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-NH/N=C/C-NH and C-NH/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·CHOH is the first crystal structure in which the interaction of the sulfa drug at the C-NH/N=C/C-NH site with three parallel NH···N, N···NH, and NH···O=S H bonds is observed. The main synthon in (tmp)(keto).0.5HO and (tmp)(ox)·2CHOH is the motif of fused (6) and (5) rings instead of the (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.