Emulsion Stability and USP 729
An emulsion is usually comprised of two or more immiscible liquids where one liquid in the form of droplets is dispersed (the dispersed phase) in another liquid (the continuous phase).
The surface of each droplet is an interface between hydrophilic and hydrophobic molecules and therefore thermodynamically unstable. The stability of an emulsion can also be affected by many external factors including storage methods (glass vs. plastic), time, and temperature. Light scattering techniques are the norm for determining the particle size distributions of emulsions. Oftentimes an emulsion that has become unstable will produce a shift in mean diameter of a light scattering PSD. However, the size and quantity of the particles which cause instability cannot be determined using these techniques.
This detail becomes extremely important when dealing with injectable fat emulsions. The coalescence of fat globules in intravenous lipid emulsions (IVLEs) can cause pulmonary embolisms in small blood vessels with diameters ranging between 4 and 9 µm and in larger blood vessels that have diameters ~20µm. Therefore the US Pharmacopeia contains a number of particle sizing procedures such as USP-788 and USP-729. USP-729 requires that the mean droplet size as well as the extent of the large-diameter droplet tail (>5µm) be determined. The volume weighted percent of PFAT5 (percentage of fat greater than 5 microns) must not exceed 0.05%. A single particle counting technique such as SPOS is required to determine the PFAT5 in emulsions. For many years the Accusizer line of instruments has been the premier instrument for this determination. The figure below shows the volume-weighted distribution of an unstable emulsion that has become increasingly unstable over time.
Globule size distribution of a lipid emulsion after heat stress for 0 - 40 hours measured on the AccuSizer