{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:41:11Z","timestamp":1790890871663,"version":"4.1.0"},"reference-count":28,"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":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Lumefantrine (benflumetol) is a fluorene derivative belonging to the aryl amino alcohol class of anti-malarial drugs and is commercially available in fixed combination products with \u03b2-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. However, until now, no exhaustive impurity profile of lumefantrine has been established, encompassing process-related and degradation impurities in active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Using HPLC-DAD\/UV-ESI\/ion trap\/MS, a comprehensive impurity profile was established based upon analysis of market samples as well as stress, accelerated and long-term stability results. <jats:italic>In-silico<\/jats:italic> toxicological predictions for these lumefantrine related impurities were made using Toxtree<jats:sup>\u00ae<\/jats:sup> and Derek<jats:sup>\u00ae<\/jats:sup>.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Several new impurities are identified, of which the desbenzylketo derivative (DBK) is proposed as a new specified degradant. DBK and the remaining unspecified lumefantrine related impurities are predicted, using Toxtree<jats:sup>\u00ae<\/jats:sup> and Derek<jats:sup>\u00ae<\/jats:sup>, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>From unstressed, stressed and accelerated stability samples of lumefantrine API and FPPs, nine compounds were detected and characterized to be lumefantrine related impurities. One new lumefantrine related compound, DBK, was identified and characterized as a specified degradation impurity of lumefantrine in real market samples (FPPs). The <jats:italic>in-silico<\/jats:italic> toxicological investigation (Toxtree<jats:sup>\u00ae<\/jats:sup> and Derek<jats:sup>\u00ae<\/jats:sup>) indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1475-2875-10-51","type":"journal-article","created":{"date-parts":[[2011,3,2]],"date-time":"2011-03-02T00:04:44Z","timestamp":1299024284000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Stability-indicating HPLC-DAD\/UV-ESI\/MS impurity profiling of the anti-malarial drug lumefantrine"],"prefix":"10.1186","volume":"10","author":[{"given":"Mathieu","family":"Verbeken","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sultan","family":"Suleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bram","family":"Baert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elien","family":"Vangheluwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Van Dorpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Burvenich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Duchateau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans H","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"De Spiegeleer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,2,28]]},"reference":[{"key":"1643_CR1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/j.trstmh.2004.09.013","volume":"99","author":"C Falade","year":"2005","unstructured":"Falade C, Makanga M, Premji Z, Ortmann CE, Stockmeyer M, de Palacios PI: Efficacy and safety of artemether-lumefantrine (Coartem (R)) tablets (six-dose regimen) in African infants and children with acute) uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg. 2005, 99: 459-467. 10.1016\/j.trstmh.2004.09.013.","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"1643_CR2","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1046\/j.1365-3156.1998.00250.x","volume":"3","author":"C Hatz","year":"1998","unstructured":"Hatz C, Abdulla S, Mull R, Schellenberg D, Gathmann I, Kibatala P, Beck HP, Tanner M, Royce C: Efficacy and safety of CGP 56697 (artemether and benflumetol) compared with chloroquine to treat acute falciparum malaria in Tanzanian children aged 1-5 years. Trop Med Int Health. 1998, 3: 498-504. 10.1046\/j.1365-3156.1998.00250.x.","journal-title":"Trop Med Int Health"},{"issue":"4","key":"1643_CR3","doi-asserted-by":"publisher","first-page":"355","DOI":"10.2307\/2787095","volume":"60","author":"M van Vugt","year":"1997","unstructured":"van Vugt M: Concerns about the privatization of public goods: A social dilemma analysis. Soc Psychol Q. 1997, 60 (4): 355-367. 