Production of Nano-emulsions at Relevant Industrial Rates: Use of Innovative Scale-up Strategies

T. Panagiotou, R.J. Fisher
Delphi Scientific, LLC,
United States

Keywords: nano-emulsions, drug delivery, scale-up, energy dissipation, droplet formation


There currently exists a spectrum of industries that require stable nano-emulsions with narrow droplet size distributions as marketable intermediates and/or final product formulations. In addition to the pharmaceutical industry’s drug delivery platforms for direct use in nano-medicine applications, the food/nutraceutics, personal care and cosmetics, and advanced materials industries are also key participants. Their efforts are primarily directed to incorporation of nano-emulsions into macro-sized matrices to enhance quality performance characteristics. Production of nano-emulsions is currently expensive and energy intensive due to specialized equipment used in production and high energy required for the formation of uniform nanodroplets. Additionally, the complex nature of the nano-emulsions, which include immiscible liquids, surfactants, viscosity modifiers and other excipients, makes it difficult to extrapolate production conditions from one nano-emulsion formulation to other formulations. A methodology to utilize continuous processing for large scale manufacturing, and reduce the cost and energy demands is presented here. Process development programs at the bench scale are optimized with respect to operational maps to identify the key variables that must be controlled to yield the desired product specifications. The ability to manipulate the mass, heat and momentum transport processes is critical in accomplishing optimal process performance, which translates to efficient use of input energy and lower operating costs. A major objective is to maximize the fraction of input energy that is utilized in forming new surfaces, i.e., droplets. This process is associated with the efficacy obtained through focused energy density transfer rates. The source of these useful energies is from the energy dissipation rate per unit mass (within a given control volume) that is not converted to losses, such as viscous heating from turbulent eddy collapse and wall shear. For product consistency with respect to uniformity of droplet sizes, with a narrow size distribution, it is imperative that each fluid element processed be exposed to identical local environmental conditions. That is, they must be exposed to the same thermodynamic state, mixing intensity, and residence time to sustain the controlling mechanisms that are in play. The purpose is to produce uniformity in characteristic time and length scales for the transport processes, whether the mechanisms are occurring in tandem or an individual one is controlling the phenomenological events. Hence, we have developed processing equipment to be integrated into systems at both the bench and commercial scales that can accomplish these goals. Our system components can, through manipulated process variables and associated control strategies, produce tunable features such as mixing intensity and processing environments to induce a specific mechanism. This is particularly important when changing process scales; i.e., to maintain mechanistic integrity. For this purpose, we used the concept of dynamic similitude. For example, dimensionless parameters that access the magnitude of molecular versus advection/convection transport processes and interfacial instabilities are employed. Consequently, we will discuss a relatively straightforward approach for mechanistic integrity in our multi-species, multi-phase system using manifold and component stacking methodologies.