Salt and Cocrystals Combining Sulfathiazole with Pyrimethamine

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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.

Original languageEnglish
Pages (from-to)7811-7820
Number of pages10
JournalCrystal Growth and Design
Issue number11
Publication statusPublished - 1 Nov 2023
Externally publishedYes


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