{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:26:19Z","timestamp":1792517179430,"version":"4.5.0"},"reference-count":42,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pharmaceutical Sciences"],"published-print":{"date-parts":[[2022,1]]},"DOI":"10.1016\/j.ejps.2021.106026","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T05:01:35Z","timestamp":1632891695000},"page":"106026","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":50,"special_numbering":"C","title":["NDMA analytics in metformin products: Comparison of methods and pitfalls"],"prefix":"10.1016","volume":"168","author":[{"given":"Matthias","family":"Fritzsche","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Blom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Keitel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Goettsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maic","family":"Seegel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Leicht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brunhilde","family":"Guessregen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Hickert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Reifenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Cimelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romane","family":"Baranowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Desmartin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Barrau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Bristow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"O'Neill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Kirsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Krueger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Saal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Mouton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Schlingemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejps.2021.106026_bib0001","first-page":"109","article-title":"Chemical models for possible nitrosamine artifact formation in environmental analysis","volume":"19","author":"Angeles","year":"1978","journal-title":"IARC Sci. Publ."},{"key":"10.1016\/j.ejps.2021.106026_bib0002","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1021\/acs.oprd.0c00224","article-title":"Potential for the formation of N-Nitrosamines during the manufacture of active pharmaceutical ingredients: an assessment of the risk posed by trace nitrite in water","volume":"24","author":"Ashworth","year":"2020","journal-title":"Org. Process Res. Dev."},{"key":"10.1016\/j.ejps.2021.106026_bib0003","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.chemosphere.2019.01.053","article-title":"Formation of N-nitrosamines during the analysis of municipal secondary biological nutrient removal process effluents by US EPA method 521","volume":"221","author":"Chuang","year":"2019","journal-title":"Chemosphere"},{"key":"10.1016\/j.ejps.2021.106026_bib0004","unstructured":"EDQM, 2020 a. Ad hoc projects of the OMCL network. https:\/\/www.edqm.eu\/en\/ad-hoc-projects-omcl-network."},{"key":"10.1016\/j.ejps.2021.106026_bib0005","unstructured":"EDQM, 2020 b. Ph.Eur. 10.1, 0931; Metformin hydrochloride (04\/2020)."},{"key":"10.1016\/j.ejps.2021.106026_bib0006","unstructured":"EDQM, 2021 a. Ph.Eur. 10.4, 2232; Losartan potassium (04\/2021)."},{"key":"10.1016\/j.ejps.2021.106026_bib0007","unstructured":"EDQM, 2021 b. Ph.Eur. 10.4, 2423; Valsartan (04\/2021)."},{"key":"10.1016\/j.ejps.2021.106026_bib0008","unstructured":"EDQM, 2021 c. Ph.Eur. 10.4, 2456; Irbesartan (04\/2021)."},{"key":"10.1016\/j.ejps.2021.106026_bib0009","unstructured":"EDQM, 2021 d Ph.Eur. 10.4, 2573; Candesartan cilexetil (04\/2021)."},{"key":"10.1016\/j.ejps.2021.106026_bib0010","unstructured":"EDQM, 2021 e. Ph.Eur. 10.4, 2600; Olmesartan medoxomil (04\/2021)."},{"key":"10.1016\/j.ejps.2021.106026_bib0011","unstructured":"EDQM, 2021 f. Ph.Eur. 10.6, 2.5.42.; N-Nitrosamines in Active Substances (01\/2022)."},{"key":"10.1016\/j.ejps.2021.106026_bib0012","unstructured":"EMA, 2018. CHMP List of outstanding issues to be addressed by the marketing authorisation holders for angiotensin-IIreceptor antagonists (sartans) containing a tetrazole group. https:\/\/www.ema.europa.eu\/en\/documents\/referral\/angiotensin-ii-receptor-antagonists-sartans-article-31-referral-chmp-list-questions-be-addressed_en-0.pdf."},{"key":"10.1016\/j.ejps.2021.106026_bib0013","unstructured":"EMA, 2019 a. EMA update on metformin diabetes medicines. https:\/\/www.ema.europa.eu\/en\/documents\/press-release\/ema-update-metformin-diabetes-medicines_en.pdf."},{"key":"10.1016\/j.ejps.2021.106026_bib0014","unstructured":"EMA, 2019 b. Information on nitrosamines for marketing authorisation holders. https:\/\/www.ema.europa.eu\/en\/documents\/referral\/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders-obsolete_.pdf."