Although mechanistic numerical simulations can offer great insights into a process, they are limited with respect to resolved process time. While statistical models provide long-term predictability, determining the underlying probability distributions is often challenging. In this work, detailed CFD-DEM simulations of a pharmaceutical Wurster coating process for microspheres are used to evaluate the input parameters for a novel Monte-Carlo simulation approach. The combined strengths of both modeling approaches make it possible to predict the coating mass and thickness distributions over the entire process time. It was observed that smaller beads receive a thicker coating layer since they pass the spray zone closer to the nozzle. Moreover, it was established that, in contrast to the airflow rate, the spray rate has a great impact on the inter-particle coating variability. A stochastic model was developed to investigate the relative contribution of coating layer variability and fill weight variability to the product non-uniformity in a capsule filling process of Multiple Unit Pellet Systems (MUPS).

ABSTRACT A vertical in‐line continuous powder mixing device (CMT – Continuous Mixing Technology) has been modelled with the discrete element method (DEM) utilizing a calibrated cohesive contact model. The vertical design of the mixing device allows independent control of mean residence time (MRT) and shear rate. The hold‐up mass and outlet flow are controlled by an exit valve, located at the bottom of the in‐line mixer. A virtual design of experiments (DoE) of DEM simulations has been performed and parameters such as particle velocities, powder bed shape, residence time distribution (RTD), travel distance, and mixing quality are evaluated for the complete operating space. The RTD of the DEM model has been validated with tracer experiments. The resulting RTD has been fitted with an analytical form (generalized cascade of n continuous stirred tank reactors) and utilized to study the downstream response of the continuous mixing device to upstream fluctuations in the inlet material stream. The results indicate a high mixing quality and good filtering properties across the operating space. However, the combination of low hold‐up mass and high impeller speeds leads to a reduced filtering capability and wider exit valve openings, indicating a less desirable operating point.