{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:26:26Z","timestamp":1761863186155},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Malar J"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as \u03b2-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of \u03b2-artemether and lumefantrine FDC products.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30\u00b0C, were evaluated. \u03b2-artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1mM phosphate buffer pH 3.0 (52:48; V\/V) at a flow of 1.0 ml\/min and 3 \u03bcl injection volume. Quantification was performed at 210 nm and 335 nm for \u03b2-artemether and for lumefantrine, respectively. <jats:italic>In-silico<\/jats:italic> toxicological evaluation of the related impurities was made using Derek Nexus v2.0\u00ae.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Both \u03b2-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (\u00b1 RSD) of 99.7 % (\u00b1 0.7%) for \u03b2-artemether and 99.7 % (\u00b1 0.6%) for lumefantrine. All identified \u03b2-artemether-related impurities were predicted in Derek Nexus v2.0\u00ae to have toxicity risks similar to \u03b2-artemether active pharmaceutical ingredient (API) itself.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>A rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of \u03b2-artemether and lumefantrine. This method can be applied in the routine regulatory quality control of FDC products. The <jats:italic>in-silico<\/jats:italic> toxicological investigation using Derek Nexus\u00ae indicated that the overall toxicity risk for \u03b2-artemether-related impurities is comparable to that of \u03b2-artemether API.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1475-2875-12-145","type":"journal-article","created":{"date-parts":[[2013,4,30]],"date-time":"2013-04-30T14:26:32Z","timestamp":1367331992000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A rapid stability-indicating, fused-core HPLC method for simultaneous determination of \u03b2-artemether and lumefantrine in anti-malarial fixed dose combination products"],"prefix":"10.1186","volume":"12","author":[{"given":"Sultan","family":"Suleman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsten","family":"Vandercruyssen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelien","family":"Wynendaele","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"D\u2019Hondt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Bracke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc","family":"Duchateau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Burvenich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathelijne","family":"Peremans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bart","family":"De Spiegeleer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2013,4,30]]},"reference":[{"key":"2755_CR1","volume-title":"World Malaria Report, Global Malaria Programme","author":"WHO","year":"2008","unstructured":"WHO: World Malaria Report, Global Malaria Programme. 2008, Geneva: World Health Organization Publication, http:\/\/whqlibdoc.who.int\/publications\/2008\/9789241563697_eng.pdf [Accessed on June 22, 2012 at 18:50]"},{"key":"2755_CR2","volume-title":"World Malaria Report, Global Malaria Programme","author":"WHO","year":"2011","unstructured":"WHO: World Malaria Report, Global Malaria Programme. 2011, Geneva: World Health Organization Publication, http:\/\/www.who.int\/malaria\/world_malaria_report_2011\/en\/ [Accessed on June 22, 2012 at 19:10]"},{"key":"2755_CR3","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S0140-6736(12)60034-8","volume":"379","author":"CJ Murray","year":"2012","unstructured":"Murray CJ, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, Fullman N, Naghavi M, Lozano R, Lopez AD: Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet. 2012, 379: 413-10.1016\/S0140-6736(12)60034-8.","journal-title":"Lancet"},{"key":"2755_CR4","volume-title":"Guidelines for the treatment of malaria","author":"WHO","year":"2010","unstructured":"WHO: Guidelines for the treatment of malaria. 2010, Geneva: World Health Organization"},{"key":"2755_CR5","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1097\/01.qco.0000186848.46417.6c","volume":"18","author":"EA Ashley","year":"2005","unstructured":"Ashley EA, White NJ: Artemisinin-based combinations. Cur Opin Infect Dis. 2005, 18: 531-36. 10.1097\/01.qco.0000186848.46417.6c.","journal-title":"Cur Opin Infect Dis"},{"key":"2755_CR6","first-page":"p188","volume-title":"Essential Malariology","author":"HM Gilles","year":"1993","unstructured":"Gilles HM, Warrell DA: Essential Malariology. 1993, London: Arnold Publishers, p188-"},{"key":"2755_CR7","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMoa0808859","volume":"361","author":"AM Dondorp","year":"2009","unstructured":"Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, Yeung AS, Singhasivanon P, Day PJ, Lindegardh N, Socheat D, White NJ: Artemisinin resistance Plasmodium falciparum malaria. N Engl J Med. 2009, 361: 455-467. 