Recent Advances and Mechanistic Insights into Hydrotropic Solubilization: From Conventional Agents to Novel Combination Strategies

Abstract

The poor aqueous solubility of emerging drug candidates remains a formidable challenge in pharmaceutical development, directly limiting oral bioavailability and therapeutic efficacy. Hydrotropic solubilization has gained significant attention as a versatile, cost-effective, and environmentally friendly technique to enhance the solubility of hydrophobic drugs without the need for organic solvents. This review provides a comprehensive overview of recent advances in the fundamental mechanisms underlying hydrotropy, including molecular self-aggregation, complexation, and the role of the Minimum Hydrotropic Concentration in initiating the solubilization process. The discussion categorizes hydrotropic agents into synthetic, natural, and novel classes, highlighting a strategic shift toward biocompatible and green alternatives. Findings from literature revealed recent advances in formulation strategies, such as the development of hydrotropic solid dispersions and mixed hydrotropy: a synergistic approach that achieves multifold solubility enhancement while minimizing individual agent concentrations and potential toxicity. By integrating advanced characterization techniques; including spectroscopic, microscopic, and thermodynamic studies with a critical analysis of regulatory and safety considerations for the commercialization of hydrotropic systems. These insights provide a structural framework for overcoming the solubility barrier and optimizing the delivery of next-generation therapeutic agents using hydrotropes.