Abstract
BackgroundArtemisinin-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 simple, but stability-indicating method for the simultaneous assay of β-artemether and lumefantrine FDC products.MethodsThree reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30°C, were evaluated. β-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 1mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 μl injection volume. Quantification was performed at 210 nm and 335 nm for β-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0®.ResultsBoth β-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 β-artemether and 99.7 % (± 0.6%) for lumefantrine. All identified β-artemether-related impurities were predicted in Derek Nexus v2.0® to have toxicity risks similar to β-artemether active pharmaceutical ingredient (API) itself.ConclusionsA rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of β-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 β-artemether-related impurities is comparable to that of β-artemether API.
Highlights
Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment
The World Health Organization (WHO) has recommended that all anti-malarials should consist of a combination of an artemisinin derivative with a co-drug such as lumefantrine, amodiaquine or mefloquine; most malaria endemic countries have adopted artemisinin-based anti-malarial combination therapy (ACT) as first-line treatment of P. falciparum malaria in place of chloroquine, quinine and sulphadoxine-pyrimethamine fixed dose combinations [5]
asymmetry factor (As) stability-indicating HPLC method for simultaneous assay of β-artemether and lumefantrine fixed dose combination anti-malarial products was developed, using a fused-core reversed-phase amide stationary phase combined with an isocratic acetonitrile sodium phosphate mobile phase [Acetonitrile/1 mM phosphate buffer pH 3.0 (52:48, v/v)]
Summary
Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. 243 million people annually develop symptomatic malaria [1] Most of these can be attributed to Plasmodium falciparum, but Plasmodium vivax and Plasmodium knowlesi can cause severe diseases. Malaria case management remains a vital component of malaria control strategies This entails early diagnosis and prompt treatment with effective anti-malarial medicines [4]. The World Health Organization (WHO) has recommended that all anti-malarials should consist of a combination of an artemisinin derivative with a co-drug such as lumefantrine, amodiaquine or mefloquine; most malaria endemic countries have adopted artemisinin-based anti-malarial combination therapy (ACT) as first-line treatment of P. falciparum malaria in place of chloroquine, quinine and sulphadoxine-pyrimethamine fixed dose combinations [5]. The emergence of resistance is of great concern [6,7,8], and this problem is fuelled by poor quality anti-malarial drugs
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