Differences in Coformer Interactions of the 2,4-Diaminopyrimidines Pyrimethamine and Trimethoprim

The identification and study of supramolecular synthons is a fundamental task in the design of pharmaceutical cocrystals. The malaria drug pyrimethamine (pyr) and the antibiotic trimethoprim (tmp) are both 2,4-diaminopyrimidine derivatives, providing the same C-NH₂/N=C/C-NH₂ and C-NH₂/N=C interaction sites. In this article, we analyze and compare the synthons observed in the crystal structures of tmp and pyr cocrystals and molecular salts with sulfamethazine (smz), α-ketoglutaric acid (keto), oxalic acid (ox), sebacic acid (seb), and azeliac acid (az). We show that the same coformer interacts with different binding sites of the 2,4-diaminopyrimidine ring in the respective tmp and pyr cocrystals or binds at the same site but gives H bonding patterns with different graph set notions. Pyr·smz·CH₃OH is the first crystal structure in which the interaction of the sulfa drug at the C-NH₂/N=C/C-NH₂ site with three parallel NH₂···N, N···NH_sulfonamide, and NH₂···O=S H bonds is observed. The main synthon in (tmp⁺)(keto^-).0.5H₂O and (tmp⁺)₂(ox^2-)·2CH₃OH is the motif of fused R ₂ ¹(6) and R ₁ ²(5) rings instead of the R ₂ ²(8) motif typically observed in tmp⁺ and pyr⁺ carboxylates. Tmp/az is a rare example of cocrystal-salt polymorphism where the two solid-state forms have the same composition, stoichiometry, and main synthon. Theoretical calculations were performed to understand the order of stability, which is tmp·az cocrystal > (tmp⁺)(az^-) salt. Finally, two three-component tmp/sulfa drug/carboxylate cocrystals with a unique ternary synthon are described.