Boosting Terbinafine Solubility through Hot Melt Extrusion Coprocessing Guided by QbD

Abstract

The formulation of hydrophobic drugs, such as terbinafine hydrochloride (TbHCl), presents significant challenges due to their low aqueous solubility, which severely limits oral bioavailability. This study explores the application of hot-melt extrusion (HME) to enhance the dissolution rate of TbHCl through the development of solid dispersions (SDs) employing extrusion-grade polymers, namely polyvinylpyrrolidone-vinyl acetate copolymer (PVP VA64) and Soluplus®. For helping the HME process and get a synergic effect in solubility was added xylitol. A Quality by Design (QbD) framework was adopted, integrating risk assessment tools and design of experiments (DoE) methodologies to identify critical material attributes (CMAs) and critical process parameters (CPPs) impacting dissolution performance. Results demonstrated that both the type and concentration of the polymer significantly influenced the dissolution behavior, with Soluplus® exhibiting superior performance attributable to its dual solubilization mechanisms. The optimized formulation, containing 42.2% Soluplus® and an extrusion residence time of 15.88 minutes, achieved a 2.03-fold increase in dissolution rate compared to the untreated drug. Solid-state characterization indicated that HME effectively reduced TbHCl crystallinity, thereby improving wettability and solubility, and resulting in the formation of a microfine solid dispersion with Soluplus®. These findings underscore the potential of HME as a viable strategy for the co-processing of active pharmaceutical ingredients, offering an effective approach to addressing the solubility limitations of poorly water-soluble drugs.