{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:27:41Z","timestamp":1790702861689,"version":"4.1.0"},"reference-count":17,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,11,20]],"date-time":"2022-11-20T00:00:00Z","timestamp":1668902400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Rapid Comm Mass Spectrometry"],"published-print":{"date-parts":[[2023,1,15]]},"abstract":"<jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>\n                      The high resolving power of the Orbitrap mass spectrometer in a high\u2010resolution accurate mass gas chromatography (HRAM\u2010GC\u2010MS) system provides greater selectivity and sensitivity for the identification and quantification of volatile analytes at low parts per billion (ppb) levels. Hence, it can be applied for the analysis of pharmaceutical impurities like\n                      <jats:italic>N<\/jats:italic>\n                      \u2010nitrosodimethylamine (NDMA) in metformin hydrochloride products (METs).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Different METs extracted by a dichloromethane\/aqueous system were analyzed by HRAM\u2010GC\u2010MS under softer electron ionization (EI) at 30\u2009eV. The accurate masses of NDMA and its internal standard NDMA\u2010d6 were analyzed by full scan and targeted selected ion monitoring modes under 60\u2009000 and 30\u2009000 full width at half maximum at\n                      <jats:italic>m<\/jats:italic>\n                      \/\n                      <jats:italic>z<\/jats:italic>\n                      200, respectively. Data acquisition and processing were managed by Xcalibur and Trace Finder software, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Limits of detection (LOD) and quantification (LOQ) at 10 and 20\u2009ng\/g were achieved, which is below the allowed daily intake of 32\u2009ng\/g. The mass errors measured from experimental data were within \u00b12\u2009ppm of the theoretical values over a period of a week. Sample analysis showed that 180 out of 212 samples (85%) were below LOD and 15 out of 212 samples (7 %) were within LOD and LOQ. Only 17 samples (8%) were found to be above LOQ, comprising one active pharmaceutical ingredient (API), five immediate\u2010release METs and 11 extended\u2010released METs. Amongst these, seven extended\u2010release METs and one API exceeded the daily allowed intake, 32\u2009ng\/g.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The validated method has been successfully applied for NDMA analysis in various forms of METs. The method is rather straightforward without an additional clean\u2010up step. The scope can also be extended to other volatile impurities in finished pharmaceutical products.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/rcm.9414","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T05:34:46Z","timestamp":1665725686000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Analysis of\n                    <i>N<\/i>\n                    \u2010nitrosodimethylamine in metformin hydrochloride products by high\u2010resolution accurate mass gas chromatography mass spectrometry"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2648-7382","authenticated-orcid":false,"given":"Chee\u2010Leong","family":"Kee","sequence":"first","affiliation":[{"name":"Health Sciences Authority, Pharmaceutical Laboratory Applied Sciences Group  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zeng","sequence":"additional","affiliation":[{"name":"Health Sciences Authority, Pharmaceutical Laboratory Applied Sciences Group  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4504-4248","authenticated-orcid":false,"given":"Xiaowei","family":"Ge","sequence":"additional","affiliation":[{"name":"Health Sciences Authority, Pharmaceutical Laboratory Applied Sciences Group  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing\u2010Quan","family":"Lim","sequence":"additional","affiliation":[{"name":"Health Sciences Authority, Pharmaceutical Laboratory Applied Sciences Group  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Gek","family":"Teo Jessie","sequence":"additional","affiliation":[{"name":"Health Sciences Authority, Pharmaceutical Laboratory Applied Sciences Group  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Yong","family":"Low","sequence":"additional","affiliation":[{"name":"Health Sciences Authority, Pharmaceutical Laboratory Applied Sciences Group  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,20]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2018.11.010"},{"key":"e_1_2_6_3_1","volume-title":"Overall Evaluations of Carcinogenicity: An Updating of IARC Monograph Volumes 1 to 42","author":"International Agency for Research on Cancer","year":"1987"},{"key":"e_1_2_6_4_1","unstructured":"Accessed August 22 2022.https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-updates-and-press-announcements-ndma-metformin"},{"key":"e_1_2_6_5_1","unstructured":"EMA update on metformin diabetes medicines EMA\/660975\/2019 published on 6 December2019."},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010022\u201000702\u20104"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2022.121740"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2021.1917547"},{"key":"e_1_2_6_9_1","unstructured":"EDQM 2022c. Ph.Eur. 10.6 0931; metformin hydrochloride (04\/2020)."},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c02120"},{"key":"e_1_2_6_11_1","unstructured":"Accessed August 22 2022.https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/search-list-recalled-metformin-products"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2022.121687"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2021.106026"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2020.113460"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/rcm.7505"},{"key":"e_1_2_6_16_1","unstructured":"Accessed August 22 2022.https:\/\/www.hsa.gov.sg\/docs\/default-source\/announcements\/safety-alerts\/determination-of-ndma-in-metformin-by-hram-gcms_pl_hsa_2021mar01.pdf"},{"key":"e_1_2_6_17_1","unstructured":"Combined Direct Injection N\u2010Nitrosodimethylamine (NDMA) and N\u2010Nitrosodiethylamine (NDEA) Impurity Assay GC\/MS \u00a0published by the USFDA on 12\/11\/2018."},{"key":"e_1_2_6_18_1","volume-title":"Gas Chromatography and Mass Spectrometry: A Practical Guide","author":"Sparkman OD","year":"2011"}],"container-title":["Rapid Communications in Mass Spectrometry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rcm.9414","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/rcm.9414","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rcm.9414","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T16:21:32Z","timestamp":1761495692000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/rcm.9414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,20]]},"references-count":17,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1,15]]}},"alternative-id":["10.1002\/rcm.9414"],"URL":"https:\/\/doi.org\/10.1002\/rcm.9414","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/RCM.9414\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/RCM.9414\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/RCM.9414\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/RCM.9414\/v2\/decision1","asserted-by":"object"}]},"ISSN":["0951-4198","1097-0231"],"issn-type":[{"value":"0951-4198","type":"print"},{"value":"1097-0231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,20]]},"assertion":[{"value":"2022-08-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e9414"}}