Impact of API Particle Size On a Sustained Release Oral Tablet Formulation

The objective of this study was to understand the impact of API particle size on various blend and tablet quality attributes of a sustained release oral tablet formulation produced via a direct compression process. The API primary particle size and agglomerate size were identified as critical material attributes through a risk assessment performed by preliminary hazards analysis. The two factor, three level experiment design consisted of three lots of API with different primary particle size and agglomerate size controlled by three milling conditions. After milling, the API primary particle size and agglomerate size were characterized by various methods including static light scattering, image analysis, and sieve analysis. Tablets were manufactured at a 1 kg scale using high shear blending followed by direct compression. A model was then developed to assess the impact of API primary and agglomerate particle size on several bulk blend and tablet quality attributes. An approach based on risk assessment and limited design of experiments focused on critical material attributes can generate significant process understanding. The knowledge gained at small scale can be leveraged to generate a preliminary design space.