Particles in practice
It is one thing to know the size, shape and appearance of particles, but one also needs to know how these parameters affect
product and process performance. As noted above, small particles don't necessarily dissolve more rapidly than large particles
of the same chemical.
In early phase development, it is critical to investigate how particles of the proposed new API will dissolve in the body.
Using methods specified in the pharmacopoeia, one can mimic the environment of the mouth and gut, and determine where in the
GI tract an API is likely to dissolve. This information can potentially justify whether the candidate molecule is worth pursuing.
One might also investigate whether the particle size within the finished product has an impact on release rates.
Rheological studies are also valuable because subtle changes to particle size, distribution and shape can affect the rheology
positively or negatively. With medicines that are suspensions, for example, it is important to control viscosity to prevent
settling during storage, and to mitigate inconsistent dosing.
Many techniques are available to establish, measure and monitor particle characteristics, and there is much that can be learned
about the effect of particle size and morphology on end product performance. However, when using results to set specifications
or manage quality control, it is always necessary to seek out the detail of the methodology used to generate data because
different methods 'see' particles in different ways.
To take an obvious example, one might have a particle size specification such as "50% of particles (by mass) must be less
than 80 μm" set after sieve tests on representative batches. This would not necessarily be confirmed by analysis of the same
batches using laser diffraction and reporting the d50 (diameter of the 50th percentile), even though, at first sight, the
two specifications might seem to be equivalent. In the case of laser diffraction, the key parameter is particle volume rather
than mass, and particle orientation and shape are not accounted for in the same manner.
Using techniques that permit the recording of visual images makes it possible to give further supporting evidence to the robustness
of a particle characterisation method that generates only numeric data. In this way, it is possible to ensure that the procedure
is characterising primary particles and not agglomerates, and that the method of analysis does not have a destructive effect
on the distribution being recorded.
The author would like to acknowledge Malvern Instruments.
Victoria Jones Laboratory Manager, Physical Science Laboratory, RSSL
1. P. Kippax, Pharm. Technol. Eur.,
2. D.J. Burgess et al., AAPS J.,
6(3), 23–24 (2004).
3. J. Netterwald, Pharmaceutical Formulation and Quality (December/January 2010).
4. US Pharmacopoeia
5. European Pharmacopoeia, Chapter 2.9.31, Laser Diffraction Measurement of Particle Size, Supplement 5.6 (2006).