},{"key":"10.1016\/j.ejps.2021.106026_bib0015","unstructured":"EMA, 2020. Suspension of ranitidine medicines in the EU. https:\/\/www.ema.europa.eu\/en\/documents\/press-release\/suspension-ranitidine-medicines-eu_en.pdf."},{"key":"10.1016\/j.ejps.2021.106026_bib0016","unstructured":"EMA, 2021. CHAMPIX (varenicline) - lots to be recalled due to presence of impurity N-nitroso-varenicline. https:\/\/www.ema.europa.eu\/en\/documents\/dhpc\/direct-healthcare-professional-communication-dhpc-champix-varenicline-lots-be-recalled-due-presence_en.pdf."},{"key":"10.1016\/j.ejps.2021.106026_bib0017","unstructured":"EMA\/CHMP, 2020. Procedure under article 5(3) of regulation EC (No) 726\/2004; assessment report: nitrosamine impurities in human medicinal products. https:\/\/www.ema.europa.eu\/en\/documents\/referral\/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf."},{"key":"10.1016\/j.ejps.2021.106026_bib0018","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/0039-9140(84)80181-2","article-title":"Chemical ionization mass spectrometry of nitrosamines","volume":"31","author":"Fang","year":"1984","journal-title":"Talanta"},{"key":"10.1016\/j.ejps.2021.106026_bib0019","unstructured":"FDA, 2021. FDA updates and press announcements on NDMA in metformin. https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-updates-and-press-announcements-ndma-metformin."},{"key":"10.1016\/j.ejps.2021.106026_bib0020","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/11534750-000000000-00000","article-title":"Clinical pharmacokinetics of metformin","volume":"50","author":"Graham","year":"2011","journal-title":"Clin. Pharmacokinet."},{"key":"10.1016\/j.ejps.2021.106026_bib0021","first-page":"1288","article-title":"[Determination of N-nitrosodimethylamine in metformin hydrochloride and its preparations by high performance liquid chromatography-tandem mass spectrometry]","volume":"38","author":"Guo","year":"2020","journal-title":"Se Pu"},{"key":"10.1016\/j.ejps.2021.106026_bib0022","doi-asserted-by":"crossref","first-page":"3830","DOI":"10.1039\/C8AY01206G","article-title":"Comparison between two derivatization methods of nitrite ion labeled with 15N applied to liquid chromatography-tandem mass spectrometry","volume":"10","author":"Haiyan","year":"2018","journal-title":"Anal. Methods"},{"key":"10.1016\/j.ejps.2021.106026_bib0023","doi-asserted-by":"crossref","first-page":"67A","DOI":"10.1021\/ac00238a765","article-title":"Evaluation of analytical methods used for regulation of foods and drugs","volume":"54","author":"Horwitz","year":"1982","journal-title":"Anal. Chem."},{"key":"10.1016\/j.ejps.2021.106026_bib0024","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/BF00322724","article-title":"Precision in analytical measurements: expected values and consequences in geochemical analyses","volume":"351","author":"Horwitz","year":"1995","journal-title":"Fresenius J. Anal. Chem."},{"key":"10.1016\/j.ejps.2021.106026_bib0025","unstructured":"HSA, 2019. Update on impurities in metformin products. https:\/\/www.hsa.gov.sg\/announcements\/safety-alert\/update-on-impurities-in-metformin-products."},{"key":"10.1016\/j.ejps.2021.106026_bib0026","doi-asserted-by":"crossref","DOI":"10.1016\/j.jpba.2020.113877","article-title":"Insight into the formation of N-nitrosodimethylamine in metformin products","volume":"195","author":"Jire\u0161","year":"2021","journal-title":"J. Pharm. Biomed. Anal."},{"key":"10.1016\/j.ejps.2021.106026_bib0027","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/BF00379052","article-title":"Measurement of nitrosodimethylamine by capillary gas chromatography-mass spectrometry with the 15N-labelled compound as an internal standard","volume":"54","author":"Kosaka","year":"1984","journal-title":"Int. Arch. Occup. Environ. Health"},{"key":"10.1016\/j.ejps.2021.106026_bib0028","doi-asserted-by":"crossref","DOI":"10.1016\/j.jpba.2020.113460","article-title":"Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography\u2013tandem mass spectrometry","volume":"189","author":"Lim","year":"2020","journal-title":"J. Pharm. Biomed. Anal."},{"key":"10.1016\/j.ejps.2021.106026_bib0029","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1021\/acs.oprd.0c00323","article-title":"Pathways for N-nitroso compound formation: secondary amines and beyond","volume":"24","author":"L\u00f3pez-Rodr\u00edguez","year":"2020","journal-title":"Org. Process Res. Dev."},{"key":"10.1016\/j.ejps.2021.106026_bib0030","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/S1872-2040(10)60466-5","article-title":"Determination of ten volatile nitrosamines in cosmetics by gas chromatography tandem mass spectrometry","volume":"39","author":"Ma","year":"2011","journal-title":"Chin. J. Anal. Chem."