10.1056\/NEJMoa0808859.","journal-title":"N Engl J Med"},{"key":"2755_CR8","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1126\/science.1098876","volume":"305","author":"C Roper","year":"2004","unstructured":"Roper C, Pearce R, Nair S, Sharp B, Nosten F, Anderson T: Intercontinental spread of pyrimethamine-resistant malaria. Science. 2004, 305: 1124-10.1126\/science.1098876.","journal-title":"Science"},{"key":"2755_CR9","doi-asserted-by":"publisher","first-page":"49","DOI":"10.2217\/thy.09.84","volume":"7","author":"H Kaur","year":"2010","unstructured":"Kaur H, Green MD, Hostetler DM, Fern\u00e1ndez FM, Newton PN: Anti-malarial drug quality: methods to detect suspect drugs, A Review. Therapy. 2010, 7: 49-57. 10.2217\/thy.09.84.","journal-title":"Therapy"},{"key":"2755_CR10","volume-title":"Counterfeit medicines. Fact sheet No. 275","author":"WHO","year":"2006","unstructured":"WHO: Counterfeit medicines. Fact sheet No. 275. 2006, 1211 Geneva 27 Switzerland: WHO Media Center, [http:\/\/whqlibdoc.who.int\/fact_sheet\/2006\/FS_275.pdf] [Accessed on 15 June 2012 at 11:30"},{"key":"2755_CR11","unstructured":"WHO: Drug policy. [http:\/\/www.searo.who.int\/EN\/Section10\/Section21\/Section340_4040.htm] [Accessed on 16 June 2012 at 10:25]"},{"key":"2755_CR12","volume-title":"Stability testing of new drug substances and products CPMP\/ICH\/2736\/99;","author":"ICH guidelines - International Conference on Harmonization, Q1A(R2","year":"2003","unstructured":"ICH guidelines - International Conference on Harmonization, Q1A(R2: Stability testing of new drug substances and products CPMP\/ICH\/2736\/99;. 2003, [http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2009\/09\/WC500002651.pdf], [Accessed on 19 June 2012 at 19:35]"},{"key":"2755_CR13","doi-asserted-by":"publisher","first-page":"142","DOI":"10.2174\/157341210791202627","volume":"6","author":"K Hamid","year":"2010","unstructured":"Hamid K, Mushir A, Alka A, Javed A: Stability testing of pharmaceutical products - comparison of stability testing guidelines. Cur Pharm Anal. 2010, 6: 142-150. 10.2174\/157341210791202627.","journal-title":"Cur Pharm Anal"},{"key":"2755_CR14","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1007\/s00216-010-3912-4","volume":"398","author":"B Baert","year":"2010","unstructured":"Baert B, De Spiegeleer B: Quality analytics of internet pharmaceuticals. Anal Bioanal Chem. 2010, 398: 125-136. 10.1007\/s00216-010-3912-4.","journal-title":"Anal Bioanal Chem"},{"key":"2755_CR15","first-page":"598","volume-title":"The complete drug reference","author":"Martindale","year":"2009","unstructured":"Martindale: The complete drug reference. 2009, Lambeth High Street, London: Pharmaceutical press, 598-599. 36","edition":"36"},{"key":"2755_CR16","unstructured":"The Merck Index. 2001, USA: Merck & Co., Inc, 13"},{"key":"2755_CR17","volume-title":"Guidelines for Temperature Control of Drug Products during Storage and Transportation (GUI-0069)","author":"Health Canada\/Health Products and Food Branch Inspectorate","year":"2012","unstructured":"Health Canada\/Health Products and Food Branch Inspectorate: Guidelines for Temperature Control of Drug Products during Storage and Transportation (GUI-0069). 2012, http:\/\/infitrak.com\/ims\/wp-content\/uploads\/GUI-0069-eng.pdf, [Accessed on 19 June 2012 at 23:10]"},{"key":"2755_CR18","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1590\/S1984-82502009000400018","volume":"45","author":"ID Cesar","year":"2009","unstructured":"Cesar ID, Pianetti GA: Quantitation of artemether in pharmaceutical raw material and injections by high performance liquid chromatography. Braz J Pharm Sci. 2009, 45: 737-742. 10.1590\/S1984-82502009000400018.","journal-title":"Braz J Pharm Sci"},{"key":"2755_CR19","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1046\/j.1365-3156.2001.00793.x","volume":"6","author":"A Magnus","year":"2001","unstructured":"Magnus A, Atemnkeng Katelijne De C, Jacqueline Plaizier V: Quality control of active ingredients in artemisinin-derivative anti-malarials within Kenya and DR Congo. Trop Med Int Health. 2001, 6: 980-982. 10.1046\/j.1365-3156.2001.00793.x.","journal-title":"Trop Med Int Health"},{"key":"2755_CR20","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.jpba.2012.06.002","volume":"70","author":"BMJ De Spiegeleer","year":"2012","unstructured":"De Spiegeleer BMJ, D\u2019Hondt M, Vangheluwe E, Vandercruyssen K, De Spiegeleer BVI, Jansen H, Ilse K, Van Gompel J: Relative response factor determination of \u03b2-artemether degradants by a dry heat stress approach. J Pharm Biomed Anal. 2012, 70: 111-116.","journal-title":"J Pharm Biomed Anal"},{"key":"2755_CR21","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.jpba.2008.05.006","volume":"48","author":"ID Cesar","year":"2008","unstructured":"Cesar ID, Nogueira FHA, Pianetti GA: Comparison of HPLC, UV spectrophotometry and potentiometric titration methods for the determination of lumefantrine in pharmaceutical products. J Pharm Biomed Anal. 2008, 48: 223-226. 