Guidance on Drug Substance Particle Size Controls for Solid Oral Dose Forms

Drug substance particle size is a critical property affecting drug product performance. Smaller particles dissolve faster and may improve bioavailability of the drug as a result. Smaller particles are typically dispersed more uniformly, leading to lower inter-tablet potency variation. Unfortunately, smaller particles can also result in poor powder handling characteristics or other processing issues. For example, powders can fail to flow through hoppers or stick to tooling surfaces, leading to poor tablet weight uniformity or tablet appearance issues. During crystallization, smaller particles can also be difficult to filter from the crystallization media. This can lead to higher levels of residual solvents and other impurities. Particle design and size selection are therefore critical to achieving a balance between manufacturability, bioavailability, and content uniformity. In this chapter, the impact of particle size on bioavailability is introduced and the impact on content uniformity is considered in depth. Control of the variability of tablet potency is discussed in relation to the overall particle size distribution. The risk-based selection of a positive control such as a screen to limit the maximum allowable particle size is discussed in relation to the occurrence of rare, but highly super-potent tablets.