10.2307\/2787095.","journal-title":"Soc Psychol Q"},{"key":"1643_CR4","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/S0035-9203(00)90082-8","volume":"94","author":"M van Vugt","year":"2000","unstructured":"van Vugt M, Looareesuwan S, Wilairatana P, McGready R, Villegas L, Gathmann I, Mull R, Brockman A, White NJ, Nosten F: Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria. Trans R Soc Trop Med Hyg. 2000, 94: 545-548. 10.1016\/S0035-9203(00)90082-8.","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"1643_CR5","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1086\/516524","volume":"176","author":"L vonSeidlein","year":"1997","unstructured":"vonSeidlein L, Jaffar S, Pinder M, Haywood M, Snounou G, Gemperli B, Gathmann I, Royce C, Greenwood B: Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697. J Infect Dis. 1997, 176: 1113-1116. 10.1086\/516524.","journal-title":"J Infect Dis"},{"key":"1643_CR6","doi-asserted-by":"publisher","first-page":"2868","DOI":"10.3390\/molecules14082868","volume":"14","author":"KA de Villiers","year":"2009","unstructured":"de Villiers KA, Egan TJ: Recent advances in the discovery of haem-targeting drugs for malaria and schistosomiasis. Molecules. 2009, 14: 2868-2887. 10.3390\/molecules14082868.","journal-title":"Molecules"},{"key":"1643_CR7","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.ejphar.2003.11.003","volume":"484","author":"M Traebert","year":"2004","unstructured":"Traebert M, Dumotier B, Meister L, Hoffmann P, Dominguez-Estevez M, Suter W: Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol. 2004, 484: 41-48. 10.1016\/j.ejphar.2003.11.003.","journal-title":"Eur J Pharmacol"},{"key":"1643_CR8","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/BF03040424","volume":"116","author":"DK Pirker-Krassnig","year":"2004","unstructured":"Pirker-Krassnig DK, Wernsdorfer G, Sirichaisinthop J, Rojanawatsirivet C, Kollaritsch H, Wernsdorfer WH: Comparative study on the in vitro activity of lumefantrine and desbutyl-benflumetol in fresh isolates of Plasmodium vivax from Thailand. Wien Klin Wochenschr. 2004, 116: 47-52. 10.1007\/BF03040424.","journal-title":"Wien Klin Wochenschr"},{"key":"1643_CR9","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/S0001-706X(97)00141-1","volume":"70","author":"WH Wernsdorfer","year":"1998","unstructured":"Wernsdorfer WH, Landgraf B, Kilimali V, Wernsdorfer G: Activity of benflumetol and its enantiomers in fresh isolates of Plasmodium falciparum from East Africa. Acta Trop. 1998, 70: 9-15. 10.1016\/S0001-706X(97)00141-1.","journal-title":"Acta Trop"},{"key":"1643_CR10","doi-asserted-by":"crossref","first-page":"31","DOI":"10.4269\/ajtmh.1997.57.31","volume":"57","author":"F Ballereau","year":"1997","unstructured":"Ballereau F, Prazuck T, Schrive I, Lafleuriel MT, Rozec D, Fisch A, Lafaix C: Stability of essential drugs in the field: Results of a study conducted over a two-year period in Burkina Faso. Am J Trop Med Hyg. 1997, 57: 31-36.","journal-title":"Am J Trop Med Hyg"},{"issue":"1","key":"1643_CR11","doi-asserted-by":"crossref","first-page":"32","DOI":"10.12973\/ejac\/78054","volume":"2","author":"SBKB Bari","year":"2007","unstructured":"Bari SBKB, Jaiswal YS, Shikhedkar AA: Impurity profile: Significance in active pharmaceutical ingredient. Eurasian J Anal Chem. 2007, 2 (1): 32-53.","journal-title":"Eurasian J Anal Chem"},{"key":"1643_CR12","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1002\/psc.1167","volume":"15","author":"V Vergote","year":"2009","unstructured":"Vergote V, Burvenich C, Van de Wiele C, De Spiegeleer B: Quality specifications for peptide drugs: a regulatory-pharmaceutical approach. J Pept Sci. 2009, 15: 697-710. 10.1002\/psc.1167.","journal-title":"J Pept Sci"},{"key":"1643_CR13","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.ab.2008.02.014","volume":"376","author":"B De Spiegeleer","year":"2008","unstructured":"De Spiegeleer B, Vergote V, Pezeshki A, Peremans K, Burvenich C: Impurity profiling quality control testing of synthetic peptides using liquid chromatography-photodiode array-fluorescence and liquid chromatography-electrospray ionization-mass spectrometry: The obestatin case. Anal Biochem. 2008, 376: 229-234. 