{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:33:44Z","timestamp":1793277224703,"version":"4.5.0"},"reference-count":53,"publisher":"Elsevier BV","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["jpharmsci.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pharmaceutical Sciences"],"published-print":{"date-parts":[[2026,6]]},"DOI":"10.1016\/j.xphs.2026.104296","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T06:11:25Z","timestamp":1777011085000},"page":"104296","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":3,"title":["Something in the air\u2013Unveiling the role of atmospheric nitrogen oxides in nitrosamine formation from amine-containing APIs: Mechanistic insights and risk assessment"],"prefix":"10.1016","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6883-4812","authenticated-orcid":false,"given":"Rok","family":"Grahek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3437-0651","authenticated-orcid":false,"given":"Renat","family":"Selimov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8110-9248","authenticated-orcid":false,"given":"Miha","family":"Drev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7178-8936","authenticated-orcid":false,"given":"Holger","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0120-948X","authenticated-orcid":false,"given":"Paul","family":"Garbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3248-6247","authenticated-orcid":false,"given":"Brunhilde","family":"Guessregen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4799-1086","authenticated-orcid":false,"given":"Joerg","family":"Schlingemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-5748","authenticated-orcid":false,"given":"Olivier","family":"Dirat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7101-7748","authenticated-orcid":false,"given":"Krishna","family":"Veerubhotla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7210-3875","authenticated-orcid":false,"given":"Ian W.","family":"Ashworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6753-4856","authenticated-orcid":false,"given":"Paula","family":"Tomlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.xphs.2026.104296_bib0001","unstructured":"EMA. EMA reviewing medicines containing valsartan from Zhejiang Huahai following detection of an impurity: some valsartan medicines being recalled across the EU. Available at: https:\/\/www.ema.europa.eu\/en\/news\/ema-reviewing-medicines-containing-valsartan-zhejiang-huahai-following-detection-impurity-some."},{"key":"10.1016\/j.xphs.2026.104296_bib0002","unstructured":"FDA. FDA provides update on its ongoing investigation into ARB drug products; reports on finding of a new nitrosamine impurity in certain lots of losartan and product recall. 2019."},{"key":"10.1016\/j.xphs.2026.104296_bib0003","unstructured":"Health Canada. Apotex recalls Apo-Acyclovir tablets due to a nitrosamine impurity. Available at: https:\/\/recalls-rappels.canada.ca\/en\/alert-recall\/apotex-recalls-apo-acyclovir-tablets-due-nitrosamine-impurity. Accessed 27 May 2025."},{"key":"10.1016\/j.xphs.2026.104296_bib0004","unstructured":"Health Canada. Amitriptyline antidepressant drugs recalled because of a nitrosamine impurity. Available at: https:\/\/recalls-rappels.canada.ca\/en\/alert-recall\/amitriptyline-antidepressant-drugs-recalled-because-nitrosamine-impurity. Accessed 27 May 2025."},{"key":"10.1016\/j.xphs.2026.104296_bib0005","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijpharm.2022.121740","article-title":"Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite","volume":"620","author":"Schlingemann","year":"2022","journal-title":"Int J Pharm"},{"key":"10.1016\/j.xphs.2026.104296_bib0006","unstructured":"FDA. FDA alerts patients and health care professionals to nitrosamine impurity findings in certain metformin extended-release products. 2020."},{"key":"10.1016\/j.xphs.2026.104296_bib0007","unstructured":"EMA. EMA update on metformin diabetes medicines. Available at: https:\/\/www.ema.europa.eu\/en\/documents\/press-release\/ema-update-metformin-diabetes-medicines_en.pdf."},{"key":"10.1016\/j.xphs.2026.104296_bib0008","unstructured":"HSA. Update on impurities in metformin products. Available at: https:\/\/www.hsa.gov.sg\/announcements\/safety-alert\/update-on-impurities-in-metformin-products."},{"key":"10.1016\/j.xphs.2026.104296_bib0009","unstructured":"FDA. Laboratory analysis of ranitidine and nizatidine products. Available at:https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/laboratory-tests-ranitidine. Accessed 27 May 2025."