Crystal engineering of the composition of pharmaceutical phases. 3. Primary amide supramolecular heterosynthons and their role in the design of pharmaceutical co-crystals

Abstract

A Cambridge Structural Database study of supramolecular synthons involving primary amides reveals that 84% form amide-amide dimers, whereas 14% form catemers in the absence of other competing hydrogen bond donors and/or acceptors. However in the presence of chemically different but complementary functional groups, e.g., carboxylic acids or aromatic nitrogen moieties, primary amides tend to form supramolecular heterosynthons. Supramolecular heterosynthons represent an opportunity for design of multi-component crystals (co-crystals) in which one molecule contains a primary amide and a second molecule (the co-crystal former) contains the functional group that is complementary to the primary amide. The results of the CSD analysis facilitated the selection of components for seven new primary amide co-crystals: A. Isonicotinamide/2-hydroxybenzoic acid (1:1); B. Nicotinäamide/3-hydroxybenzoic acid (1:1); C. Pyrazinamide/2,5-dihydroxybenzoic acid (1:1); D. Carbamazepine (CBZ)/4,4′-bipyridine (2:1); E. CBZ/4-aminobenzoic acid (2:1); F. CBZ/4-aminobenzoic acid/H₂O (2:1:1); G. CBZ/2,6-pyridinedicarboxylic acid (1:1). The molecular recognition events involving the amide moieties are discussed in the context of our experimental results and their implications for crystal engineering of pharmaceutical co-crystals.