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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

Sultan Suleman Wega, Kirsten Vandercruyssen, Evelien Wynendaele UGent, Matthias D'Hondt, Nathalie Bracke, Luc Duchateau UGent, Christian Burvenich UGent, Kathelijne Peremans UGent and Bart De Spiegeleer UGent (2013) MALARIA JOURNAL. 12.
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.
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author
organization
alternative title
A rapid stability-indicating, fused-core HPLC method for simultaneous determination of beta-artemether and lumefantrine in anti-malarial fixed dose combination products
year
type
journalArticle (original)
publication status
published
subject
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, β-artemether
journal title
MALARIA JOURNAL
Malar. J.
volume
12
article number
145
pages
11 pages
Web of Science type
Article
Web of Science id
000318978800002
JCR category
TROPICAL MEDICINE
JCR impact factor
3.489 (2013)
JCR rank
2/22 (2013)
JCR quartile
1 (2013)
ISSN
1475-2875
DOI
10.1186/1475-2875-12-145
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
4126872
handle
http://hdl.handle.net/1854/LU-4126872
date created
2013-09-04 17:17:41
date last changed
2017-06-16 12:38:32
@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},
}

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.