A Sulfathiazole–Amantadine Hydrochloride Cocrystal: The First Codrug Simultaneously Comprising Antiviral and Antibacterial Components

Abstract

A novel cocrystallization form of amantadine hydrochloride (AMNH) with sulfathiazole (SUZ), as the first example of dual-drug cocrystal simultaneously containing antiviral drug and antibacterial agent, is designed and successfully synthesized. The structure of resulting cocrystal SUZ–AMNH is thoroughly characterized. The single crystal X-ray diffraction reveals that a 1:1 ratio of the two components exists in the cocrystal structure, in which the interactions between SUZ and AMNH molecules are mainly dominated by N–H···O hydrogen bonds and N–H+(AMNH)···Cl–···H–N(SUZ) charge-assisted hydrogen bonds, constructing a three-dimensional supramolecular structure. The dissolubility and permeability of the cocrystal are systematically studied under physiological pH environments. It has been found that SUZ in the cocrystal shows a 1.83–5.23 times increase in water solubility and ca. 2-fold enhancement in penetrability compared with pure SUZ. Intriguingly, the simultaneously improved physicochemical properties for SUZ can bring about the strengthening in antibacterial activities, displaying enhanced inhibition of bacterial strains and lower values of minimum inhibitory concentration. The present investigation not only provides a promising method for therapeutic hybridization of antiviral and antibacterial drugs against coinfection, but also exploits a new pathway of the drug–drug cocrystallization strategy toward widening new applications for conventional drugs.