Investigation of Scaling Parameters On the Particle Size Reduction Profile In Rotor Stator Wet Mills

A well defined formulation process requires understanding and controlling the powder properties of key inputs, most notably, the active pharmaceutical ingredient (API) particle size.  In many instances, API crystallization control is necessary to achieve the desired particle size.  However, it is sometimes necessary to reduce the particle size further.  In these instances wet milling offers an opportunity to reduce particle size below what can be achieved by crystallization alone.  The current literature offers limited insight into the fundamentals of particle size reduction during wet milling as well as translation of lab scale proof of concept to the pilot and manufacturing scale.  In this investigation, comparisons of lab and pilot plant scale data for a given API are explored in reference to mill type, flow rate, and shear frequency to demonstrate the impact of scale on the feasibility of meeting the target API particle size.  For lab and plant experiments, the particle size was measured real-time using focused beam reflectance measurement (FBRM) and correlated to spot slurry samples analyzed by light scattering as well as microscope images.  The benefit of a fundamental understanding of this technology will aid in building a platform to translate lab scale development to the pilot plant and, subsequently, the manufacturing scale.