Advanced Formulation Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs: A Comprehensive Review

Poor aqueous solubility remains one of the major challenges in the development of oral pharmaceutical formulations, as it significantly limits the bioavailability of many therapeutic agents. A large proportion of newly discovered drug candidates fall into Biopharmaceutics Classification System (BCS) Class II or IV, where solubility is a critical barrier to effective absorption. Enhancing the bioavailability of poorly soluble drugs is essential to achieve desired therapeutic outcomes, reduce dosing frequency, and improve patient compliance. Numerous formulation strategies have been developed to address this issue, ranging from conventional physical and chemical modifications to advanced nanotechnology-based systems. Physical approaches such as particle size reduction, solid dispersions, and lipid-based formulations aim to improve dissolution rates, while chemical techniques like salt formation and prodrug development enhance solubility through molecular modification. Novel drug delivery systems, including nanoparticles, nanosuspensions, liposomes, and self-emulsifying drug delivery systems (SEDDS), offer promising alternatives by improving both solubility and stability. Despite their advantages, these strategies face limitations related to scalability, stability, and regulatory acceptance. This review provides a comprehensive overview of the current and emerging techniques used to enhance the bioavailability of poorly soluble drugs, with a focus on their mechanisms, advantages, limitations, and potential for clinical translation.