Relative response factor determination of β-artemether degradants by a dry heat stress approach

Abstract

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

A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products

“…Impurity profiling of both β-artemether and lumefantrine as well as in-silico toxicity profile of lumefantrine and its related impurities have been reported in previous publications [20,23,28]. Here, in-silico toxicological profile of β-artemether was compared against its related identified impurities using Derek Nexus®.…”

“…[20]. Briefly, approximately 20.0 mg of β-artemether API was accurately weighed and transferred into a glass HPLC vial.…”

“…Exhaustive impurity profiling of β-artemether (including its possible degradants) was also reported [20,28]. Therefore, to make in-silico toxicological comparative predictions for β-artemether and its identified related impurities, Derek Nexus v2.0 for Windows developed by Lhasa Ltd (Leeds, UK) was used.…”

“…Currently, there are HPLC methods for the assay of β-artemether in finished pharmaceutical products (FPP) [18-20], as well as for lumefantrine analysis [21-23]. Only a few HPLC methods were reported for the quantitative determination of β-artemether and lumefantrine in fixed combination anti-malarial products [24-26].…”

Detailed structural study of β-artemether: Density functional theory (DFT) calculations of Infrared, Raman spectroscopy, and vibrational circular dichroism

“…Artemether, a widely used antimalarial drug recommended by the World Health Organization (WHO) [3], is a methyl ether derivative of artemisinin, which is a peroxide lactone isolated from the Chinese antimalarial plant, Artemisia annua. It is a relatively lipophilic drug [4] with high efficiency, low toxicity, easy to use, no cross-resistance with chloroquine, etc. Among the two epimers of Artemether (α-and β-artemether), β-isomer (CAS no.…”