},{"key":"10.1016\/j.xphs.2026.104296_bib0010","unstructured":"EMA. Nitrosamine impurities: the network's response. Available at: https:\/\/www.ema.europa.eu\/en\/annual-report\/2019\/nitrosamine-impurities-networks-response.html. Accessed 27 May 2025."},{"issue":"5","key":"10.1016\/j.xphs.2026.104296_bib0011","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/j.xphs.2023.03.007","article-title":"NDMA formation due to active ingredient degradation and nitrite traces in drug product","volume":"112","author":"Golob","year":"2023","journal-title":"J Pharm Sci"},{"issue":"12","key":"10.1016\/j.xphs.2026.104296_bib0012","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1021\/acs.oprd.0c00462","article-title":"Ranitidine\u2014investigations into the root cause for the presence of N-nitroso-N,N-dimethylamine in ranitidine hydrochloride drug substances and associated drug products","volume":"24","author":"King","year":"2020","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.xphs.2026.104296_bib0013","unstructured":"EMA. Suspension of ranitidine medicines in the EU. Available at:https:\/\/www.ema.europa.eu\/en\/documents\/press-release\/suspension-ranitidine-medicines-eu_en.pdf."},{"key":"10.1016\/j.xphs.2026.104296_bib0014","unstructured":"FDA. FDA requests removal of all ranitidine products (Zantac) from the market. Available at:https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-requests-removal-all-ranitidine-products-zantac-market#:\u223c:text=FDA%20Advises%20Consumers%2C%20Patients%20and,Show%20Risk%20to%20Public%20Health&text=The%20U.S.%20Food%20and%20Drug,drugs%20from%20the%20market%20immediately."},{"key":"10.1016\/j.xphs.2026.104296_bib0015","doi-asserted-by":"crossref","DOI":"10.1021\/acs.oprd.3c00100","article-title":"The nitrosamine \u201cSaga\u201d: lessons learned from five years of scrutiny","author":"Nudelman","year":"2023","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.xphs.2026.104296_bib0016","doi-asserted-by":"crossref","DOI":"10.1021\/acs.oprd.5c00097","article-title":"Drug substance and drug product workflows for quality risk management for the presence of nitrosamines in medicines","author":"Dirat","year":"2025","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.xphs.2026.104296_bib0017","doi-asserted-by":"crossref","DOI":"10.1021\/acs.oprd.3c00073","article-title":"A consideration of the extent that tertiary amines can form N-nitroso dialkylamines in pharmaceutical products","author":"Ashworth","year":"2023","journal-title":"Org Process Res Dev"},{"issue":"12","key":"10.1016\/j.xphs.2026.104296_bib0018","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1016\/j.xphs.2023.10.001","article-title":"Revisiting the landscape of potential small and drug substance related nitrosamines in pharmaceuticals","volume":"112","author":"Burns","year":"2023","journal-title":"J Pharm Sci"},{"issue":"5","key":"10.1016\/j.xphs.2026.104296_bib0019","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.xphs.2022.11.013","article-title":"The landscape of potential small and drug substance related nitrosamines in pharmaceuticals","volume":"112","author":"Schlingemann","year":"2022","journal-title":"J Pharm Sci"},{"key":"10.1016\/j.xphs.2026.104296_bib0020","unstructured":"Lhasa Limited. Nitrites in excipients database. Available at: https:\/\/www.lhasalimited.org\/Initiatives\/nitrites.htm."},{"issue":"6","key":"10.1016\/j.xphs.2026.104296_bib0021","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1016\/j.xphs.2022.04.016","article-title":"A nitrite excipient database: a useful tool to support N-nitrosamine risk assessments for drug products","volume":"112","author":"Boetzel","year":"2022","journal-title":"J Pharm Sci"},{"issue":"9","key":"10.1016\/j.xphs.2026.104296_bib0022","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"},{"issue":"9","key":"10.1016\/j.xphs.2026.104296_bib0023","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.xphs.2026.104296_bib0024","unstructured":"FDA. Control of nitrosamine impurities in human drugs - guidance for industry. Available at: https:\/\/www.fda.gov\/media\/141720\/download."