},{"key":"10.1016\/j.ejps.2021.106026_bib0031","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1016\/S0040-4039(01)81245-4","article-title":"N-nitrosamines via the phase-transfer mediated nitrosation of secondary amines with sodium nitrite and n-haloamides","volume":"25","author":"Nakajima","year":"1984","journal-title":"Tetrahedron Lett."},{"issue":"7","key":"10.1016\/j.ejps.2021.106026_bib0032","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1080\/14740338.2021.1917547","article-title":"Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products","volume":"20","author":"Nasr","year":"2021","journal-title":"Expert Opin. Drug Saf."},{"key":"10.1016\/j.ejps.2021.106026_bib0033","doi-asserted-by":"crossref","first-page":"5748","DOI":"10.1039\/C4AY02967D","article-title":"Analysis of nine N-nitrosamines using liquid chromatography-accurate mass high resolution-mass spectrometry on a Q-Exactive instrument","volume":"7","author":"Ngongang","year":"2015","journal-title":"Anal. Methods"},{"key":"10.1016\/j.ejps.2021.106026_bib0034","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.jpba.2018.11.010","article-title":"NDMA impurity in valsartan and other pharmaceutical products: analytical methods for the determination of N-nitrosamines","volume":"164","author":"Parr","year":"2019","journal-title":"J. Pharm. Biomed. Anal."},{"key":"10.1016\/j.ejps.2021.106026_bib0035","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1002\/jssc.201401143","article-title":"Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: a comprehensive review","volume":"38","author":"Reddy","year":"2015","journal-title":"J. Sep. Sci."},{"key":"10.1016\/j.ejps.2021.106026_bib0036","series-title":"N-Nitroso Compounds: Analysis, Formation and Occurence. International Agency for Research on","author":"Roller","year":"1980"},{"key":"10.1016\/j.ejps.2021.106026_bib0037","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/j.2050-0416.1986.tb04373.x","article-title":"The chemistry of nitrosamine formation: relevance to malting and brewing","volume":"92","author":"Wainright","year":"1986","journal-title":"J. Inst. Brew."},{"key":"10.1016\/j.ejps.2021.106026_bib0038","series-title":"Analysis of Crowdsourced Metformin Tablets from Individuals Reveals Widespread Contamination With N-Nitrosodimethylamine (NDMA) in the United States","author":"Wu","year":"2020"},{"key":"10.1016\/j.ejps.2021.106026_bib0039","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1208\/s12249-011-9677-z","article-title":"Reactive impurities in excipients: profiling, identification and mitigation of drug\u2013excipient incompatibility","volume":"12","author":"Wu","year":"2011","journal-title":"AAPS PharmSciTech"},{"key":"10.1016\/j.ejps.2021.106026_bib0040","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1208\/s12248-020-00473-w","article-title":"A cautionary tale: quantitative LC-HRMS analytical procedures for the analysis of N-nitrosodimethylamine in metformin","volume":"22","author":"Yang","year":"2020","journal-title":"AAPS J."},{"key":"10.1016\/j.ejps.2021.106026_bib0041","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1021\/jp0677703","article-title":"N-nitrosation of amines by NO2 and NO:\u2009 a theoretical study","volume":"111","author":"Zhao","year":"2007","journal-title":"J. Phys. Chem. A"},{"key":"10.1016\/j.ejps.2021.106026_bib0042","doi-asserted-by":"crossref","first-page":"5304","DOI":"10.3390\/molecules25225304","article-title":"N-nitrosodimethylamine contamination in the metformin finished products","volume":"25","author":"Zmys\u0142owski","year":"2020","journal-title":"Molecules"}],"container-title":["European Journal of Pharmaceutical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0928098721003298?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0928098721003298?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T12:00:12Z","timestamp":1760529612000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0928098721003298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":42,"alternative-id":["S0928098721003298"],"URL":"https:\/\/doi.org\/10.1016\/j.ejps.2021.106026","relation":{},"ISSN":["0928-0987"],"issn-type":[{"value":"0928-0987","type":"print"}],"subject":[],"published":{"date-parts":[[2022,1]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"NDMA analytics in metformin products: Comparison of methods and pitfalls","name":"articletitle","label":"Article Title"},{"value":"European Journal of Pharmaceutical Sciences","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejps.2021.106026","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 The Author(s). Published by Elsevier B.V.","name":"copyright","label":"Copyright"}],"article-number":"106026"}}