10.1016\/j.ab.2008.02.014.","journal-title":"Anal Biochem"},{"key":"1643_CR14","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/S0731-7085(97)00131-3","volume":"16","author":"EC Nicolas","year":"1998","unstructured":"Nicolas EC, Scholz TH: Active drug substance impurity profiling - Part I. LC\/UV diode array spectral matching. J Pharm Biomed Anal. 1998, 16: 813-824. 10.1016\/S0731-7085(97)00131-3.","journal-title":"J Pharm Biomed Anal"},{"key":"1643_CR15","doi-asserted-by":"publisher","first-page":"article 6","DOI":"10.1208\/pt030206","volume":"3","author":"J Roy","year":"2002","unstructured":"Roy J: Pharmaceutical impurities - A mini review. AAPS PharmSciTech. 2002, 3: article 6-10.1208\/pt030206.","journal-title":"AAPS PharmSciTech"},{"key":"1643_CR16","unstructured":"ICH guidelines - International Conference on Harmonization, Q3A(R2) Impurities in new drug substances CPMP\/ICH\/2737\/99. (October 2006). [Accessed on 5 November 2010 at 11:06], [http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2009\/09\/WC500002675.pdf]"},{"key":"1643_CR17","unstructured":"Authorized Lumefantrine USP Salmous Standard (Februari 2009). [Accessed on 24 October 2010 at 17:14], [http:\/\/www.usp.org\/pdf\/EN\/nonUSStandards\/lumefantrine.pdf]"},{"key":"1643_CR18","unstructured":"Lumefantrine: Document QAS\/06.186\/FINAL (WHO Ph. Int. - July 2008). [Accessed on 24 October 2010 at 17:37], [http:\/\/www.who.int\/medicines\/publications\/pharmacopoeia\/Lumef_monoFINALQAS06_186_July08.pdf]"},{"key":"1643_CR19","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1081\/JLC-200053022","volume":"28","author":"H Lee","year":"2005","unstructured":"Lee H: Pharmaceutical applications of liquid chromatography coupled with mass spectrometry (LC\/MS). J Liq Chromatogr Relat Technol. 2005, 28: 1161-1202. 10.1081\/JLC-200053022.","journal-title":"J Liq Chromatogr Relat Technol"},{"key":"1643_CR20","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":"1643_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":"1643_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":"1643_CR23","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1365\/s10337-009-1446-8","volume":"71","author":"V Munjal","year":"2010","unstructured":"Munjal V, Paliwal N, Chaursia BK, Varshney B, Ahmed T, Paliwal J: LC-tandem mass spectrometry method for quantification of lumefantrine in human plasma and its application to bioequivalence study. Chromatographia. 2010, 71: 505-510. 10.1365\/s10337-009-1446-8.","journal-title":"Chromatographia"},{"key":"1643_CR24","unstructured":"ICH guidelines - International Conference on Harmonization, Q1A(R2) Stability testing of new drug substances and products CPMP\/ICH\/2736\/99. (August 2003). [Accessed on 5 November 2010 at 12:10], [http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2009\/09\/WC500002651.pdf]"},{"key":"1643_CR25","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":"1643_CR26","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":"1643_CR27","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.toxlet.2008.05.006","volume":"180","author":"IC Munro","year":"2008","unstructured":"Munro IC, Renwick AG, Danielewska-Nikiel B: The threshold of toxicological concern (TTC) in risk assessment. Toxicol Lett. 2008, 180: 151-156. 10.1016\/j.toxlet.2008.05.006.","journal-title":"Toxicol Lett"},{"key":"1643_CR28","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/0378-4274(95)03390-7","volume":"80","author":"E Kristiansen","year":"1995","unstructured":"Kristiansen E, Madsen C: Induction of protein droplet (alpha(2-mu)-globulin) nephropathy in male-rats after short-term dosage with 1,8-cineole and L-limonene. Toxicol Lett. 1995, 80: 147-152. 10.1016\/0378-4274(95)03390-7.","journal-title":"Toxicol Lett"}],"container-title":["Malaria Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1475-2875-10-51.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T13:10:24Z","timestamp":1630501824000},"score":1,"resource":{"primary":{"URL":"https:\/\/malariajournal.biomedcentral.com\/articles\/10.1186\/1475-2875-10-51"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,2,28]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["1643"],"URL":"https:\/\/doi.org\/10.1186\/1475-2875-10-51","relation":{},"ISSN":["1475-2875"],"issn-type":[{"value":"1475-2875","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,2,28]]},"assertion":[{"value":"23 December 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"51"}}