},{"key":"10.1016\/j.xphs.2026.104296_bib0025","doi-asserted-by":"crossref","DOI":"10.1021\/acs.oprd.3c00274","article-title":"N-nitrosodimethylamine formation in metformin drug products by reaction of dimethylamine and atmospheric NO2","author":"Fukuda","year":"2023","journal-title":"Org Process Res Dev"},{"issue":"8","key":"10.1016\/j.xphs.2026.104296_bib0026","doi-asserted-by":"crossref","first-page":"3182","DOI":"10.1021\/acs.oprd.4c00088","article-title":"Strategy to assess and control nitrosamine formation in API during storage: a sitagliptin case study","volume":"28","author":"Badia","year":"2024","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.xphs.2026.104296_bib0027","series-title":"Atmospheric Chemistry and Physics: From Air Pollution to Climate Change","author":"Seinfeld","year":"2016"},{"key":"10.1016\/j.xphs.2026.104296_bib0028","series-title":"Air Quality and Health in Cities: A State of Global Air Report 2022","year":"2022"},{"issue":"1","key":"10.1016\/j.xphs.2026.104296_bib0029","first-page":"1","article-title":"Solubility equilibria of the nitrogen oxides and oxyacids in dilute aqueous solution","volume":"4","author":"Schwartz","year":"1981","journal-title":"Adv Environ Sci Eng"},{"key":"10.1016\/j.xphs.2026.104296_bib0030","series-title":"Trace Atmospheric Constituents: Properties, Transformations, and Fates","first-page":"1","article-title":"Kinetics of reactive dissolution of nitrogen oxides into aqueous solution","author":"Schwartz","year":"1983"},{"key":"10.1016\/j.xphs.2026.104296_bib0031","unstructured":"FDA. Orange book: approved drug products with therapeutic equivalence evaluations."},{"issue":"26","key":"10.1016\/j.xphs.2026.104296_bib0032","doi-asserted-by":"crossref","first-page":"6665","DOI":"10.1021\/jm701032y","article-title":"Trends in active pharmaceutical ingredient salt selection based on analysis of the Orange Book database","volume":"50","author":"Paulekuhn","year":"2007","journal-title":"J Med Chem"},{"key":"10.1016\/j.xphs.2026.104296_bib0033","doi-asserted-by":"crossref","DOI":"10.1021\/acs.oprd.2c00366","article-title":"Formation of dialkyl-N-nitrosamines in aqueous solution: an experimental validation of a conservative predictive model and a comparison of the rates of dialkyl and trialkylamine nitrosation","author":"Ashworth","year":"2023","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.xphs.2026.104296_bib0034","doi-asserted-by":"crossref","DOI":"10.1021\/acs.oprd.3c00084","article-title":"Approaches and considerations for the investigation and synthesis of N-nitrosamine drug substance-related impurities (NDSRIs)","author":"Ashworth","year":"2023","journal-title":"Org Process Res Dev"},{"issue":"11","key":"10.1016\/j.xphs.2026.104296_bib0035","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/0278-6915(87)90266-3","article-title":"Identification of minor nitrosation products of the alkaloid gramine by mass spectrometry","volume":"25","author":"Ahmad","year":"1987","journal-title":"Food Chem Toxicol"},{"issue":"0","key":"10.1016\/j.xphs.2026.104296_bib0036","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1039\/p19790000299","article-title":"The chemistry of nitroso-compounds. Part 11. Nitrosation of amines by the two-phase interaction of amines in solution with gaseous oxides of nitrogen","volume":"1","author":"Challis","year":"1979","journal-title":"J Chem Soc Perkin Trans"},{"issue":"12","key":"10.1016\/j.xphs.2026.104296_bib0037","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1039\/p29780001296","volume":"2","author":"Challis","year":"1978","journal-title":"J Chem Soc Perkin Trans"},{"issue":"21","key":"10.1016\/j.xphs.2026.104296_bib0038","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1039\/c39760000877","article-title":"Nitrosation under alkaline conditions","author":"Challis","year":"1976","journal-title":"J Chem Soc Chem Commun"},{"key":"10.1016\/j.xphs.2026.104296_bib0039","doi-asserted-by":"crossref","DOI":"10.1021\/acs.oprd.5c00182","article-title":"Three-pronged approach (active pharmaceutical ingredients, excipients, and NOx-free air) successfully suppressed the formation of nitroso-atomoxetine to 0.097 ppm","author":"Nomura","year":"2025","journal-title":"Org Process Res Dev"},{"issue":"2","key":"10.1016\/j.xphs.2026.104296_bib0040","doi-asserted-by":"crossref","DOI":"10.1016\/j.xphs.2025.104067","article-title":"NNitrosamine formation in pharmaceutical drug products: development and validation of a biased, conservative, predictive model","volume":"115","author":"Ashworth","year":"2026","journal-title":"J Pharm Sci"},{"key":"10.1016\/j.xphs.2026.104296_bib0041","series-title":"Physical Organic Chemistry","author":"Isaacs","year":"1995"},{"key":"10.1016\/j.xphs.2026.104296_bib0042","series-title":"Solvents and Solvent Effects in Organic Chemistry","author":"Reichardt","year":"2003"},{"issue":"17","key":"10.1016\/j.xphs.2026.104296_bib0043","doi-asserted-by":"crossref","first-page":"5494","DOI":"10.1021\/jo00122a031","article-title":"Gas\/solid