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.

Relative response factor determination of rmbeta-artemether degradants by a dry heat stress approach, Journal of Pharmaceutical and Biomedical Analysis (2010), doi:10.1016/j.jpba.2012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. During the stability evaluation of -artemether containing finished drug products, a consistent 20 and disproportional increase in the UV-peak areas of -artemether degradation products, 21 when compared to the peak area decline of -artemether itself, was observed. This suggested 22 that the response factors of the formed -artemether degradants were significantly higher than 23 β-artemether. Dry heat stressing of -artemether powder, as a single compound, using 24 different temperatures (125 °C -150 °C), times (10 min -90 min) and environmental 25 conditions (neutral, KMnO 4 and zinc), resulted in the formation of 17 degradants. The vast 26 majority of degradants seen during the long-term and accelerated ICH stability study of the 27 drug product, were also observed here. The obtained stress results allowed the calculation of 28 the overall average relative response factor (RRF) of -artemether degradants, i.e. 21.2, 29 whereas the individual RRF values of the 9 most prominent selected degradants ranged from 30 4.9 to 42.4. Finally, Ames tests were performed on -artemether as well as a representative 31 stressed sample mixture, experimentally assessing their mutagenic properties. Both were 32 found to be negative, suggesting no mutagenicity problems of the degradants at high 33 concentrations. Our general approach and specific results solve the developmental quality 34 issue of mass balance during stability studies and the related genotoxicity concerns of the key 35 antimalarial drug -artemether and its degradants. 36

Triple intrathecal solution of cytarabine, methotrexate sodium, and methylprednisolone sodium succinate was stable for up to 12 hours when stored at 5 °C and protected from light.

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