An Assessment of Techniques for Evaluating the Physical Stability of Parenteral Emulsions

Abstract

The physical stability of the parenteral emulsions is a key product quality issue. The purpose of this study is to develop, prepare and characterize model phospholipid emulsions and to critically evaluate various physical stability-indicating methods. Oil-in-water (O/W) emulsions were prepared using 20% (w/w) medium chain triglycerides (MCT) or soybean oil in 2.21% (w/w) aqueous glycerin solutions emulsified with 0.1 to 1.8 % (w/w) lecithin. The reproducibility of emulsion preparation was determined by measuring the volume-based mean droplet diameter using photon correlation spectroscopy (PCS) and zeta potential using electrophoretic light scattering. Evaluation of stability-indicating methods was conducted by comparing the mean droplet growth rate of a thermally-stressed emulsion using PCS, a light obscuration particle counter (HIAC, equipped with a laser diode sensor) and a droplet image analyzer interfaced with transmission electron microscopy (TEM) using osmium tetraoxide fixation. Emulsions with identical compositions and preparation properties had reproducible mean droplet diameter and initial zeta potential values with RSD <5.0%. Upon the application of thermal stress, the volume-based diameter increased linearly with time for all three sizing techniques (PCS, HIAC, and TEM). The droplet growth rates estimated using PCS and TEM were nearly identical. PCS is a sufficiently accurate technique for measuring emulsion stability and is less time-consuming than TEM. The HIAC technique only measured the size of droplets with diameters larger than about 1 micron, which was considerably greater than the mean droplet diameter as determined by PCS and microscopic image analysis (TEM). Moreover, the growth rate obtained using HIAC was much greater than the rates estimated by PCS and TEM; therefore the HIAC technique was not an accurate measure of the physical stability of the thermally stressed emulsions.