{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T21:09:59Z","timestamp":1785877799050,"version":"3.56.0"},"reference-count":26,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:00:00Z","timestamp":1741737600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013120","name":"European Medicines Agency","doi-asserted-by":"publisher","award":["EMA\/2020\/46\/L1.02"],"award-info":[{"award-number":["EMA\/2020\/46\/L1.02"]}],"id":[{"id":"10.13039\/501100013120","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Testing and Analysis"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The presence of nitrosamines in numerous human medicinal products (HMP) has recently emerged as a cause for concern. Following the initial discovery of carcinogenic low molecular weight nitrosamines such as nitrosodimethylamine (NDMA) in HMP, regulatory authorities worldwide requested marketing authorization holders to perform risk assessments for the presence of nitrosamines in their products. The initially observed contaminations\u2014mainly low molecular weight nitrosamines\u2014were generated by organic solvent impurities or by\u2010products from synthesis and nitrite carried over to finished products (FP). More recently, complex nitrosamine drug substance\u2010related impurities (NDSRIs) have been reported arising from direct nitrosation of active pharmaceutical ingredients (APIs) at secondary amine groups in the presence of nitrite derived from excipients. In addition, an alternative route of API nitrosation is conceivable due to interaction with gastric acid and physiological nitrite after drug intake. Within this study, 13 secondary amine bearing APIs were selected to individually identify susceptibilities for nitrosation by using high physiological limit values in terms of pH and nitrite. Therefore, artificial gastric media were fortified with 200\u2009\u03bcM sodium nitrite and increasing concentrations of APIs at pH\u20093.15 and 37\u00b0C for 2\u2009h. All NDSRI concentrations were quantitatively determined via validated liquid chromatography\u2013tandem mass spectrometry (LC\u2013MS\/MS) methodology. Additionally, time\u2010dependent nitrosations of selected APIs were monitored to kinetically assess the proportion of NDSRIs after the gastric passage. All results and observations were further processed by means of structure activity relationship (SAR) predictions to identify highly susceptible compounds in the group of concern.<\/jats:p>","DOI":"10.1002\/dta.3874","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:35:23Z","timestamp":1741826123000},"page":"1772-1784","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Quantitative Investigation of Nitrosamine Drug Substance\u2010Related Impurities (NDSRIs) Under Artificial Gastric Conditions by Liquid Chromatography\u2013Tandem Mass Spectrometry and Structure\u2013Activity Relationship Analysis"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-3900","authenticated-orcid":false,"given":"Matthias","family":"Vogel","sequence":"first","affiliation":[{"name":"Federal Institute for Drugs and Medical Devices  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia\u00a0E.","family":"Escher","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Toxicology and Experimental Medicine  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuel","family":"Weiler","sequence":"additional","affiliation":[{"name":"Federal Institute for Drugs and Medical Devices  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Londenberg","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Toxicology and Experimental Medicine  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Deppenmeier","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Biotechnology University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhys","family":"Whomsley","sequence":"additional","affiliation":[{"name":"European Medicines Agency  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.5487\/TR.2015.31.3.279"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2018.05.008"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2011.02.005"},{"key":"e_1_2_9_5_1","unstructured":"European Medicines Agency \u201cProcedure Under Article 5(3) of Regulation EC (No) 726\/2004 Nitrosamine Impurities in Human Medicinal Products \u201d (2020) https:\/\/www.ema.europa.eu\/en\/documents\/referral\/nitrosamines\u2010emea\u2010h\u2010a53\u20101490\u2010assessment\u2010report_en.pdf. 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