title: Relative response factor determination of β-artemether degradants by a dry heat stress approach.
abstract: During the stability evaluation of β-artemether containing finished drug products, a consistent and disproportional increase in the UV-peak areas of β-artemether degradation products, when compared to the peak area decline of β-artemether itself, was observed. This suggested that the response factors of the formed β-artemether degradants were significantly higher than β-artemether. Dry heat stressing of β-artemether powder, as a single compound, using different temperatures (125-150 °C), times (10-90 min) and environmental conditions (neutral, KMnO(4) and zinc), resulted in the formation of 17 degradants. The vast majority of degradants seen during the long-term and accelerated ICH stability study of the drug product, were also observed here. The obtained stress results allowed the calculation of the overall average relative response factor (RRF) of β-artemether degradants, i.e. 21.2, whereas the individual RRF values of the 9 most prominent selected degradants ranged from 4.9 to 42.4. Finally, Ames tests were performed on β-artemether as well as a representative stressed sample mixture, experimentally assessing their mutagenic properties. Both were found to be negative, suggesting no mutagenicity problems of the degradants at high concentrations. Our general approach and specific results solve the developmental quality issue of mass balance during stability studies and the related genotoxicity concerns of the key antimalarial drug β-artemether and its degradants.
authors: Drug Quality and Registration (DruQuaR) Group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium. Bart.DeSpiegeleer@UGent.be
authors: Bart M J
authors: BM
authors: De Spiegeleer
authors: Matthias
authors: M
authors: D'Hondt
authors: Elien
authors: E
authors: Vangheluwe
authors: Kirsten
authors: K
authors: Vandercruyssen
authors: Bart V I
authors: BV
authors: De Spiegeleer
authors: Herwig
authors: H
authors: Jansen
authors: Ilse
authors: I
authors: Koijen
authors: Jacques
authors: J
authors: Van Gompel
mesh_terms: D000962:Antimalarials / Q000032:analysis* / Q000633:toxicity; D000077549:Artemether; D037621:Artemisinins / Q000032:analysis* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D004355:Drug Stability; D004356:Drug Storage; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D009152:Mutagenicity Tests; D011208:Powders; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011208:Powders; D000077549:Artemether