Hydrogen bonding in sulfonamides

Abstract

The hydrogen‐bond connectivity in 39 sulfonamide crystal structures has been deciphered and described using graph set notation. The hydrogen‐bond connectivity observed is used to gain information on hydrogen‐bond preferences of specific donor and acceptor atoms of related sulfonamide molecules. The amido protons show a greater preference for hydrogen bonding to amidine nitrogens and cocrystal guests, whereas the amino protons show a greater preference for hydrogen bonding to sulfonyl oxygens, forming the only dominant hydrogen‐bond pattern, a chain with an eight atom repeat unit. Preferential hydrogen bonding between the amidine group and the guest carboxyl group was observed in five cocrystal structures of sulfamethazine. Sulfamoxole displays a conformation and a hydrogen‐bond motif not seen in any other structures. Sulfamerazine and sulfamethazine, differing by a methyl group, show no similarity in hydrogen‐bond pattern, whereas sulfamethoxydiazine and sulfamethoxymethazine, which have sterically similar but chemically different heterocycles, show a striking similarity in hydrogen‐bond pattern. Sulfamethoxydiazine, sulfamethoxymethazine, and sulfamethoxazole also show a large variation in hydrogen‐bond pattern between polymorphs. Studies such as this, by revealing details of hydrogen‐bonding patterns in closely related organic crystal structures, can potentially provide predictive capability among the crystal structures of pharmaceutical solids. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:2058–2077, 2001