Modularity and three-dimensional isostructurality of novel synthons in sulfonamide–lactam cocrystals

Abstract

The design of novel supramolecular synthons for functional groups relevant to drugs is an essential prerequisite for applying crystal engineering in the development of novel pharmaceutical cocrystals. It has been convincingly shown over the past decade that molecular level control and modulation can influence the physicochemical properties of drug cocrystals. Whereas considerable advances have been reported on the design of cocrystals for carboxylic acids and carboxamide functional groups, the sulfonamide group, which is a cornerstone of sulfa drugs, is relatively unexplored for reproducible heterosynthon-directed crystal engineering. The occurrence of synthons and isostructurality in sulfonamide–lactam cocrystals (SO2NH2...CONH hydrogen bonding) is analyzed to define a strategy for amide-type GRAS (generally recognized as safe) coformers with sulfonamides. Three types of supramolecular synthons are identified for the N—H donor of sulfonamide hydrogen bonding to the C=O acceptor of amide. Synthon 1: catemer synthonC21(4) chain motif, synthon 2: dimer–cyclic ring synthonR22(8)R42(8) motifs, and synthon 3: dimer–catemer synthon ofR22(8)C11(4)Dnotation. These heterosynthons of the cocrystals observed in this study are compared with the N—H...O dimerR22(8) ring andC(4) chain motifs of the individual sulfonamide structures. The X-ray crystal structures of sulfonamide–lactam cocrystals exhibit interesting isostructurality trends with the same synthon being present. One-dimensional, two-dimensional and three-dimensional isostructurality in crystal structures is associated with isosynthons and due to their recurrence, novel heterosynthons for sulfonamide cocrystals are added to the crystal engineer's toolkit. With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.