Solubility and dissolution testing of selected sulfadoxine/pyrimethamine mixtures

Abstract

Although malaria is an age old disease it continues to plague mankind especially in the African regions. Pregnant women are more likely to be infected with malaria due to the hormonal changes with more severe symptoms and outcomes. Intermittent preventive therapy with sulfadoxine (S) and pyrimethamine (P) are considered to be an effective way of preventing malaria in pregnant women; but the increase of the resistance of the malaria parasite to sulfadoxine and pyrimethamine is still a major concern. Some of the possible causes of resistance include the poor solubility and dissolution rate of both drugs. Addressing these problems might be a positive stepping stone towards combating malaria resistance in the future. The focus of this study was to determine the solubility and dissolution properties and possible chemical interactions in the powder mixtures compared to the single components. Distilled water, phosphate buffer (pH 6.8) and 0.1 N HCl were used as media for solubility and dissolution testing. The results of the SP combinations emphasised that sulfadoxine and pyrimethamine is more soluble in distilled water and PBS; but when in combination both of these actives’ solubility decreases in 0.1 N HCl. In contrast with the solubility results, the best results obtained during dissolution testing were in 0.1 N HCl. For each dissolution medium, only some of the SP combinations correspond with the USP requirements (60% or higher dissolution in 30 minutes) for each tablet. Differential scanning calorimetry (DSC) and x-ray powder diffraction (XRPD) were used to establish if interactions occur in the powder mixtures. The DSC results showed that during heating of certain SP combination ratios, shifting of melting point and even melting point depression occurs. This may indicate the possibility of a eutectic mixture being formed. With a percentage pyrimethamine of 55% (w/w) or higher in the mixture, two distinguishable melting endotherms were visible. XRPD results indicated that during exposure of SP combinations to distilled water, no other solid-state forms such as co-crystals of sulfadoxine and pyrimethamine formed. To conclude, there is definitely an increase in the solubility and dissolution rate of sulfadoxine and pyrimethamine when in combination. The significance and origin of the increased solubility requires further investigation. The possibility of a eutectic mixture being formed also warrants further investigation.