Investigation of solubility and permeability of sulfadoxine and pyrimethamine mixtures

Abstract

Sulfadoxine and pyrimethamine are commercially available in a fixed dose combination (FDC) product, which is used as prophylaxis against malaria. These drugs are still on the World Health Organization’s (WHO) essential drug list, making research on sulfadoxine and pyrimethamine relevant. The Biopharmaceutics Classification System (BCS) categorize drugs according to their solubility and permeability properties. Some drugs, like sulfadoxine, have not yet been classified due to a lack of information regarding these properties. In this study, the solubility, dissolution and membrane permeability of sulfadoxine and pyrimethamine (single compounds and various combination ratios) were investigated. Solid state investigations were employed to explain the results obtained for the solubility and dissolution in the combinations as compared to that of the single compounds. Two sets of solubility studies were performed, for the first set; both single compounds and different combination ratios were tested in water. Increased solubility was obtained for both compounds in combination as compared to that of the single compounds. On average, sulfadoxine produced a two-fold increase in solubility when combined with pyrimethamine, while pyrimethamine produced a nine-fold increase in solubility when combined with sulfadoxine. From these results, it was decided to focus on the single compounds and the Sulfadoxine and pyrimethamine are commercially available in a fixed dose combination (FDC) product, which is used as prophylaxis against malaria. These drugs are still on the World Health Organization’s (WHO) essential drug list, making research on sulfadoxine and pyrimethamine relevant. The Biopharmaceutics Classification System (BCS) categorize drugs according to their solubility and permeability properties. Some drugs, like sulfadoxine, have not yet been classified due to a lack of information regarding these properties. In this study, the solubility, dissolution and membrane permeability of sulfadoxine and pyrimethamine (single compounds and various combination ratios) were investigated. Solid state investigations were employed to explain the results obtained for the solubility and dissolution in the combinations as compared to that of the single compounds. Two sets of solubility studies were performed, for the first set; both single compounds and different combination ratios were tested in water. Increased solubility was obtained for both compounds in combination as compared to that of the single compounds. On average, sulfadoxine produced a two-fold increase in solubility when combined with pyrimethamine, while pyrimethamine produced a nine-fold increase in solubility when combined with sulfadoxine. From these results, it was decided to focus on the single compounds and the 1:1 mol and 1:1 weight ratio combinations. With each solubility study a different solvent was used. Though the mutual solubility enhancement effect was also present in different solvents (varying in pH value and polarity), it was not as pronounced as in water. Powder dissolutions were performed on three combinations (the FDC, 1:1 mol and 1:1 weight combinations). In each case the single compounds were also tested in the same quantities as for each combination. The results displayed an increase in dissolution rate when these drugs were combined, which is in accordance with the solubility data. Certain physico-chemical investigations (nuclear magnetic resonance spectroscopy, isothermal microcalorimetry and vapour sorption analysis) proved a possible intermolecular interaction occurs between sulfadoxine and pyrimethamine. However, this interaction only occurred in solution. No co-crystal formation was evident from any solid state test; however differential scanning calorimetry (DSC) showed a possible eutectic mixture. The results obtained for the in vitro permeability studies (porcine intestinal tissue and Caco-2 monolayer studies) proved a relationship exists between the results obtained for the solubility studies and the permeability studies. An increase in permeation was observed for several of the combinations compared to the single compounds. This study provided information regarding the solubility and permeability characteristics of sulfadoxine and pyrimethamine. As evident, an interaction occurs between these two drugs, the mechanism of which should be further investigated. Furthermore, the possibility of a eutectic mixture should be explored and then tested to investigate the influence it might have on the solubility and permeability of both drugs.