In-Depth Understanding of the Impact of Material Properties on the Performance of Jet Milling of Active Pharmaceutical Ingredients

<b>Background/Objectives:</b> Among different milling techniques, spiral air jet milling can produce finer particles without the use of solvents or additives, thereby improving the bioavailability and content uniformity of the final dosage form. However, milling can complicate downstream processability of active pharmaceutical ingredients (APIs) due to reduced bulk powder flowability and post-milling lump formation. Process settings are often optimized only for particle size reduction, without sufficient consideration of manufacturability, largely because of limited API availability and a lack of knowledge about influential material properties. This study aimed to investigate the impact of material properties and process settings on milling performance and downstream manufacturability. <b>Methods:</b> Four APIs, examined in a total of eight grades, were characterized for their bulk mechanical properties and compression energy parameters using a compaction simulator. These grades were subjected to milling experiments within a design-of-experiments framework. Statistical analyses were performed, and population balance models (PBMs) were developed and calibrated for each experiment to link material properties and process settings to milling outcomes. <b>Results:</b> A higher gas flow rate was identified as the most significant contributor to particle size reduction. The influence of mechanical properties, particularly Young's modulus and Poisson's ratio, was evident and correlated with unmilled particle sizes. PBM analyses showed that a higher gas feed rate decreased the critical particle size for breakage, while intrinsic mechanical properties affected the breakage rate function. <b>Conclusions:</b> By integrating material properties and process settings into PBM analyses, specific breakage mechanisms could be identified. These findings provide a framework for optimizing jet milling not only for particle size reduction but also for downstream processability of APIs.