Formation of Nanoemulsions by Stirred Media Milling

Emulsions are widely used in the pharmaceutical and food industry. In recent years an increasing use of emulsion-based delivery systems for bioactive substances involving small particle sizes is notable. Apart from spontaneous formation of microemulsions, in general energy has to be introduced into the system, i.e. the formation process of nanoemulsions (thermodynamically metastable systems) is not spontaneous and the droplet-breakup process needs application of external energy input. Within this account we show that highly stable nanoemulsions can be produced by an alternative and scalable process applying stirred media milling. Alkane (hexadecane, dodecane)-Tween85-water-systems have been used as model emulsion systems to demonstrate the feasibility of the approach. The influence of fundamental process parameters such as emulsion formulation (c.f. oil mass fraction and oil-to-emulsifier mass ratio), stressing conditions (grinding bead size and stirrer tip speed), process time and especially temperature on the emulsion droplet size and size distribution has been studied in detail. Low oil-to-emulsifier ratios are most appropriate with respect to obtaining small mean droplet sizes and narrow droplet size distributions. It is shown that the smallest mean droplet sizes (at constant oil-to-emulsifier ratio) are obtained at the lowest oil mass concentrations. Product emulsions of Sauter diameters x1,2 below 25 nm have been obtained in the hexadecane-Tween85-water system using ZrO2 grinding beads of 100 μm and 400 μm in diameter, respectively. Interestingly, working at high stress intensities is not appropriate: higher stress intensities lead to a more intense mixing that increases the coalescence rate. Remarkably, lowering the process temperature below the solidification temperature of the oil phase, i.e. ‘grinding’ of the solid oil, is advantageous as compared to emulsification of the liquid oil: Coalescence and ripening can be significantly reduced. Smallest product droplets with x1,2 < 10 nm are obtained in the hexadecane-Tween85-water system after a short processing time of clearly below 1 hour. The feasibility of the process proposed to produce nanoemulsions using oil phases loaded with the hydrophobic organic compounds pyrene and trans-stilbene is demonstrated.