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

TL;DR

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 is developed.

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.

Figures (8)

• Figure 1: Effect of stabilizer concentration on W/O emulsion stability. Representative optical micrographs (top; selected aging times) and temporal evolution of the mean droplet size (bottom) for CCl$_4$/water W/O emulsions prepared by probe sonication (10 min, 20% amplitude, 30 $^\circ$C) with Tween 80 concentrations of 1--10 mg/L. Error bars denote the dispersion obtained from image-based analysis of multiple micrographs per time point.
• Figure 2: Effect of ultrasound amplitude on W/O emulsion evolution. Optical micrographs (top panels) illustrate droplet morphology at representative aging times, and the plot (bottom) shows mean droplet size as a function of time for emulsions prepared at different sonication amplitudes. Conditions: CCl$_4$ (oil) / water (dispersed), Tween 80 = 5 mg/L, sonication time = 10 min, temperature = 30 $^\circ$C. Error bars indicate the variability from image-based measurements.
• Figure 3: Effect of ultrasound probe diameter on W/O emulsion evolution. Representative optical micrographs (top panels) and temporal evolution of the mean droplet size (bottom) for CCl$_4$/water W/O emulsions prepared using a small vs. large sonication probe. Conditions: Tween 80 = 5 mg/L, sonication time = 10 min, amplitude = 20%, temperature = 30 $^\circ$C. Error bars denote the variability obtained from image-based measurements of multiple micrographs per time point.
• Figure 4: Ionic--non-ionic surfactant pairing in CCl$_4$-based W/O/W emulsions. Optical micrographs (0--4 h) and corresponding evolution of mean droplet size for CTAB--Tween 80, CTAB--Poloxamer 407, SDS--Tween 80, and SDS--Poloxamer 407 formulations. Error bars denote the standard deviation obtained from image-based analysis across multiple fields of view.
• Figure 5: Ionic--polymeric surfactant screening for W/O/W multiple emulsions. Representative optical micrographs (0--4 h) and corresponding evolution of mean droplet size for CTAB--HPMC, CTAB--PVP, SDS--HPMC, and SDS--PVP systems. Error bars indicate the variability obtained from replicate image analysis.