10.1016\/j.jpba.2008.05.006.","journal-title":"J Pharm Biomed Anal"},{"key":"2755_CR22","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1365\/s10337-008-0894-x","volume":"69","author":"KR Patil","year":"2009","unstructured":"Patil KR, Rane VP, Sangshetti JN, Shinde DB: A stability-indicating lc method for lumefantrine. Chromatographia. 2009, 69: 375-379. 10.1365\/s10337-008-0894-x.","journal-title":"Chromatographia"},{"key":"2755_CR23","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/1475-2875-10-51","volume":"10","author":"M Verbeken","year":"2011","unstructured":"Verbeken M, Suleman S, Baert B, Vangheluwe E, Van Dorpe S, Burvenich C, Duchateau L, Jansen FH, De Spiegeleer B: Stability-indicating HPLC-DAD\/UV-ESI\/MS impurity profiling of the anti-malarial drug lumefantrine. Malar J. 2011, 10: 51-10.1186\/1475-2875-10-51.","journal-title":"Malar J"},{"key":"2755_CR24","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/j.jpba.2008.05.022","volume":"48","author":"ID Cesar","year":"2008","unstructured":"Cesar ID, Nogueira FHA, Pianetti GA: Simultaneous determination of artemether and lumefantrine in fixed dose combination tablets by HPLC with UV detection. J Pharm Biomed Anal. 2008, 48: 951-954. 10.1016\/j.jpba.2008.05.022.","journal-title":"J Pharm Biomed Anal"},{"key":"2755_CR25","unstructured":"Authorized Lumefantrine and Artemether Tablets USP Salmous Standard. 2009, [http:\/\/www.usp.org\/sites\/default\/files\/usp_pdf\/EN\/nonUSStandards\/lumefantrineArtemetherTablets.pdf], [Accessed on 19\/06\/2012 at 19:30]"},{"key":"2755_CR26","volume-title":"International Pharmacopoeia","author":"WHO","year":"2008","unstructured":"WHO: International Pharmacopoeia. 2008, Geneva: World Health Organization, 4","edition":"4"},{"key":"2755_CR27","volume-title":"European Pharmacopoeia","author":"European Directorate for the Quality of Medicines","year":"2006","unstructured":"European Directorate for the Quality of Medicines: European Pharmacopoeia. 2006, Strasbourg: EDQM, 5","edition":"5"},{"key":"2755_CR28","volume-title":"J Pharm Anal","author":"K Vandercruyssen","year":"2013","unstructured":"Vandercruyssen K, D\u2019Hondt M, Vergote V, Jansen H, Burvenich C, De Spiegeleer B: LC-UV\/MS quality analytics of paediatric artemether formulations. J Pharm Anal. 2013, Manuscript accepted for publication"},{"key":"2755_CR29","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1002\/minf.200900006","volume":"29","author":"CM Ellison","year":"2010","unstructured":"Ellison CM, Madden JC, Judson P, Cronin MTD: Using in-silico tools in a weight of evidence approach to aid toxicological assessment. Mol Inf. 2010, 29: 97-110. 10.1002\/minf.200900006.","journal-title":"Mol Inf"},{"key":"2755_CR30","doi-asserted-by":"publisher","first-page":"499","DOI":"10.2174\/138955707780619554","volume":"7","author":"CG Mohan","year":"2007","unstructured":"Mohan CG, Gandhi T, Garg D, Shinde R: Computer-assisted methods in chemical toxicity prediction. Mini Rev Med Chem. 2007, 7: 499-507. 10.2174\/138955707780619554.","journal-title":"Mini Rev Med Chem"},{"key":"2755_CR31","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1177\/096032719101000405","volume":"10","author":"DM Sanderson","year":"1991","unstructured":"Sanderson DM, Earnshaw CG: Computer Prediction of Possible Toxic Action from Chemical Structure; The DEREK System. Hum Exp Toxicol. 1991, 10: 261-273. 10.1177\/096032719101000405.","journal-title":"Hum Exp Toxicol"},{"key":"2755_CR32","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0021-9673(02)01536-4","volume":"987","author":"GA Shabir","year":"2003","unstructured":"Shabir GA: Validation of high-performance liquid chromatography methods for pharmaceutical analysis. Understanding the differences and similarities between validation requirements of the US Food and Drug Administration, the US Pharmacopeia and the International Conference on Harmonization. J Chromatogr A. 2003, 987: 57-66. 10.1016\/S0021-9673(02)01536-4.","journal-title":"J Chromatogr A"}],"container-title":["Malaria Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1475-2875-12-145.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T23:39:07Z","timestamp":1630539547000},"score":1,"resource":{"primary":{"URL":"https:\/\/malariajournal.biomedcentral.com\/articles\/10.1186\/1475-2875-12-145"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,4,30]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,12]]}},"alternative-id":["2755"],"URL":"https:\/\/doi.org\/10.1186\/1475-2875-12-145","relation":{},"ISSN":["1475-2875"],"issn-type":[{"value":"1475-2875","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,4,30]]},"assertion":[{"value":"20 February 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 April 2013","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 April 2013","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"145"}}