Do I need particle size specifications for my pharmaceutical product?
Specifications define the critical to quality factors to which a pharmaceutical product must conform to be acceptable for
its intended application. Quality by Design highlights the importance of identifying and controlling all the parameters that can influence final product performance: ICH Topic Q6A identifies particle size as a potentially important
variable.1 The specific need for a particle size specification is determined by assessing if and how this parameter affects performance.
For solid or suspension delivery systems, bioavailability is often directly related to particle size because it controls dissolution/solubility
characteristics. Dissolution rate is directly proportional to particle surface area (Noyes-Whitney equation), so a finer particle
size promotes faster drug dissolution. Particle size distribution is also relevant as a narrow distribution produces more
uniform dissolution. Formulations with even a small number of relatively large particles may take some time to dissolve completely,
but this may be the design intent.
For suspensions, stability is an important issue because if the active ingredient settles there is a greater chance of non-uniform
delivery. Stokes' law relates settling velocity to the physical characteristics of the fluid and the size of particles in
the suspension. The relationship here is a strong one: velocity correlates with the square of particle diameter. For suspension
stability, a very low settling velocity is preferable and is more easily achieved with finer particles.
Perhaps less obviously, particle size may also affect a formulation's behaviour during processing and, ultimately, its content
uniformity, which is critical. Take, for example, the widespread operation of direct compression tableting; particle size
can influence segregation behaviour, the ease with which powder flows through the press and the compressibility of a formulation.
In turn, these factors affect the consistency of tablet weight and composition, how the press operates and the mechanical
properties of the finished product.
Figure 1 shows a near-infrared chemical image of a recalled tablet. The active ingredientrich domains (the red areas) are
much larger in the right side of the tablet than in the left, demonstrating that composition is not uniform. The product was
recalled in this case as the larger particle size may have caused some unit doses to fail potency specifications. Poor control
of particle size clearly resulted in a substandard product.
As analytical techniques become more sophisticated, researchers are increasingly able to show that particle shape, as well
as size, can be influential. The tableting example illustrates this point as segregation, flow properties and compressibility
are a function of both size and shape, not size alone. It is not uncommon to find particle size specifications supplemented with complementary shape criteria.
In summary, if any critical performance attributes depend on particle size or shape, a suitable specification is needed. If
other variables can fully define performance, then none is necessary. In practice, particle size specifications are common
within the industry for tablets, dry powder inhalers, suspensions and creams.
What issues should be considered when selecting a particle sizing technique/instrument?
Once the need for a particle size specification is established, it must be defined in the most relevant way. Here, an understanding
of different particle size measurement techniques (operating principles and the reported variable) is essential. There are
many ways of defining particle size, but only perfect spheres, which are rare in the manufacturing environment, can be described
fully using a single number (a diameter). For particles with irregular shapes, there are multiple, equally valid measures
of size including:
- equivalent volume diameter (diameter of a sphere with the same volume)
- circle equivalent diameter (diameter of a circle with the same projected area)
- longest dimension (arguably most relevant when particles are highly irregular — long and thin).