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Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine

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Abstract
Background 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 β-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 processrelated and degradation impurities in active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). Methods 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. In-silico toxicological predictions for these lumefantrine related impurities were made using Toxtree® and Derek®. Results 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® and Derek®, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself. Conclusions 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 in-silico toxicological investigation (Toxtree® and Derek®) indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.
Keywords
HPLC-DAD/UV-ESI/MS, In-silico toxicity, Lumefantrine, Impurities, Anti-malarial drug

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Chicago
Verbeken, Mathieu, Sultan Suleman Wega, Bram Baert, Elien Vangheluwe, Sylvia Van Dorpe, Christian Burvenich, Luc Duchateau, Frans H Jansen, and Bart De Spiegeleer. 2011. “Stability-indicating HPLC-DAD/UV-ESI/MS Impurity Profiling of the Anti-malarial Drug Lumefantrine.” Malaria Journal 10.
APA
Verbeken, M., Wega, S. S., Baert, B., Vangheluwe, E., Van Dorpe, S., Burvenich, C., Duchateau, L., et al. (2011). Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine. MALARIA JOURNAL, 10.
Vancouver
1.
Verbeken M, Wega SS, Baert B, Vangheluwe E, Van Dorpe S, Burvenich C, et al. Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine. MALARIA JOURNAL. 2011;10.
MLA
Verbeken, Mathieu, Sultan Suleman Wega, Bram Baert, et al. “Stability-indicating HPLC-DAD/UV-ESI/MS Impurity Profiling of the Anti-malarial Drug Lumefantrine.” MALARIA JOURNAL 10 (2011): n. pag. Print.
@article{1178152,
  abstract     = {Background
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 \ensuremath{\beta}-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 processrelated and degradation impurities in active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs).
Methods
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. In-silico toxicological predictions for these lumefantrine related impurities were made using Toxtree{\textregistered} and Derek{\textregistered}.
Results
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{\textregistered} and Derek{\textregistered}, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself.
Conclusions
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 in-silico toxicological investigation (Toxtree{\textregistered} and Derek{\textregistered}) indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.},
  articleno    = {51},
  author       = {Verbeken, Mathieu and Wega, Sultan Suleman and Baert, Bram and Vangheluwe, Elien and Van Dorpe, Sylvia and Burvenich, Christian and Duchateau, Luc and Jansen, Frans H and De Spiegeleer, Bart},
  issn         = {1475-2875},
  journal      = {MALARIA JOURNAL},
  keyword      = {HPLC-DAD/UV-ESI/MS,In-silico toxicity,Lumefantrine,Impurities,Anti-malarial drug},
  language     = {eng},
  title        = {Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine},
  url          = {http://dx.doi.org/10.1186/1475-2875-10-51},
  volume       = {10},
  year         = {2011},
}

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