{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T22:50:51Z","timestamp":1787611851190,"version":"build-2736575974"},"reference-count":22,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"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":["Biomedical Chromatography"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>N<\/jats:italic>\n                    \u2010Nitroso impurities are very hazardous genotoxic carcinogens that can occur as by\u2010products or breakdown products in pharmaceutical compounds. In this study, a sensitive and quality\u2010by\u2010design\u2013based high\u2010performance liquid chromatography method approach was developed and validated for the trace\u2010level determination of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010nitroso tizanidine in pharmaceutical formulations. Chromatographic separation was achieved using an XSelect HSS T3 column (100\u00c5, 150\u2009\u00d7\u20094.6\u2009mm, 3.5\u2009\u03bcm) and an isocratic mobile phase made up of 0.1% formic acid buffer and methanol (50:50 v\/v) at a flow rate of 0.6\u2009mL\/min to separate the samples. The detection wavelength was set at 230\u2009nm. The temperature of the column and sample was kept at 50\u00b0C and 10\u00b0C, respectively. A Box Behnken design was employed to evaluate the effects of critical method parameters, flow rate, column temperature, and methanol concentration on critical quality attributes, including retention time, tailing factor, and theoretical plate count. Quadratic models demonstrated good statistical significance with high correlation coefficients and nonsignificant lack\u2010of\u2010fit (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&gt;\u20090.05). The method was validated in accordance with ICHQ2 (R2) guidelines and exhibited excellent specificity, linearity, precision, accuracy, robustness, and sensitivity. The developed QbD\u2013based method is suitable for routine quality control and regulatory monitoring of N\u2010NTIZ in both active pharmaceutical ingredients and finished dosage forms.\n                  <\/jats:p>","DOI":"10.1002\/bmc.70474","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T11:09:54Z","timestamp":1778756994000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Quality\u2010by\u2010Design\u2013Driven Development and Validation of a Sensitive HPLC Method for Trace\u2010Level Determination of Nitrosamine Impurity in a Muscle Relaxant Drug Formulation"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9384-292X","authenticated-orcid":false,"given":"Vinod Kumar","family":"Manglige","sequence":"first","affiliation":[{"name":"Department of Chemistry, University College of Sciences Acharya Nagarjuna University  Nagarjuna Nagar Andhra Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6171-8046","authenticated-orcid":false,"given":"Syam Sundhar Sai Kumar","family":"Boppana","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University College of Sciences Acharya Nagarjuna University  Nagarjuna Nagar Andhra Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8753-9713","authenticated-orcid":false,"given":"Kiran Kumar","family":"Chagarlamudi","sequence":"additional","affiliation":[{"name":"Department of Chemistry Vignan's Foundation for Science Technology &amp; Research  Guntur Andhra Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2555-8637","authenticated-orcid":false,"given":"Venkata Siva Suryanarayana","family":"Gurram","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University College of Sciences Acharya Nagarjuna University  Nagarjuna Nagar Andhra Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3665-9039","authenticated-orcid":false,"given":"Rajesh","family":"Damarapurapu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University College of Sciences Acharya Nagarjuna University  Nagarjuna Nagar Andhra Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8530-019X","authenticated-orcid":false,"given":"Sumanth","family":"Mullangi","sequence":"additional","affiliation":[{"name":"Department of Chemistry Koneru Lakshmaiah Education Foundation  Guntur (District) Andhra Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2478\/acph\u20102021\u20100008"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.70101"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/sscp.70048"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/sscp.70180"},{"key":"e_1_2_8_6_1","unstructured":"EMA.2023.Nitrosamine Impurities\u2014Guidance for Marketing Authorisation Holders. European Medicines Agency 2023."},{"key":"e_1_2_8_7_1","unstructured":"EMA & FDA.2023.Control of Nitrosamine Impurities in Human Drugs\u2014Guidelines. EMA 2023; FDA Guidance 2020."},{"key":"e_1_2_8_8_1","unstructured":"European Directorate for the Quality of Medicines (EDQM).2022. \u201cN\u2010Nitrosamine Contamination\u2014In Brief.\u201d Council of Europe EDQM."},{"key":"e_1_2_8_9_1","unstructured":"European Medicines Agency (EMA).2020.Questions and Answers on \u201cInformation on Nitrosamines for Marketing Authorisation Holders."},{"key":"e_1_2_8_10_1","unstructured":"FDA.2020. \u201cControl of Nitrosamine Impurities in Human Drugs\u2014Guidance for Industry.\u201d U.S. Food and Drug Administration."},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/10826076.2015.1087409"},{"key":"e_1_2_8_12_1","volume-title":"StatPearls","author":"Ghanavatian S.","year":"2023"},{"key":"e_1_2_8_13_1","volume-title":"IARC Monographs on the Evaluation of Carcinogenic Risks to Humans","author":"IARC","year":"1978"},{"key":"e_1_2_8_14_1","unstructured":"International Council for Harmonisation (ICH).2022. \u201cM7 (R2): Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.\u201d"},{"key":"e_1_2_8_15_1","unstructured":"International Council for Harmonisation (ICH).2023. \u201cICH guideline Q2(R2): Validation of Analytical Procedures.\u201dhttps:\/\/database.ich.org\/sites\/default\/files\/ICH_Q2(R2)_Guideline_2023_1130.pdf."},{"key":"e_1_2_8_16_1","article-title":"Analytical Strategies for Nitrosamine Impurities in Sartan Drugs: Challenges and Solutions","volume":"197","author":"Kim S.","year":"2021","journal-title":"Journal of Pharmaceutical and Biomedical Analysis"},{"issue":"3","key":"e_1_2_8_17_1","article-title":"Risk Assessment of Nitrosamine Contamination in Medicinal Products","volume":"19","author":"Lachenmeier D. W.","year":"2022","journal-title":"International Journal of Environmental Research and Public Health"},{"key":"e_1_2_8_18_1","volume-title":"Clinical and Research Information on Drug\u2010Induced Liver Injury","author":"Liver Tox","year":"2012"},{"key":"e_1_2_8_19_1","article-title":"Trace Analysis of N\u2010Nitrosodimethylamine (NDMA) in Pharmaceutical Products Containing Metformin","volume":"178","author":"Schmidtsdorff S.","year":"2020","journal-title":"Journal of Pharmaceutical and Biomedical Analysis"},{"key":"e_1_2_8_20_1","article-title":"Determination of N\u2010Nitrosodimethylamine in Ranitidine by Liquid Chromatography\u2013High Resolution Mass Spectrometry","volume":"192","author":"Tian Y.","year":"2021","journal-title":"Journal of Pharmaceutical and Biomedical Analysis"},{"key":"e_1_2_8_21_1","unstructured":"U.S. Food and Drug Administration (FDA).2023. \u201cFDA Updates and Press Announcements on Nitrosamine Impurities.\u201d"},{"key":"e_1_2_8_22_1","unstructured":"United States Pharmacopeia (USP).2021. \u201cUSP <1225> Validation of Compendial Procedures.\u201d USP\u2013NF 44(1)."},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495\u2010199753030\u201000007"}],"container-title":["Biomedical Chromatography"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bmc.70474","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bmc.70474","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bmc.70474","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T06:21:34Z","timestamp":1781763694000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/bmc.70474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":22,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/bmc.70474"],"URL":"https:\/\/doi.org\/10.1002\/bmc.70474","archive":["Portico"],"relation":{},"ISSN":["0269-3879","1099-0801"],"issn-type":[{"value":"0269-3879","type":"print"},{"value":"1099-0801","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,14]]},"assertion":[{"value":"2025-12-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70474"}}