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 R₂¹(6) and R₁²(5) rings instead of the R₂²(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.