(201d) Discrete Element Modeling of High Shear Wet Granulation: Effect of Process Parameters and Equipment Scale on Particle Level Mechanisms

Wet granulation is a commonly employed unit operation in the pharmaceutical manufacturing of many oral solid dosage products. Wet granulation affords processing robustness by preventing segregation of materials, improving flow, and reducing the sensitivity to input material variability. Several mechanisms are at play during wet granulation. These include wetting and nucleation, growth and consolidation, and breakage/attrition. Particle level mechanisms influence the resulting granule properties, and thus the final quality attributes of the drug product. While particle level mechanisms strongly influence process performance, these quantities are challenging to measure experimentally. Numerical tools, such as the Discrete Element Method (DEM), can be used in conjunction with experiments to elucidate how particle level processes affect resulting granule properties. In this work, the DEM technique was employed to study the effect of process parameters and equipment scale on particle-level physics involved in wet granulation. Material calibration was performed to ensure that the computational elements represent a typical pharmaceutical material (microcrystalline cellulose). Particle velocity and localized forces were calculated from DEM simulations. These quantities were verified experimentally using advanced real-time analytic tools. The studies provide a quantitative relationship between the process variables (impeller tip speed, granulator fill level, granulator blade design and equipment scale) and measurable properties (velocity profiles, normal, and shear stress distributions) in the radial, tangential and axial directions.  The DEM simulations showed that impeller tip speed had the most significant effect on resulting particle velocities while fill level, granulator blade design and equipment scale had minimal impact on particle velocities. Normal and shear stress distribution were affected by impeller tip speed, fill level, and equipment scale while blade design had minimal impact within the space studied. By numerical calculations of pressure, velocity, and shear stress in different regions of the granulator, this study provides guidelines on achieving reproducible particle environment with changes in scale, granulator design, fill level, and impeller speed.