{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T22:13:52Z","timestamp":1788300832524,"version":"build-2803163510"},"reference-count":18,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,12,30]],"date-time":"2023-12-30T00:00:00Z","timestamp":1703894400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100012245","name":"Science and Technology Planning Project of Guangdong Province","doi-asserted-by":"publisher","award":["201802010047"],"award-info":[{"award-number":["201802010047"]}],"id":[{"id":"10.13039\/501100012245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biomedical Chromatography"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In the production of doxofylline, the common occurrence of toxic <jats:italic>p<\/jats:italic>\u2010toluene sulfonate generation prompted the development and validation of a method using HPLC with ultraviolet detection (HPLC\u2010UV). This method is designed for detecting four potential genotoxic impurities (PGIs) present in both doxofylline drug substance and tablets, with a focus on the UV\u2010absorbing group <jats:italic>p<\/jats:italic>\u2010toluene sulfonate. The four impurities were methyl 4\u2010methylbenzenesulfonate (PGI\u20101), ethyl 4\u2010methylbenzenesulfonate (PGI\u20102), 2\u2010hydroxyethyl 4\u2010methylbenzenesulfonate (PGI\u20103), and 2\u2010(4\u2010methylphenyl)sulfonyloxyethyl 4\u2010methylbenzenesulfonate (PGI\u20104). In this method, chromatographic separation was achieved using a Waters Symmetry C<jats:sub>18<\/jats:sub> column (250 mm \u00d7 4.6 mm, 5 \u03bcm). The mobile phases consisted of 20% acetonitrile as mobile phase A and pure acetonitrile as mobile phase B, operating in gradient elution mode at a flow rate of 1.0 mL\/min. According to the guidelines of the International Conference on Harmonization, it was determined that this method could quantify four PGIs at 0.0225 \u03bcg\/mL in samples containing 60 mg\/mL. The validated approach demonstrated excellent linearity (R<jats:sup>2<\/jats:sup> &gt; 0.999) across the concentration range of 30%\u2013200% (relative to 0.075 \u03bcg\/mL doxofylline) for the four PGIs. The accuracy of this method for the four PGIs ranged from 94.8% to 100.4%. The reverse\u2010phase\u2010HPLC\u2010UV analytical method developed in this study is characterized by its speed and precision, making it suitable for the sensitive analysis of benzene sulfonate PGIs in doxofylline drug substances and tablets.<\/jats:p>","DOI":"10.1002\/bmc.5790","type":"journal-article","created":{"date-parts":[[2023,12,30]],"date-time":"2023-12-30T05:39:09Z","timestamp":1703914749000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Simultaneous and trace\u2010level quantification of four benzene sulfonate potential genotoxic impurities in doxofylline active pharmaceutical ingredients and tablets using high\u2010performance liquid chromatography with ultraviolet detection"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4776-0814","authenticated-orcid":false,"given":"Tingyu","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Drug Research and Transformation, School of Pharmacy Guangdong Pharmaceutical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaqing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Drug Research and Transformation, School of Pharmacy Guangdong Pharmaceutical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiekeng","family":"Lao","sequence":"additional","affiliation":[{"name":"Department of Drug Research and Transformation, School of Pharmacy Guangdong Pharmaceutical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Drug Research and Transformation, School of Pharmacy Guangdong Pharmaceutical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Drug Research and Transformation, School of Pharmacy Guangdong Pharmaceutical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yicong","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Drug Research and Transformation, School of Pharmacy Guangdong Pharmaceutical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Drug Research and Transformation, School of Pharmacy Guangdong Pharmaceutical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,30]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(00)00626-8"},{"key":"e_1_2_6_3_1","first-page":"472","volume-title":"National Pharmacopoeia Commission. The two general principles of Chinese Pharmacopoeia","author":"ChP","year":"2020"},{"key":"e_1_2_6_4_1","unstructured":"EMEA CHMP. (2006).Guidelines on the limit of genotoxic impurities. European Medicines Agency Committee for Medicinal Products for Human Use London.https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-limits-genotoxic-impurities_en.pdf (June)."},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx9501849"},{"key":"e_1_2_6_6_1","unstructured":"FDA CDER. (2008).Guidance for industry: Genotoxic and carcinogenic impurities in drug substances and products: Recommended approaches. In Draft December.http:\/\/www.fda.gov\/cder\/guidance\/index.htm"},{"issue":"4","key":"e_1_2_6_7_1","first-page":"CR297","article-title":"Efficacy and safety of doxofylline compared to theophylline in chronic reversible asthma\u2014A double\u2010blind randomized placebo\u2010controlled multicentre clinical trial","volume":"8","author":"Goldstein M. 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