Incompatibility of antimalarial drugs: challenges in formulating combination products for malaria

Abstract

Lipophilic drugs require more advance formulation, especially if the intention is to make solutions or semisolid formulations. This also accounts for most antimalarial drugs. Although some of these antimalarial drugs are soluble in lipid vehicles, few of them, such as lumefantrine (LF), are also poorly soluble in oily vehicles. Trying to dissolve and formulate LF as a liquid formulation together with other antimalarial drugs is, therefore, a major task. When mixed in solution together with artemether (AR), precipitation occurs, sometimes with LF precipitating out on its own, and sometimes with AR precipitating out alongside LF. In this study, it was hypothesized that the use of fatty acids could lead to enhanced solubility in lipid formulation. Addition of the fatty acid solved the dissolution challenges, making LF soluble for over a year at room temperature (21–23 °C); but further research is needed to test the mechanism of action of the fatty acid. In addition, design of experiments (MODDE^® 13) revealed that the amount of fatty acid in the formulation was the only significant factor for LF precipitation.

Graphical Abstract

Keywords:

• Artemether
• lumefantrine
• solubility
• incompatibility
• malaria
• fatty acids

Author contributions

Ellen K. G. Mhango: design of experiment, research, analysis, and writing the original draft. Benjamin R. Sveinbjornsson: NMR work and writing of NMR results. Bergthora S. Snorradottir: supervision on design of experiment. Sveinbjorn Gizurarson: main supervisor of the whole project.

Disclosure statement

Authors declare no conflict of interest with this manuscript.

Data availability statement

Upon reasonable request, data can be obtained from the corresponding author.

Additional information

Funding

This work was supported by the Eimskipasjóður (University of Iceland Doctoral Fund).