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ABSTRACT: Background
Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as ?-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of ?-artemether and lumefantrine FDC products.Methods
Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30°C, were evaluated. ?-Artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1 mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 ?l injection volume. Quantification was performed at 210 nm and 335 nm for ?-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0®.Results
Both ?-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (± RSD) of 99.7 % (± 0.7%) for ?-artemether and 99.7 % (± 0.6%) for lumefantrine. All identified ?-artemether-related impurities were predicted in Derek Nexus v2.0® to have toxicity risks similar to ?-artemether active pharmaceutical ingredient (API) itself.Conclusions
A rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of ?-artemether and lumefantrine. This method can be applied in the routine regulatory quality control of FDC products. The in-silico toxicological investigation using Derek Nexus® indicated that the overall toxicity risk for ?-artemether-related impurities is comparable to that of ?-artemether API.
SUBMITTER: Suleman S
PROVIDER: S-EPMC3651282 | biostudies-literature | 2013 Apr
REPOSITORIES: biostudies-literature
Suleman Sultan S Vandercruyssen Kirsten K Wynendaele Evelien E D'Hondt Matthias M Bracke Nathalie N Duchateau Luc L Burvenich Christian C Peremans Kathelijne K De Spiegeleer Bart B
Malaria journal 20130430
<h4>Background</h4>Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as β-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and ...[more]