Novel Synthons in Sulfamethizole Cocrystals: Structure–Property Relations and Solubility

Abstract

The sulfamethizole antibiotic drug has rich hydrogen bond functionalities (donors: amine NH2 and imine NH; acceptors: sulfonyl O, thiazolidine N and S, and imidine N), which makes it a functionally diverse molecule to form cocrystals. A cocrystal screen of sulfamethizole (SMT) with COOH, NH2, pyridine, and CONH2 functional group containing coformers, e.g., p-aminobenzoic acid (PABA), vanillic acid (VLA), p-aminobenzamide (ABA), 4,4-bipyridine (BIP), suberic acid (SBA), oxalic acid (OA), and adipic acid (ADP), resulted in six cocrystals and one salt, namely, SMT–ADP (1:0.5), SMT–PABA (1:1), SMT–VLA (1:1), SMT–ABA (1:1), SMT–BIP (1:1), SMT–SBA (1:0.5), and SMT–OA (1:1). The novel crystalline adducts were synthesized by liquid-assisted cogrinding and isothermal solvent crystallization. In addition to single-crystal X-ray diffraction, the phase composition of the powder samples was confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Hydrogen bonding interactions between the coformers and SMT are analyzed as six different synthons. In addition to strong N–H···O and O–H···N hydrogen bonds, the cocrystal structures are sustained by weak C–H···O hydrogen bonds. The not so common chalcogen–chalcogen (S···O) type II intermolecular interaction in SMT–ADP cocrystal and chalcogen–nicogen (S···N) type II interaction in SMT–BIP cocrystal were observed. The products were characterized by vibrational spectroscopy to obtain information on the strengths of the intermolecular interactions. Solubility and dissolution experiments on SMT–ADP, SMT–SBA, and SMT–OA showed a lower intrinsic dissolution rate (IDR) and equilibrium solubility compared to SMT in 0.1 N HCl medium, which is ascribed to stronger N–H···O, N–H···N, and O–H···O hydrogen bonds and better crystal packing. The decreased IDR could be useful in controlled/extended release of SMT to improve therapeutic activity of the drug by minimizing its fast systemic elimination in vivo. Furthermore, we observed that SMT–OA salt is formed spontaneously when the components were mixed in acidic medium (0.1 N HCl), whereas in neutral medium (phosphate buffer) no SMT–OA salt formation was observed.