(421g) An Approach for Scaling up Jet Milling of Pharmaceutical APIs in Loop Mills of Similar Design

In the pharmaceutical industry a significant percentage of marketed drugs and new chemical entities are classified as BCS Class II therefore the need for particle size control of active ingredients in oral solid dosage forms continues to prevail. For such molecules bioavailability can be enhanced via particle size control, and milling remains a dominant approach to achieve this.

Several advances have been made with regards to available tools and methodologies to characterize the mechanical properties of APIs and predict particle breakage in milling processes. However some challenges that are still encountered include (1) Translating the characterization of mechanical properties, often conducted on single particles, to bulk milling behaviour; (2) Factors such as particle size distribution and particle shape can and do influence bulk flow and thus could impact bulk milling behaviour of pharmaceutical organic materials; (3) Some approaches take too much time or require too much material than is typically available at early stages of drug development; (4) The mode of stress operation during the mechanical properties assessment can be quite different to what actually happens during milling processes; (5) Some methodologies rank order materials with respect to milling propensity but don’t necessarily quantify the amount of energy to apply in, for example, a jet milling process. Thus, some trial and error is still necessary for each material to be milled, most especially in cases where there are upper and lower particle size limits for the milled material.

This paper presents a modified approach for scaling up milling processes between lab and plant mills of similar design. Using small amounts of material the methodology involves characterizing the milling propensities of organic materials in a lab loop mill as a function of mechanistic energy input, which is then used to reproducibly scale up the milling process in a plant scale mill of similar design. An additional advantage of this approach is that since the milling propensity vs. mechanistic energy data is generated in a mill of similar design to the plant scale mill it can help with understanding, as early as possible, the risks associated with milling the material such as amorphous generation and operational issues. Furthermore, the material generated from the lab milling studies can be used for small scale development work in order to understand impacts on drug product formulation and API crystallization processes. Case studies will be presented where this approach of matching the milling energy across scales has been used to successfully achieve milled product with similar powder properties.