Cocrystallization with syringic acid presents a new opportunity for effectively reducing the hepatotoxicity of isoniazid

Abstract

<b>Objective:</b> With the aim of surmounting the severe hepatotoxicity induced by antituberculosis drug isoniazid (INH), a novel cocrystal of INH with hepatoprotective nutraceutical syringic acid (SYA), namely INH-SYA, was designed and prepared through cocrystallization strategy, which is an intriguing attempt to reduce the toxic side effects of INH.<b>Significance:</b> The study not only provides new thinking for inhibiting toxic side effects of drugs through cocrystallization strategy, but also opens a new pathway for the application of nutraceuticals in the pharmacy.<b>Methods:</b> INH and SYA were successfully crystallized into the same crystal lattice through combining volatilization with solvent assisted methods. The resulting cocrystal was structurally characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC).<b>Results:</b> The SCXRD analysis for the present cocrystal revealed that it has a 1:1 ratio of INH to SYA with two molecules INH homodimers and two SYA molecules, in which they are arranged alternately linked by hydrogen bonds to form a six molecules ring structure (R⁶₆(40)) in crystal. The systematic evaluation of the <i>in vitro/in vivo</i> suggested that, owing to the formation of cocrystal, the dissolution efficiency of SYA was increased 5.85-fold compared with that of coarse SYA, and the oral bioavailability of the cocrystal in rats was enhanced by 3.66 times. As a result, the present INH-SYA cocrystal almost removed INH induced serious hepatotoxicity, which was further demonstrated by the hepatotoxicity studies in rats.<b>Conclusion:</b> INH-SYA cocrystal could effectively reduce the hepatotoxicity of INH.