{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:43:16Z","timestamp":1775979796553,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Rapid Comm Mass Spectrometry"],"published-print":{"date-parts":[[2026,5,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>The occurrence of complex nitrosamines, namely, N\u2010nitroso drug substance related impurities (NDRSI) in pharmaceuticals is of great concern due to their potential carcinogenic and mutagenic properties. This creates the need for more rigid and more specific methods of analysis to determine NDSRI levels in pharmaceutical products. The main analysis problem is that it is difficult to separate these impurities and the active pharmaceutical ingredient by chromatography, which is due to their structural similarity. This study describes how a new method of measuring two specific impurities in the Leucovorin drug product, N\u2010nitroso leucovorin and di\u2010nitroso leucovorin, was developed and validated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Quantification was done by selective reaction monitoring by a positive electrospray ionization source. The required separation was achieved with the use of a reverse\u2010phase C\u20108 column and gradient\u2010elution in the methanol and water solutions, both adjusted with 0.1% formic acid.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Linearity of the method was established in a range of 0.1 to 1.5 ng\/mL, which is effectually 10% to 150% of its necessary regulatory limit. The procedure had a detection limit of 0.05 ng\/mL and a quantitation limit of 0.1 ng\/mL. Additionally, it also demonstrated excellent specificity, precision, linearity, accuracy, and robustness when dealing with the two impurities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This methodology will therefore offer a crucial solution to drug manufacturers to track and control N\u2010nitroso leucovorin and Di\u2010nitroso leucovorin concentrations, which will have a positive impact on regulatory compliance and patient safety.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/rcm.70049","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T03:59:26Z","timestamp":1773201566000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Efficient and Simultaneous LC\u2010MS\/MS Detection of N\u2010Nitroso and Di\u2010Nitroso Leucovorin in Leucovorin Drug Products: Method Development and Validation"],"prefix":"10.1002","volume":"40","author":[{"given":"Jaya","family":"Yalamanchili","sequence":"first","affiliation":[{"name":"Department of Chemistry, GITAM School of Science GITAM Deemed to be University  Vishakhapatnam Andhra Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Himavathi","family":"Ganja","sequence":"additional","affiliation":[{"name":"Department of Chemistry, GITAM School of Science GITAM Deemed to be University  Vishakhapatnam Andhra Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0292-8545","authenticated-orcid":false,"given":"Suresh","family":"Salakolusu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, GITAM School of Science GITAM Deemed to be University  Vishakhapatnam Andhra Pradesh India"},{"name":"Analytical Discovery Chemistry Aragen Life Sciences Pvt. Ltd.  Hyderabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2019.05.022"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2023.105403"},{"key":"e_1_2_11_4_1","unstructured":"European Medicines Agency (EMA) \u201cCHAMPIX (Varenicline) \u2013 Lots to Be Recalled due to Presence of Impurity N\u2010Nitroso\u2010Varenicline \u201d (2021)."},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c02120"},{"key":"e_1_2_11_6_1","unstructured":"U.S. Food and Drug Administration (FDA) \u201cPfizer Expands Voluntary Nationwide Recall to Include All Lots of CHANTIX (Varenicline) Tablets due to N\u2010Nitroso Varenicline Content \u201d (2021)."},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2022.11.013"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2022.04.016"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2023.01.021"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2023.02.024"},{"key":"e_1_2_11_11_1","unstructured":"European Medicines Agency (EMA) \u201cQuestions and Answers for Marketing Authorisation Holders\/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726\/2004 Referral on Nitrosamine Impurities in Human Medicinal Products \u201d EMA\/409815\/2020 Rev.22."},{"key":"e_1_2_11_12_1","unstructured":"U.S. Food and Drug Administration (FDA) \u201cRecommended Acceptable Intake Limits for Nitrosamine Drug Substance\u2010Related Impurities (NDSRIs); Guidance for Industry Control of Nitrosamine Impurities in Human Drugs \u201d Silver Spring MD USA (2023)."},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2024.105640"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/00043426-199608000-00014"},{"key":"e_1_2_11_15_1","first-page":"264","article-title":"Lessons From the Leucovorin Shortages Between 2009 and 2012 in a Medicare Advantage Population: Where Do We Go From Here?","volume":"7","author":"Hayes M. S.","year":"2014","journal-title":"American Health & Drug Benefits"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.11-6-694"},{"key":"e_1_2_11_17_1","article-title":"Folic Acid and Folinic Acid for Reducing Side Effects in Patients Receiving Methotrexate for Rheumatoid Arthritis","volume":"5","author":"Shea B.","year":"2013","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"e_1_2_11_18_1","first-page":"441","article-title":"Folic Acid Supplementation Prevents Deficient Blood Folate Levels and Hyperhomocysteinemia During Long\u2010Term, Low\u2010Dose Methotrexate Therapy for Rheumatoid Arthritis: Implications for Cardiovascular Disease Prevention","volume":"25","author":"Morgan S. 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