reactions with nitrogen dioxide","volume":"60","author":"Kaupp","year":"1995","journal-title":"J Org Chem"},{"issue":"11","key":"10.1016\/j.xphs.2026.104296_bib0044","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.xphs.2026.104296_bib0045","doi-asserted-by":"crossref","first-page":"7217","DOI":"10.1021\/jp9910688","article-title":"Heterogeneous reaction of NO2: characterization of gas-phase and adsorbed products from the reaction, 2NO2(g) + H2O(a) \u2192 HONO(g) + HNO3(a) on hydrated silica particles","volume":"103","author":"Goodman","year":"1999","journal-title":"J Phys Chem A"},{"issue":"2","key":"10.1016\/j.xphs.2026.104296_bib0046","doi-asserted-by":"crossref","first-page":"463","DOI":"10.5194\/acp-10-463-2010","article-title":"Kinetics and mechanisms of heterogeneous reaction of NO2on CaCO3surfaces under dry and wet conditions","volume":"10","author":"Li","year":"2010","journal-title":"Atmos Chem Phys"},{"key":"10.1016\/j.xphs.2026.104296_bib0047","doi-asserted-by":"crossref","unstructured":"Fair J. Mass transfer. In: Albright, ed. Albright's Chemical Engineering Handbook. 1st ed. Boca Raton: CRC Press:591-614. https:\/\/doi.org\/10.1201\/9781420014389.ch8.","DOI":"10.1201\/9781420014389.ch8"},{"issue":"3","key":"10.1016\/j.xphs.2026.104296_bib0048","first-page":"789","article-title":"Carcinogenic N-nitrosamine formation: a requirement for nitric oxide","volume":"27","author":"Cooney","year":"1992","journal-title":"J Environ Sci Health Part A: Environ Sci Eng Toxicol"},{"key":"10.1016\/j.xphs.2026.104296_bib0049","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.jpba.2017.10.035","article-title":"Artifactual degradation of secondary amine-containing drugs during accelerated stability testing when saturated sodium nitrite solutions are used for humidity control","volume":"149","author":"Sluggett","year":"2018","journal-title":"J Pharm Biomed Anal"},{"key":"10.1016\/j.xphs.2026.104296_bib0050","unstructured":"EMA. Appendix 2 to questions and answers for marketing authorisation holders\/applicants on the CHMP opinion for the Article 5(3) of Regulation (EC) No 26\/2004 referral on nitrosamine impurities in human medicinal products - carcinogenic potency categorisation approach for N-nitrosamines. Available at:https:\/\/www.ema.europa.eu\/en\/documents\/other\/appendix-2-carcinogenic-potency-categorisation-approach-n-nitrosamines_en.pdf. Accessed 06 OCT."},{"key":"10.1016\/j.xphs.2026.104296_bib0051","first-page":"153","article-title":"M\u00e9moire sur la puissance motrice de la chaleur","volume":"14","author":"Clapeyron","year":"1834","journal-title":"J \u00c9c Polytech"},{"issue":"5","key":"10.1016\/j.xphs.2026.104296_bib0052","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1016\/j.xphs.2022.12.022","article-title":"Regulatory experiences with root causes and risk factors for nitrosamine impurities in pharmaceuticals","volume":"112","author":"Horne","year":"2023","journal-title":"J Pharm Sci"},{"issue":"1","key":"10.1016\/j.xphs.2026.104296_bib0053","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ijpharm.2017.02.001","article-title":"Salt disproportionation: a material science perspective","volume":"520","author":"Thakral","year":"2017","journal-title":"Int J Pharm"}],"container-title":["Journal of Pharmaceutical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022354926001450?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022354926001450?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T13:03:47Z","timestamp":1779368627000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022354926001450"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":53,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["S0022354926001450"],"URL":"https:\/\/doi.org\/10.1016\/j.xphs.2026.104296","relation":{},"ISSN":["0022-3549"],"issn-type":[{"value":"0022-3549","type":"print"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Something in the air\u2013Unveiling the role of atmospheric nitrogen oxides in nitrosamine formation from amine-containing APIs: Mechanistic insights and risk assessment","name":"articletitle","label":"Article Title"},{"value":"Journal of Pharmaceutical Sciences","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.xphs.2026.104296","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Author(s). Published by Elsevier Inc. on behalf of American Pharmacists Association\u00ae.","name":"copyright","label":"Copyright"}],"article-number":"104296"}}