Enhanced Bioavailability in the Oxalate Salt of the Anti-Tuberculosis Drug Ethionamide

Abstract

Ethionamide (ETH) is an anti-tuberculosis (TB) Biopharmaceutics Classification System class II drug of poor aqueous solubility. The objective of the present study was to evaluate the solubility and bioavailability parameters of ETH cocrystals/salts with Generally Regarded as Safe (GRAS) coformers. Five cocrystals, namely, ETH-GLA (glutaric acid), ETH-ADP (adipic acid), ETH-SBA (suberic acid), ETH-SEBA (sebacic acid), ETH-FA (fumaric acid), and one salt ETH-OA (oxalic acid) were prepared by liquid-assisted grinding, and their structural characterization was carried out using spectroscopic, thermal, and powder X-ray diffraction techniques. The crystal structures of ETH-ADP, ETH-SBA, ETH-FA, and ETH-OA were confirmed by X-ray diffraction. The three cocrystal structures are sustained by the robust acid⋯pyridine synthon, while the ETH-OA salt has an ionic N-H⋯O hydrogen bond between carboxylate and pyridinium ions. The ETH-OA salt exhibited the highest dissolution compared to ETH (25 times), and its cocrystals (10 to 2 times higher). The intrinsic dissolution rates are ETH-OA > ETH-GLA > ETH-FA > ETH-SBA > ETH-ADP > ETH-SEBA > ETH. The best crystal form of ETH-OA was administered orally and exhibited 2.5 times enhanced plasma concentration in rats with Cmax of 4.08 ± 0.2 μg mL-1at Tmax of 30 min, and AUC(0-8h) increased 1.9 fold to 6.49 ± 0.19 μg mL-1 h-1 compared to ETH. The oxalate salt exhibits the highest bioavailability enhancement for BCS class II drug ethionamide.