Multiple Emulsions (W/O/W) for Confined Precipitation of Drug Nanoparticles

Abstract: Multiple emulsions offer a compelling route to confine nucleation and growth during drug precipitation, yet their practical use is frequently limited by kinetic fragility and sensitivity to formulation and processing conditions. Here, we develop an ultrasound-assisted, two-stage emulsification strategy to generate water-in-oil-in-water (W/O/W) multiple emulsions with sufficient stability to function as templates for forming drug-rich submicron particulates. We first establish an operating window using simple W/O emulsions, showing that increased Tween~80 concentration and intensified sonication (higher amplitude and larger probe) yield smaller droplets and reduced coarsening tendencies. Using this window, W/O/W emulsions are formulated and systematically screened via surfactant pairing across ionic, non-ionic, and polymeric stabilizers. Ionic--non-ionic combinations provide the most favorable droplet-size control, with CTAB--Tween~80 emerging as a practically robust formulation. Cyclohexane was selected as a reproducible platform oil for downstream precipitation using the lead CTAB--Tween~80 formulation. Finally, curcumin-loaded W/O/W constructs generate curcumin-rich submicron particulates, supporting multiple emulsions as experimentally accessible microstructured environments for particle engineering of poorly soluble drugs.