Pharmaceutical Co-crystal of Antiviral Agent Efavirenz with Nicotinamide for the Enhancement of Solubility, Physicochemical Stability, and Oral Bioavailability.

Abstract

The present research work attempted to improve the oral bioavailability of the antiviral drug Efavirenz (EFV) using a pharmaceutical cocrystallization technique. EFV comes under BCS-II and has extremely low water solubility, and results in low oral bioavailability. EFV and nicotinamide (NICO) were selected in a (1:1) stoichiometric ratio and efavirenz nicotinamide cocrystal (ENCOC) was prepared through the liquid-assisted grinding method (LAG). The confirmation of the formation of a new solid phase was done through spectroscopic techniques like Fourier transmission infrared (FTIR), Raman, and 13C solid-state nuclear magnetic resonance (13C ssNMR). Thermal techniques like differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy (HSM) illustrated the thermal behavior and melting patterns of ENCOC, EFV, and NICO. The X-ray powder diffraction (XRPD) confirms the formation of a new crystalline phase in ENCOC. The Morphology was determined through scanning electron microscopy (FESEM). The results of saturated solubility studies andin vitro drug release studies exhibited 8.9-fold enhancement in solubility and 2.56-fold enhancement in percentage cumulative drug release. The percentage drug content of ENCOC was found higher than 97% and cocrystal exhibits excellent accelerated stability. The oral bioavailability of EFV (Cmax, 799.08ng/mL) exhibits significant enhancement after cocrystallization (Cmax, 5597.09ng/mL) than EFV and Efcure®-200 tablet (2896.21ng/mL). The current work investigates the scalable and cost-effective method for enhancement of physicochemical stability, solubility, and oral bioavailability of an antiviral agent EFV.