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.
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: