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

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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 beta-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 beta-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 degrees C, were evaluated. beta-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 mu l injection volume. Quantification was performed at 210 nm and 335 nm for beta-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0 (R). Results: Both beta-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 beta-artemether and 99.7 % (+/- 0.6%) for lumefantrine. All identified beta-artemether-related impurities were predicted in Derek Nexus v2.0 (R) to have toxicity risks similar to beta-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 beta-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 (R) indicated that the overall toxicity risk for beta-artemether-related impurities is comparable to that of beta-artemether API.
Keywords
beta-artemether, Anti-malaria, PERFORMANCE LIQUID-CHROMATOGRAPHY, MALARIA, PREDICTION, Finished pharmaceutical product, Quality-by-design (QbD), HPLC-UV, Fused-core, Stability-indicating assay, Lumefantrine, β-artemether

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Chicago
Wega, Sultan Suleman, Kirsten Vandercruyssen, Evelien Wynendaele, Matthias D’Hondt, Nathalie Bracke, Luc Duchateau, Christian Burvenich, Kathelijne Peremans, and Bart De Spiegeleer. 2013. “A Rapid Stability-indicating, Fused-core HPLC Method for Simultaneous Determination of Β-artemether and Lumefantrine in Anti-malarial Fixed Dose Combination Products.” Malaria Journal 12.
APA
Wega, S. S., Vandercruyssen, K., Wynendaele, E., D’Hondt, M., Bracke, N., Duchateau, L., Burvenich, C., et al. (2013). A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products. MALARIA JOURNAL, 12.
Vancouver
1.
Wega SS, Vandercruyssen K, Wynendaele E, D’Hondt M, Bracke N, Duchateau L, et al. A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products. MALARIA JOURNAL. 2013;12.
MLA
Wega, Sultan Suleman, Kirsten Vandercruyssen, Evelien Wynendaele, et al. “A Rapid Stability-indicating, Fused-core HPLC Method for Simultaneous Determination of Β-artemether and Lumefantrine in Anti-malarial Fixed Dose Combination Products.” MALARIA JOURNAL 12 (2013): n. pag. Print.
@article{4126872,
  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 beta-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 beta-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 degrees C, were evaluated. beta-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 mu l injection volume. Quantification was performed at 210 nm and 335 nm for beta-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0 (R).
Results: Both beta-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 beta-artemether and 99.7 \% (+/- 0.6\%) for lumefantrine. All identified beta-artemether-related impurities were predicted in Derek Nexus v2.0 (R) to have toxicity risks similar to beta-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 beta-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 (R) indicated that the overall toxicity risk for beta-artemether-related impurities is comparable to that of beta-artemether API.},
  articleno    = {145},
  author       = {Wega, Sultan Suleman and Vandercruyssen, Kirsten and Wynendaele, Evelien and D'Hondt, Matthias and Bracke, Nathalie and Duchateau, Luc and Burvenich, Christian and Peremans, Kathelijne and De Spiegeleer, Bart},
  issn         = {1475-2875},
  journal      = {MALARIA JOURNAL},
  keyword      = {beta-artemether,Anti-malaria,PERFORMANCE LIQUID-CHROMATOGRAPHY,MALARIA,PREDICTION,Finished pharmaceutical product,Quality-by-design (QbD),HPLC-UV,Fused-core,Stability-indicating assay,Lumefantrine,\ensuremath{\beta}-artemether},
  language     = {eng},
  pages        = {11},
  title        = {A rapid stability-indicating, fused-core HPLC method for simultaneous determination of \ensuremath{\beta}-artemether and lumefantrine in anti-malarial fixed dose combination products},
  url          = {http://dx.doi.org/10.1186/1475-2875-12-145},
  volume       = {12},
  year         = {2013},
}

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