While wet milling of active pharmaceutical ingredients (API) and other crystalline substances has commanded considerable attention there are few fundamental studies on which to base mill design, scale up and operating strategies. Often an in-line rotor-stator mixer, fed from and recirculated to a well-mixed holding tank, is used to achieve the ultimate particle size or to precondition a feed to a higher intensity device such as a ball mill. In this study, a systematic framework is developed and employed with definitive experiments performed in a Silverson L4R rotor-stator mixer, to investigate the effect of milling conditions, mixer geometry, and particle physical properties on ultimate particle size and particle breakage kinetics. By varying operating conditions, mixer geometry and crystal mechanical properties, it is possible to discriminate among various breakage mechanisms (fluid shear, particle-particle collisions, particle-wall collisions, etc.) to develop mechanistic relations to aid in process scale up and to serve as inputs to population balance and other models for the evolution of the crystal size distribution.
Based on a literature review, it was reasoned that along with size and shape, stress intensity factor and hardness were the main physical properties affecting breakage rate. To vary these properties, several crystalline materials were milled in antisolvents (e.g. sugar in isopropyl alcohol) to allow discrimination between mechanical size reduction and solubility effects. Collision rates were varied by changing particle concentration; and coatings and small geometric changes were used to consider interactions with solid surfaces. Rotor speed and volumetric throughput were adjusted to independently vary energy input and mill head residence time. Particle size distributions were measured by three different methods. A Lasentec focused beam reflectance measurement (FBRM) probe was placed in the mill to holding tank recirculation loop to continuously monitor particle size. It was also used to monitor suspension uniformity in the holding tank. Grab samples, acquired in the holding tank at well-defined time intervals, were analysed using a Horiba laser diffraction instrument and by microscopy with an automated image analysis technique. The mechanistically correlated experimental results will be presented in detail, and discussed with respect to process scale up and model development. One intended use of the correlations is as mechanistic inputs (breakage kernels) to population balance models.