Isoniazid-Resveratrol Cocrystal: A Novel Alternative for Topical Treatment of Cutaneous Tuberculosis

The current treatment for cutaneous tuberculosis consists of oral coadministration of isoniazid (INH) and rifampicin, which is often related to hepatotoxic events. Alternatively, INH could be administered on the skin aiming to avoid or minimize these side effects. The high cutaneous permeation of this drug motivated the obtainment of a cocrystal of INH and resveratrol (RES), a lipophilic compound, to provide a local effect. In this study, isoniazid–resveratrol cocrystal (INH-RES) was synthesized by reaction crystallization method, and its structure was determined from single-crystal X-ray diffraction data. Cocrystal, drug, and coformer aqueous solubility was determined in the initial pH range from 1.2 to 7.4. Mathematical models based on cocrystal constituent ionization constants (pKa), solution pH, and cocrystal solubility product (Ksp) were used to generate solubility diagrams as a function of pH. At all pH values studied, INH-RES was less soluble than INH. Permeation studies were performed with drug and cocrystal applied to porcine skin in Franz diffusion chambers. Cocrystal reduced the amount of permeated drug by 86%. The association with a coformer that has higher log P decreased INH permeation, highlighting the importance of considering the drug permeation route during the coformer selection.