(588bs) Simulation-Guided Design of a Pharmaceutical Batch Powder Blending Process

Achieving homogeneous blends of active pharmaceutical ingredients (APIs) and excipients is critical in pharmaceutical tablet manufacturing to ensure consistent dosage and optimal powder processability. Traditionally, developing and scaling up powder blending operations relies on expensive, labor-intensive experimental trials that provide very limited insight into blending dynamics. Discrete Element Method (DEM) simulations offer deeper process insights and can significantly reduce experimental costs.

In this study, DEM simulations were applied to investigate the blending dynamics of two APIs and various excipients in an industrial-scale pharmaceutical bin blender. Powder components were experimentally characterized using dynamic angle of repose tests. The results were then used to calibrate DEM parameters of three modeled powder components. Simulations of a 25-minute blending operation, including a 20-minute pre-blending stage and a 5-minute final blending step, indicated axial concentration gradients of the APIs. Experimental validation through targeted sampling and HPLC analyses confirmed these simulation predictions.

Various strategies to mitigate these API gradients were evaluated using the DEM model. Results indicated that a 90° reorientation of the blending container around the vertical axis prior to the final blending step notably improved axial homogeneity. This approach effectively minimized inhomogeneity with minimal engineering adjustments and could be further modified to drastically reduce the blending time.

The findings underscore the effectiveness of calibrated DEM simulations as tools for designing and optimizing pharmaceutical blending processes. This simulation-based methodology provides a robust framework for identifying process risks and testing mitigation strategies, enabling faster, more efficient process development while minimizing costly experimental work.