{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T21:21:39Z","timestamp":1786310499492,"version":"build-2736575974"},"reference-count":29,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T00:00:00Z","timestamp":1676937600000},"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":[[2023,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Since June 2018, globally large numbers of pharmaceuticals have been recalled due to the unexpected presence of nitrosamines. Beginning with the class of pharmaceuticals known as sartans, subsequent lines of inquiry included antidiabetic medicines, antihistamines, and antibiotics. A critical review of the U.S. Food and Drug Administration database reveals that the highest number of products\u00a0recall due to the presence of unacceptable levels of nitrosamines were losartan potassium drug products and their coformulations with other drug substances. The problem can be mainly attributed to naively adopted approval revisions and the lack of sufficient current analytical technologies to detect those contaminants in time. In this work, we developed a specific, selective, accurate, precise, and robust ultra\u2010performance liquid chromatography\u2010triple quadrupole\u2010mass spectrometry\u00a0(UPLC\u2010TQ\u2010MS\/MS) method for the estimation of eight genotoxic nitrosamine impurities in losartan and hydrochlorothiazide (HCTZ) tablets, which is the only fixed\u2010dosage combination approved by the USFDA to treat hypertension.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>All the nitrosamine impurities along with the drug substances were separated using an Agilent Pursuit XRs Ultra diphenyl column (150\u2009\u00d7\u20092.0\u00a0mm, 2.8\u00a0\u03bcm) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in methanol) at a flow rate of 0.4\u00a0ml\/min using the gradient elution program. The proposed method was validated per ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Q2 (R1) guidelines to ensure the method is suitable for its intended purpose.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Limit of detection and limit of quantification were obtained in the range of 0.25\u20130.5\u00a0ng\/mL, which was very low compared to levels specified by the USFDA, European Medicines Agency\u00a0(EMA), and other regulatory authorities that ensure the sensitivity of the method in its entire life cycle.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The developed method can be incorporated into an official monograph and applied for routine quality control analysis of losartan and HCTZ fixed\u2010dose combination tablets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/rcm.9488","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T01:23:11Z","timestamp":1675646591000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Development and validation of an analytical method for trace\u2010level quantification of genotoxic nitrosamine impurities in losartan and hydrochlorothiazide fixed\u2010dose combination tablets using ultra\u00a0performance liquid chromatography\u00a0triple quadrupole\u00a0mass spectrometry"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7453-0122","authenticated-orcid":false,"given":"Ravi","family":"Patel","sequence":"first","affiliation":[{"name":"Department of Quality Assurance, Graduate School of Pharmacy Gujarat Technological University  Gandhinagar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Purohit","sequence":"additional","affiliation":[{"name":"Department of Quality Assurance, Graduate School of Pharmacy Gujarat Technological University  Gandhinagar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-554X","authenticated-orcid":false,"given":"Ravisinh","family":"Solanki","sequence":"additional","affiliation":[{"name":"Department of Quality Assurance, Graduate School of Pharmacy Gujarat Technological University  Gandhinagar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8850-7468","authenticated-orcid":false,"given":"Dignesh","family":"Khunt","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Graduate School of Pharmacy Gujarat Technological University  Gandhinagar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chhaganbhai","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Shri Sarvajanik Pharmacy College  Mehsana India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5368-4707","authenticated-orcid":false,"given":"Rucha","family":"Patel","sequence":"additional","affiliation":[{"name":"Regulatory Affairs Division JAMP INDIA Pharmaceutical Pvt. Ltd.  Ahmedabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3369-753X","authenticated-orcid":false,"given":"Shalin","family":"Parikh","sequence":"additional","affiliation":[{"name":"Analytical Development Division Senores Pharmaceuticals  Ahmedabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"FDA announces voluntary recall of several medicines containing valsartan following detection of an impurity","year":"2018"},{"key":"e_1_2_8_3_1","volume-title":"FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan)","year":"2019"},{"key":"e_1_2_8_4_1","volume-title":"EMA 641563. Valsartan: Review of impurities extended to other sartan medicines EMA\/641563\/2018","year":"2018"},{"key":"e_1_2_8_5_1","volume-title":"Int Conf Harmon tech Requir Regist pharm hum use","author":"ICH","year":"2017"},{"key":"e_1_2_8_6_1","volume-title":"Control of Nitrosamine Impurities in Human Drugs","author":"U.S. Food & Drug Administration","year":"2021"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1079\/PNS19850015"},{"key":"e_1_2_8_8_1","volume-title":"Information about Nitrosamine Impurities in Medications","year":"2021"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c02120"},{"issue":"3","key":"e_1_2_8_10_1","first-page":"299","article-title":"Fixed combination of losartan and hydrochlorothiazide and reduction of risk of stroke","volume":"3","author":"Kjeldsen SE","year":"2007","journal-title":"Vasc Health Risk Manag"},{"key":"e_1_2_8_11_1","volume-title":"Drug Approval Package: Hyzaar (Losartan Potassium\/Hydrochlorothiazide)","year":"2003"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2018.11.010"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.JCOA.2022.100053"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.microc.2022.107402"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.1c00982"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/rcm.9414"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/10826076.2022.2126856"},{"key":"e_1_2_8_18_1","first-page":"1","volume-title":"Liquid chromatography\u2010high resolution mass spectrometry (LC\u2010HRMS) method for the determination of six nitrosamine impurities in ARB drugs. Stand Methods \u2010 Nitrosamines","author":"U. S. Food and Drug Administration (FDA)","year":"2019"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.JPBA.2019.04.049"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2021.113960"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.14233\/AJCHEM.2022.23756"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/chromsci\/bmac059"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.22037\/ijpr.2021.115102.15195"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.38212\/2224\u20106614.1063"},{"key":"e_1_2_8_25_1","volume-title":"Int Conf Harmon tech Requir Regist pharm hum use","author":"ICH","year":"2005"},{"key":"e_1_2_8_26_1","unstructured":"Pharmacopeial Forum 2020 46 5 General chapter prospectus: <1469> nitrosamine Impuritie"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(21)01330\u20101"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/J.1524\u20106175.2004.02632.X"},{"key":"e_1_2_8_29_1","volume-title":"Search List of Recalled Angiotensin II Receptor Blockers (ARBs) including Valsartan, Losartan and Irbesartan","year":"2021"},{"key":"e_1_2_8_30_1","volume-title":"Drug Recalls","year":"2022"}],"container-title":["Rapid Communications in Mass Spectrometry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rcm.9488","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/rcm.9488","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rcm.9488","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T09:16:46Z","timestamp":1761470206000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/rcm.9488"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,21]]},"references-count":29,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,4,30]]}},"alternative-id":["10.1002\/rcm.9488"],"URL":"https:\/\/doi.org\/10.1002\/rcm.9488","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/RCM.9488\/v3\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/RCM.9488\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/RCM.9488\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/RCM.9488\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/RCM.9488\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/RCM.9488\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/RCM.9488\/v3\/response1","asserted-by":"object"}]},"ISSN":["0951-4198","1097-0231"],"issn-type":[{"value":"0951-4198","type":"print"},{"value":"1097-0231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,21]]},"assertion":[{"value":"2022-11-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e9488"}}