Physico-chemical characterisation and compatibility of selected anti-malarial drugs

Abstract

Malaria is an extensive, potentially fatal disease caused by the Plasmodium parasite, which is transmitted to humans by female Anopheles mosquitoes. One specific problem is the growing resistance of the parasites to active pharmaceutical ingredients (APIs). Thus, sulfadoxine, pyrimethamine, and artesunate are available as a comb-pack kit. When combination therapy is taken orally, the APIs may influence one another's physico-chemical properties, such as solubility. Compatibility studies are usually performed between APIs and their excipients and, to a lesser extent, between different APIs indicated for the same disease or administered in an FDC. It is imperative to thoroughly investigate the compatibility of APIs to ensure that a formulation of the different components is complementary to one another. Physico-chemical characterisation studies were performed to provide insight regarding compatibility and possible influences on solubility. The study used thermal activity microcalorimetry (TAM) to investigate the compatibility of each API, individually and in combination, and found no observable interactions. Additionally, differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy were performed, proving the dispersion of one API into another. Solubility studies of sulfadoxine, pyrimethamine, and artesunate were investigated (separately and in combination) in various media over a pH range of 1.2 - 6.8. Artesunate displayed degradation in various media, except in one buffer media at pH 4.5. Additionally, a pH-dependent trend was seen with the highest solubility in potassium phosphate (PBS) buffer. Pyrimethamine presented higher solubilities at a lower pH and poor solubility in higher pH ranges. The solubility of pyrimethamine was significantly influenced by the presence of both artesunate and sulfadoxine, respectively, with the best improvement in the artesunate-pyrimethamine combination in water. In contrast, sulfadoxine exhibited improved solubility only in the acetate (ACE) buffer and water when combined with pyrimethamine.