Controlled Production of Monodisperse Double Emulsions by Two-Step Droplet Breakup in Microfluidic Devices Shingo Okushima, Takasi Nisisako,* Toru Torii, and Toshiro Higuchi Department of Precision Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan Received August 3, 2004. In Final Form: September 15, 2004 A microfluidic device having both hydrophobic and hydrophilic components is exploited for production of multiple-phase emulsions. For producing water-in-oil-in-water (W/O/W) dispersions, aqueous droplets ruptured at the upstream hydrophobic junction are enclosed within organic droplets formed at the downstream hydrophilic junction. Droplets produced at each junction could have narrow size distributions with coefficients of variation in diameter of less than 3%. Control of the flow conditions produces variations in internal/external droplet sizes and in the internal droplet number. Both W/O/W emulsions (with two types of internal droplets) and oil-in-water-in-oil emulsions were prepared by varying geometry and wettability in microchannels. Introduction A double emulsion (also referred to as a multiple emulsion) can be defined as a multiple-phase dispersion in which droplets enclosing finer droplets are suspended in a continuous liquid phase. Since double emulsions were first described in 1925, 1 both the water-in-oil-in-water (W/ O/W) type and the oil-in-water-in-oil (O/W/O) type have attracted considerable attention because of their potential applications in food science, 2 cosmetics, 3 and pharma- ceutics. 4 Many studies have focused on pharmaceutical uses of W/O/W type emulsions, which include encapsula- tion of water-soluble therapeutic agents for targetable drug delivery, 5-7 and preparation of biodegradable micro- capsules loaded with bioactive polymers by the solvent evaporation method. 8 Other applications include the extraction of hydrocarbons, 9 metal ions, 10 and organic acids 11 across a thin liquid layer mediating between the internal drops and the external continuous phase. Of the techniques explored to date, 12-14 two-stage emulsification 15 is now mostly used in the practical formulation of double emulsions. This technique exploits the turbulent shear force induced by vigorous mixing so as to rupture the droplets, and the resulting internal and external droplets each have a broad size distribution. Highly uniform emulsion droplets can be generated by membrane-emulsification techniques, 16-18 and these have been applied to the production of double emulsions. Higashi et al. used a porous glass membrane to prepare monodisperse W/O/W emulsions with a coefficient of variation (CV) below 10% for hepatic arterial chemo- therapy. 19 Sugiura et al. permeated prehomogenized water-in-oil (W/O) dispersions through arrays of micro- fabricated nozzles to produce W/O/W emulsions with CVs of 5-19%. 20 However, no technology currently exists to control the encapsulation efficiency in double-emulsion droplets with precision. In recent years, there have been intensive studies of microfluidic techniques for producing droplets of highly uniform size. 21,22 In particular, droplet preparation using micro T-junctions 23-26 offers many advantages. Droplet formation is highly reproducible at low Reynolds numbers, and the resulting drops are accurately uniform in size. Also, their size is easily varied across the channel by controlling the flow conditions. Furthermore, droplet formation can be very fast at higher flow rates; in our previous study, a breakup rate of up to 2.5 × 10 3 drops/s was confirmed. 27 In view of its flexibility and control capability, this technique has led to various promising applications, including a chemical reactor, 28 a screening * To whom correspondence should be addressed. Tel: (81) 3 5841 6072. Fax: (81) 3 5841 6072. E-mail: nisisako@intellect.pe.u- tokyo.ac.jp. (1) Seifriz, W. J. Phys. Chem. 1925, 29, 738. (2) Matsumoto, S. J. Texture Stud. 1986, 17, 141. 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Lab Chip 2002, 2, 24. (28) Burns, J. R.; Ramshaw, C. Lab Chip 2001, 1, 10. 9905 Langmuir 2004, 20, 9905-9908 10.1021/la0480336 CCC: $27.50 © 2004 American Chemical Society Published on Web 10/08/2004