By Thomas Andresen, QA Manager, Soren Lund Kristensen, CEO, and Karin Liltorp, Principal Scientist, Particle Analytical ApS
Particle characterisation, such as particle size, is of immense importance for all solid pharmaceutical products, both in relation to processability and bioavailability. Unfortunately, particle size is not always easily controlled during manufacturing and even slight changes in manufacturing conditions might lead to quite large size changes. Furthermore, a change in API supplier almost certainly leads to new particle characteristics. In all cases where a risk of change in particle size exists, it should be evaluated whether the changes will affect the drug properties – and if the method used for characterisation of the particles is still valid.
A good method for characterisation of the particles in a product should, amongst other parameters, be able to describe the product with regard to size. This appears to be a very reasonable requirement, but it is not always as simple as it seems. First of all “size” is not easily defined: Is it the length, the width, the thickness or the shape you want to know?
The size and shape is related to various other parameters such as flowability, compressibility, dissolution, etc. and the correlation is not necessarily straight forward. Thus, validation of a method for determining particle sizes should optimally be correlated to these other parameters that are critical for the current product (blending properties, dissolution rate, agglomeration tendencies etc.).
In this study two batches of the same compound - from different suppliers – and with quite different particle characteristics - were compared with regard to particle size and dissolution properties. One batch consists of small -and agglomerated- particles and the others of larger particles that do not agglomerate. In contrast to “expected” behavior, the smaller particles dissolved more slowly than the larger particles – probably because of their tendency to agglomerate. In this case, the size of the primary particles, as determined by the validated particle size method, does not give a good description of the product behavior. Thus, the current example highlights the importance of correlating your method for determination of particle size to other critical parameters for the product in question.