Particle engineering of a needle-like active pharmaceutical ingredient into size controlled agglomerates: Part I. Process scalability and development.

Pharmaceutical solid oral dosage forms often require optimized crystal size, shape, and bulk powder properties for effective drug formulation. Spherical agglomeration has emerged as a transformative technique to convert undesired crystal shapes into larger, denser agglomerates with improved flow properties. However, achieving scalable, small agglomerate sizes efficiently, remains a challenge. This study investigates spherical agglomeration integrated with a high shear wet mill to consistently achieve smaller agglomerate sizes (<300 µm) for an active pharmaceutical ingredient with challenging particle properties. A multivariate Design-of-Experiment approach was employed to evaluate the effects of key process variables; bridging liquid addition time, bridging liquid to solids ratio and wet milling speed on agglomerate attributes and bulk powder properties. Optimal process conditions were shown to generate robust agglomerates with a median size range of 30-300 µm. The agglomerates showed good scalability across 250 mL-5 L agitated stirred-tanks when targeting three median sizes (35 µm, 80 µm and 145 µm) with minimal residual solvent content as well as good flow performance. A parallel agitated-filter isolation study demonstrated that over 225 impeller revolutions (five hours of drying) was sufficient to deliver acceptable product quality. Proper agitation during drying was crucial to avoid breakage and attrition in order to preserve agglomerate properties. Overall, the intensified process significantly improved the particle size, shape, density and flowability of the API. This technique shows great potential in pharmaceutical manufacturing as an important particle engineering tool for enabling downstream processing applications.