Solidification intervention strategies for efficient encapsulation of water-soluble drugs via oil-in-water emulsion...

Efficient encapsulation of water-soluble drugs into particles remains a persistent engineering challenge, primarily because their high aqueous solubility promotes rapid diffusion from dispersed phase into the surrounding aqueous during fabrication. In conventional emulsification and solidification processes of oil-in-water (O/W) emulsions, the markedly enlarged oil-water interfacial area accelerates interfacial mass transfer, leading to severe drug loss and low encapsulation efficiency. Overcoming this limitation requires targeted intervention strategies to suppress drug migration across the oil-water interface during emulsification and subsequent solidification. This review summarizes recent advances in solidification intervention strategies for the efficient encapsulation of water-soluble drugs via O/W emulsion techniques. From a process-kinetics and time-sequence perspective, these strategies are classified into three major categories according to the relative solidification sequence of drugs and polymer matrices: (i) drug-first solidification via controlled drug precipitation, (ii) concurrent solidification through synchronized immobilization of drugs and polymers, and (iii) polymer-first solidification followed by post-loading of drugs. Representative formulation approaches and material systems, as well as their respective advantages and limitations, are critically discussed. Additionally, the mechanistic roles of non-covalent interactions in regulating drug partitioning and immobilization during emulsification are systematically analyzed, together with commonly used evaluation techniques. Finally, current challenges and future perspectives are highlighted to guide the rational design of high drug-loaded particulate systems and to facilitate the industrial translation of O/W emulsion-based encapsulation technologies for water-soluble drugs.