(430e) Impact of Scale On Wet Mill Performance

In the pharmaceutical industry, particle size control of the active pharmaceutical ingredient (API) is critical to ensure consistency in the final formulated drug product. Ideally the crystallization is designed to give a consistent particle size; however, milling is frequently used to either achieve a uniform particle size or to generate seeds for the crystallization. As an advantage for containment during processing, rotor stator wet milling has emerged as an alternative to traditional dry milling to eliminate the hazards associated with dust generation. To date, fundamental investigations to understand particle size reduction of pharmaceutical compounds during wet milling are limited.

In this study, the particle size reduction of three pharmaceutical compounds of differing morphologies was studied using lab and plant scale wet mills. For each compound, the lab scale wet mill was configured to match the condition of the pilot plant wet mill to evaluate existing scale factors such as tip speed, shear frequency and shear number. The particle size was measured real-time using focused beam reflectance measurement (FBRM) and correlated to spot slurry samples analyzed by light scattering. Additionally, lab scale milling parameters were varied to further understand the mechanisms of particle size reduction (shear vs. particle-particle/particle-wall collisions) to explore and expand on the above existing scale factors. The benefit of a fundamental understanding of this technology will aid in translating lab scale development to the pilot plant and, subsequently, the manufacturing scale.