Surfactant–Particle Engineering Hybrids: Emerging Strategies for Enhancing Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs

<b>Background/Objectives:</b> The poor aqueous solubility of many therapeutic compounds remains a key barrier to achieving optimal oral bioavailability. While traditional formulation strategies-such as surfactant-based solubilization, nanocrystals, and amorphous solid dispersions-have yielded varying degrees of success, they are often limited by poor physical stability, high excipient loads, inconsistent absorption, and safety concerns associated with long-term surfactant exposure. To address these challenges, this review evaluates surfactant-particle hybrid drug delivery systems as a next-generation platform for enhancing the oral delivery of poorly water-soluble drugs. <b>Methods:</b> A comprehensive literature analysis was conducted to examine the mechanistic foundations, formulation techniques, and translational hurdles associated with these hybrid systems. Representative in vitro and in vivo case studies were critically reviewed to assess performance consistency, particularly with respect to dissolution enhancement, supersaturation stabilization, and permeability modulation. Consideration was also given to manufacturing feasibility, excipient safety, scalability, and regulatory constraints. <b>Results:</b> Findings indicate that surfactant-particle hybrids provide synergistic benefits by integrating solubilization and stabilization functions with tailored particle design. These systems have shown consistent improvements in pharmacokinetic profiles and drug absorption across diverse drug candidates. However, limitations remain, including challenges in long-term physical stability and excipient compatibility that must be addressed for broader application. <b>Conclusions:</b> Surfactant-particle hybrid systems offer a versatile and promising approach to overcoming the limitations of poorly soluble drugs. With careful attention to formulation optimization and regulatory compliance, they have the potential to serve as a transformative platform in future oral drug delivery strategies.