Particle size is a potentially important variable in pharmaceutical production and efficacy. In solid or suspension delivery
systems, for example, dissolution and solubility characteristics, which impact the bioavailability of the API, are often controlled
by particle size, though not necessarily in ways that are intuitively obvious. The Noyes-Whitney equation describes dissolution
rate as being directly proportional to particle surface area, so one might expect small particles to dissolve more rapidly
than large particles; however, actual dissolution studies show that this is not always the case. In the majority of these
instances, this phenomenon can largely be explained by the relative surface roughness of the particles, which gives them a
larger surface area.
In suspensions, Stokes' law relates settling velocity (i.e., precipitation or aggregation) to the physical characteristics
of the fluid and the size of particles in the suspension. In practice, finer particles create a more stable suspension; however,
the stability of particle dispersion also depends on the balance of repulsive and attractive forces. If the particles have
little or no repulsive force, there will eventually be some manifestation of instability, such as aggregation. As such, it
is not only particle size that matters, but also particle shape, size distribution and zeta potential.
Victor Habbick Visions/Getty Images
Particle size can also affect the behaviour of a formulation during processing. In direct compression tabletting, particle
size can influence segregation behaviour and the compressibility of a formulation that, in turn, can affect the consistency
of tablet weight and composition, how the press operates, and the mechanical properties of the finished product.
Particle size also has a critical effect on the content uniformity of solid dosage forms, with poor results often arising
from a mismatch of drug and excipient particle size and density. Poor content uniformity may also result if drug particle
size distribution is too large, but it is generally desirable to approach the upper edge of the permitted drug particle size
range because reducing particle size too dramatically can exacerbate drug agglomeration and mixing problems.1
Similarly, particle size can affect the flow properties of powders and pastes. Increasing the polydispersity of particle size
in powders can improve flow properties; for example, in the case of powders subject to flow in an industrial process, a bimodal
distribution of particle sizes can also ensure better flow during processing.1 For pastes, where viscosity is often important, there is usually an optimum particle size distribution (PSD) that yields
minimum viscosity whilst maintaining the particle volume fraction. The PSD will also have a direct influence on the texture
of the finished product.
Overcoming the challenges
There are several methods, some of which are outlined below, that can be used to investigate particle characteristics. All
give useful information on their own, but it is often more instructive, or simply necessary, to use the techniques to complement
each other. Using laser diffraction methods to understand particle size distribution, and microscopy to understand shape,
for example, helps to build a more detailed picture of why a powder behaves in a certain way.
It is also important to note that different techniques for measuring particle size can yield different answers. This is not
a new observation. In 2004, the AAPS Journal published a report on particle size analysis and called for greater harmonisation
of methods and a wider appreciation of the difficulty of reconciling results obtained by different methods of particle sizing.2 Since then, observers have noted that some progress has been made via the Laser Diffraction Measurement of Particle Size
USP monograph (USP <429>),3,4 released in 2005, and the USP written standards regarding lipid emulsions (USP <729>). The European Pharmacopoeia also has
a chapter on laser diffraction5 and, more recently, ISO13320:2009 was published, creating a new standard, and guiding the way for robust method development.