Structural Features of Sulfamethizole and Its Cocrystals: Beauty Within

Sulfamethizole (SMZ) is an antibiotic drug with good solubility but short in vivo half-life. Thus, reducing the dissolution rate is expected to improve bioavailability and therapeutic activity through reducing the systemic elimination of SMZ. To this end, two novel pharmaceutical cocrystals, SMZ-sarcosine (SMZ-SAR) and SMZ-saccharin (SMZ-SAC), were designed and prepared according to the structural resemblance strategy. These cocrystals, along with a previously obtained SMZ-L-proline (SMZ-L-PRO) cocrystal, present an opportunity for detailed analysis of the crystal structure to identify key intermolecular interactions that guide their molecular assembly. C-13 Solid state NMR data suggested more than one symmetry independent molecules in SMZ (Z' > 1), which was confirmed by the SMZ crystal structure solved at 100 K (Z' = 3). The amine-carboxylate synthon plays an important role in the intermolecular hydrogen bonding interactions of both SMZ-SAR and SMZ-L-PRO. In contrast, no strong intermolecular hydrogen bonding and pi...pi stacking interactions between SMZ and SAC were observed in SMZ-SAC, which features a shape-fit structure. Additionally, all cocrystals demonstrated lower equilibrium solubility and intrinsic dissolution rates compared to SMZ. Therefore, they are suitable crystal forms for the possible improvement in therapeutic performance of SMZ.