Abstract
BackgroundLumefantrine (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 process-related and degradation impurities in active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs).MethodsUsing 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®.ResultsSeveral 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.ConclusionsFrom 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.
Highlights
Lumefantrine is a fluorene derivative belonging to the aryl amino alcohol class of antimalarial drugs and is commercially available in fixed combination products with b-artemether
Lumefantrine active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs) were exposed to diverse stress conditions for different periods
FPPs were put on long-term and accelerated stability studies as well according to ICH
Summary
Lumefantrine (benflumetol) is a fluorene derivative belonging to the aryl amino alcohol class of antimalarial drugs and is commercially available in fixed combination products with b-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. Lumefantrine (benflumetol) is a 2,4,7,9-substituted fluorene (2,3-benzindene) derivative (Figure 1) It was synthesized in the 1970s by the Academy of Military Medical Sciences, in Beijing, and registered in China for anti-malarial use in 1987. Biochemical studies suggest that its anti-malarial effect involves lysosomal trapping of the drug in the food vacuole of the intra-erythrocytic parasite, followed by binding to haem that is produced in the course of haemoglobin digestion. Halofantrine, an aryl amino alcohol analogue of lumefantrine, is an anti-malarial drug, but is known to be potentially cardiotoxic [7]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call