Salt and Cocrystals Combining Sulfathiazole with Pyrimethamine

Dihydrofolate reductase inhibitors, such as pyrimethamine, are known to have synergistic effects with sulfonamides. Four new solid forms combining pyrimethamine and sulfathiazole, one cocrystal (pyrimethamine-sulfathiazole (1:1)) and three solvated salt cocrystals (in which pyrimethamine and sulfathiazole are in a 1:2 molar ratio), are determined and characterized. Desolvation of the salt cocrystals leads to either a physical mixture of the starting compounds or the formation of the cocrystal (1:1) with an excess of sulfathiazole. The pyrimethamine sulfathiazole binary phase diagram was determined, which reveals that the pyrimethamine-sulfathiazole (1:2) composition point corresponds to a metastable eutectic. Obtaining this metastable eutectic as a pure powder is therefore rather difficult since it converts to a stable mixture of the (1:1) cocrystal + sulfathiazole. The abovementioned drug-drug multicomponent systems are characterized in terms of thermal stability (by TGA/DSC) and solubility. Both pyrimethamine-sulfathiazole (1:1) cocrystal and pyrimethamine-sulfathiazole (1:2) ethanol-solvated salt cocrystal result in an increase of the parent drugs' solubility.