(655f) High Shear Rotor-Stator Wet Milling for Drug Substance: Expanding Capability and Improving Scalability

Rotor-stator wet mills are used in the pharmaceutical industry as a means to control final particle size distribution.  Wet milling can be used to create seed for crystallization and also allows for normalization of the particle size to allow batches with consistent API physical properties to be delivered for downstream drug product operations.  Wet milling is robust, relatively easy to use, and broadly applicable.  Wet milling has significant cost advantages over dry milling as it overcomes challenges around yield losses and eliminates the need for expensive dry solids containment.  Wet milling also eliminates API physical property instability resulting from crystal lattice disorder that can be caused by dry milling. 

Historical rotor-stator wet mill technologies are generally capable of achieving particles sizes down to ~25 microns.  Newer higher shear wet mills allow for a reduction of particle size down to ~10 microns.  In addition to the improved particle size reduction, recent new wet mill designs better maintain geometric consistency across the product line, which provides an opportunity for enhanced scalability.  Traditional scale-up for wet mills usually involves maintaining the tip speed (i.e. shear rate) of the rotor across scales and generally allows for effective scale-up of the terminal particle size attained.  However, traditional scale-up models have limited predictive capability in regards to the particle breakage kinetics leading up to the terminal particle size.  Studies presented here confirm the importance of maintaining tip speed across scales but identified additional parameters that are important to include in scale-up models addressing particle breakage kinetics.  Additional aspects of hydrodynamics, shear rates, and equipment properties were assessed as part of these scale-up model optimization efforts.  Specific processing parameters evaluated included flow rate, solids concentration, fluid viscosity, starting particle size distribution, and pressure drop. 

Mill head geometrical design is also evaluated within the scope of studies presented here.  Custom mill heads were designed to verify optimized scale-up models.  These custom mill heads provided further insight into the importance of mill efficiency and slot events.  This, in turn, allowed for more accurate scale-up of not only the terminal particle size but also the particle breakage kinetics.  The optimized models reduce the reliance on in process controls for determining the end point of milling.