(366b) PBE-Aided Design of Slurry Milling Process to Reduce Particle Size of Intermediate and Active Pharmaceutical Ingredients

A variety of milling processes are used in pharmaceutical industry to reduce the particle size of intermediate and active pharmaceutical ingredients. Slurry milling processes are of particular interest because they significantly reduce the transfer of heat to the product compared to dry mill equipment and they can eliminate a unit operation when crystallization-milling sequence are combined prior to the isolation. In spite of its extensive use in the pharmaceutical industry, the design of slurry milling processes are not trivial due to the multivariate nature of the process. One of the most intuitive ways to describe milling processes is the use of population balances equations (PBEs). However, relating PBE parameters (i.e., breakage rate and breakage kernel) to actual milling conditions (i.e., rotor tip speed or shear rate, slurry density, mechanical, morphological, and rheological properties of the milled material milled and the suspension medium, etc.) is challenging.

In this work, a PBE approach is applied to describe the slurry milling process of a pharmaceutical intermediate. Correlations between milling conditions and model parameters are proposed. Finally, the model is inverted to determine set of operating conditions that produce desired final particle sizes.