res Dev 1999; 3: 488-492
    CrossrefPubMedSearch in Google Scholar
  • 47 Zajac MA, Zakrzewski AG, Kowal MG.. A novel method of caffeine synthesis from uracil. Synth Commun 2003; 33: 3291-3297
    CrossrefPubMedSearch in Google Scholar
  • 48 Teng Q, Zhao Y, Lu Y.. Synthesis, Characterization, and Catalytic Study of Caffeine-Derived N-heterocyclic Carbene Palladium Complexes. Organometallics 2022; 41: 161-168
    CrossrefPubMedSearch in Google Scholar
  • 49 Liu J, Wang L, Harvey-White J.. A biosynthetic pathway for anandamide. Proc Natl Acad Sci 2006; 103: 13345-50
    CrossrefPubMedSearch in Google Scholar
  • 50 Ma Q, Liu L, Zhao S.. Biosynthesis of vanillin by different microorganisms: a review. World J Microbiol Biotechnol 2022; 38: 1-9
    CrossrefPubMedSearch in Google Scholar
  • 51 Lončarić M, Sokač DG, Jokić S.. Recent advances in the synthesis of coumarin derivatives from different starting materials. Biomolecules 2020; 10: 151
    CrossrefPubMedSearch in Google Scholar
  • 52 Molleti J, Yadav GD.. Green synthesis of methyl salicylate using novel sulfated iron oxide–zirconia catalyst. Clean Technol Environ Policy 2019; 21: 533-545
    CrossrefPubMedSearch in Google Scholar
  • 53 Zhang J, Onakpoya IJ, Posadzki P.. The safety of herbal medicine: From prejudice to evidence. Evidence-based Complementary and Alternative Medicine 2015; 2015: 1-3
    CrossrefPubMedSearch in Google Scholar
  • 54 Morales-Noé A, Esteve-Turrillas FA, Armenta S.. Metabolism of third generation synthetic cannabinoids using zebrafish larvae. Drug Test Anal 2022; 14: 594-603
    CrossrefPubMedSearch in Google Scholar
  • 55 NCT01776970. Safety and Efficacy on Spasticity Symptoms of a Cannabis Sativa Extract in Motor Neuron Disease https://clinicaltrials.gov/show/NCT01776970 2013
    PubMed
  • 56 Abdel-Aziz SM, Aeron A, Kahil TA.. Health benefits and possible risks of herbal medicine. Microbes in Food and Health 2016; 97-116
    CrossrefPubMedSearch in Google Scholar
  • 57 Zhu YP.. Toxicity of the Chinese herb Mu Tong (Aristolochia manshuriensis): What history tells us. Adverse Drug React Toxicol Rev 2002; 21: 161-6
    CrossrefPubMedSearch in Google Scholar
  • 58 Schaneberg BT, Khan IA.. Analysis of products suspected of containing Aristolochia or Asarum species. J Ethnopharmacol 2004; 94: 245-9
    CrossrefPubMedSearch in Google Scholar
  • 59 Jordan SA, Cunningham DG, Marles RJ.. Assessment of herbal medicinal products: Challenges, and opportunities to increase the knowledge base for safety assessment. Toxicol Appl Pharmacol 2010; 243: 498-516
    CrossrefPubMedSearch in Google Scholar
  • 60 Tournas VH, Sapp C, Trucksess MW.. Occurrence of aflatoxins in milk thistle herbal supplements. Food Additives and Contaminants - Part A 2012; 29: 994-999
    CrossrefPubMedSearch in Google Scholar
  • 61 Park J, Kim YJ, Suh SH.. Evaluation of Hygiene Indicators and Sampling Plan for Detecting Microbial Contamination in Health Functional Foods. J Food Prot 2022; 85: 844-848
    CrossrefPubMedSearch in Google Scholar
  • 62 Dai Y, Guan R, Huang H.. Determination of Eight Volatile N-Nitrosamines in Chinese Bacon by Modified QuEChERS and Gas Chromatography-Mass Spectrometry. Food Science 2021; 42: 266-273
    CrossrefPubMedSearch in Google Scholar
  • 63 Sun M, Zhao L, Wang K.. Rapid identification of “mad honey” from Tripterygium wilfordii Hook. f. and Macleaya cordata R. Br using UHPLC/Q-TOF-MS. Food Chem 2019; 294: 448-457
    CrossrefPubMedSearch in Google Scholar
  • 64 Zhu H, Wang X, Wang X.. The toxicity and safety of Chinese medicine from the bench to the bedside. J Herb Med 2021; 28: 100450
    CrossrefPubMedSearch in Google Scholar
  • 65 Luyckx ValerieA. Nephrotoxicity of Alternative Medicine Practice. Adv Chronic Kidney Dis 2012; 19: 129-41
    CrossrefPubMedSearch in Google Scholar
  • 66 Susan C.. Smolinske, Herbal product contamination and toxicity. J Pharm Pract 2005; 18: 188-108
    CrossrefPubMedSearch in Google Scholar
  • 67 Thomas Efferth, Bernd Kaina. Toxicities by herbal medicines with emphasis to traditional Chinese medicine. Curr Drug Metab 2011; 12: 989-96
    CrossrefPubMedSearch in Google Scholar
  • 68 Wu J, Guan R, Huang H.. Effect of catechin liposomes on the nitrosamines and quality of traditional Chinese bacon. Food Funct 2019; 10: 625-634
    CrossrefPubMedSearch in Google Scholar
  • 69 Kao YT, Wang SF, Wu MH.. A substructure-based screening approach to uncover N-nitrosamines in drug substances. J Food Drug Anal 2022; 30: 150-162 10.38212/2224-6614.3400
    CrossrefPubMedSearch in Google Scholar
  • 70 Nanda KK, Tignor S, Clancy J.. Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study. J Pharm Sci 2021; 110: 3773-3775
    CrossrefPubMedSearch in Google Scholar
  • 71 Chang SH, Chang CC, Wang LJ.. A multi-analyte lc-ms/ms method for screening and quantification of nitrosamines in sartans. J Food Drug Anal 2020; 28: 292-301 10.38212/2224-6614.1063
    CrossrefPubMedSearch in Google Scholar
  • 72 Baksam VK, Saritha N, Devineni SR.. A Critical N-Nitrosamine Impurity of Anticoagulant Drug, Rivaroxaban: Synthesis, Characterization, Development of LC–MS/MS Method for Nanogram Level Quantification. Chromatographia 2022; 85: 73-82
    CrossrefPubMedSearch in Google Scholar
  • 73 Asare SO, Hoskins JN, Blessing RA.. Mass spectrometry-based fragmentation patterns of nitrosamine compounds. Rapid Communications in Mass Spectrometry 2022; 36: 9261
    CrossrefPubMedSearch in Google Scholar
  • 74 Malihi F, Wang T.. An improved analytical method for quantitation of nitrosamine impurities in ophthalmic solutions using liquid chromatography with tandem mass spectrometry. J Chromatography 2022; 2: 100037
    CrossrefPubMedSearch in Google Scholar
  • 75 Zheng J, Kirkpatrick CL, Lee D.. A Full Evaporation Static Headspace Gas Chromatography Method with Nitrogen Phosphorous Detection for Ultrasensitive Analysis of Semi-volatile Nitrosamines in Pharmaceutical Products. AAPS J 2022; 24: 23
    CrossrefPubMedSearch in Google Scholar