Particle size has a great effect on the material properties of the nanoparticles. It is a key parameter that determines the fate of nanoparticles in the biological environment. Formulation parameters and process parameters are usually referred to as major quality parameters. All these factors affect particle size and crystallization. In unstable systems, it is constantly observed that the particle size increases before the actual macro change. Therefore, the particle size can be used as an index of formulation instability.
Fig.1 Particle size and morphology of nanoparticles. (Zou, 2014)
Particle size of lipid nanoparticles is usually determined by light scattering methods, such as photon correlation spectroscopy and/or laser diffraction.
PCS, also known as dynamic light scattering (DLS), is the most extensive method for determining the size of lipid nanoparticles in a dispersion. PCS requires a very small sample rather than a large sample preparation. It is a rapid, non-invasive and non-destructive colloid sizing technology. The technology can detect particles in the size range of about 3-3,000 nm.
Although PCS is the most widely accepted method, it is an indirect particle size determination method. PCS is used to describe particle size according to its translational diffusion coefficient D. Although PCS is a simple, robust and reliable technique for describing particles with a narrow and monomodal size at the nanoscale, it is less useful for dispersions with broad or multimodal size distributions. Another drawback of this technique is the assumption that all particles are spherical.
LD, also known as laser light scattering, can be used in conjunction with PCS. LD is a powerful tool with a wider detection range (20-2,000 μm), making it a better choice for upper and micron LNP. The combination can be used to give a complete particle size distribution from ultra-small to large particles. There are also several limitations for LD. For example, this technique is not very useful in samples of several populations with different particle sizes. What's more, uncertainty may arise in the case of non-spherical particles.
FFF is a relatively new technique with the advantage of colloid separation into particle sizes before measurement. FFF is often more suitable for particle sizing than PCS because of the better resolution of small particle size differences. The separation of particles based on their sizes helps in further characterization of the separated particles. Samples characterized by FFF often need to be diluted, so again there are issues with possible changes in particle size on dilution. Dilution of the sample, a major limitation of these methods, may lead to changes in concentration of surfactants, salt, and other stabilizers thus changing the particle size and/or stability of the particles.
Other than light scattering and field-flow fractionation techniques, the Coulter Counter method can also be used for particle size determination. This method uses an electrical zone sensing mechanism to determine the absolute number of microparticles passing through an aperture of a size which only allows particles of smaller size to pass through. The particle number is determined by measuring electrical resistance which changes when particles pass through the sensing device. Unlike light scattering-based techniques, the Coulter Counter and Microscope techniques measure individual particles so they have the advantage of more direct measurement.
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