Role of Porous Silicates in Balancing Drug Loading, Stability, and Pharmacokinetics of Enzalutamide Supersaturated Lipid-Based Formulations

Supersaturated lipid-based formulation (Super-LbF) represents a promising advancement in lipid-based systems, especially for drug compounds with limited aqueous solubility and dissolution. To date, limited studies have investigated the impact of critical attributes, including solid carriers, supersaturation levels, colloidal stability, and solubilization behavior of supersaturated LbFs (Super-LbF). The present study aims to assess the effect of mesoporous silica (MCM-41, Syloid 244F) and clay-based (montmorillonite) solid carriers on the solubilization and overall biopharmaceutical performance of Super-LbFs. Enzalutamide (ENZ), a rapidly crystallizing drug, was dissolved in Super-LbF at a supersaturation level of ∼2.5 by using the heat-cool method. Further, lipid-based solid dispersions (LBSDs) were prepared via the adsorption technique and characterized using powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Solid-state characterization confirms that ENZ is present in a molecularly dissolved form within the pores or between the platelets of solid carriers. LBSDs with high supersaturation levels showed no signs of recrystallization over 90 days under accelerated storage conditions. Dissolution studies indicated that the pore size and physicochemical nature of the solid carrier influence drug release at the solid-liquid interface, contributing to sustained release behavior. In the gastrointestinal (GI) milieu, endogenous amphiphilic components interact with self-assembled colloidal phases to significantly improve the solubilization capacity (3.5-4-fold) for LBSDs compared to crystalline ENZ and their liquid counterparts. Lastly, <i>in vitro</i> findings correlated with <i>in vivo</i> drug exposure in Sprague-Dawley rats. Montmorillonite-based LBSD showed higher drug exposure compared with Syloid-based LBSD, which could be due to lipid entrapment within the pore of silica. In conclusion, the study demonstrates that porous silicates act as functional carriers for modulating the physicochemical stability and biopharmaceutical performance of supersaturated lipid formulations.