Model-based design and the implementation of dosing and blending unit-operations for continuous direct compression

Abstract

This thesis presents a comprehensive investigation and implementation of models for individual process units within a continuous dosing and blending module, aiming to support risk-based decision-making and data-driven process development. A material library was constructed using a reduced yet diverse set of material attributes (e.g., flowability, particle size, density, cohesion), enabling targeted experimentation and transferability of insights to various materials. <br/> A model for selecting feeding equipment configurations was developed based on feeder emptying curve parameters and the intra-bin variability. The study highlighted the advantages of flat-bottom feeders and the necessity of screw variety for material-specific selection. Key correlations were found between bulk/tapped density and curve parameters, while hopper design and agitator features were shown to mitigate flow issues like ratholing. <br/> Blending process analysis emphasized the role of flow regimes (shear, avalanching, cataracting, fluidized) and their dependence on material properties, blender fill level, and impeller speed. The integration of a sieving step improved blend uniformity by breaking API aggregates. The strategic placement of lubricant addition ports and weir plates was shown to enhance process robustness, particularly for high drug load formulations. <br/> Theoretical assessments using Egermann's equation enabled pre-selection of blend formulations based on drug load and particle size distribution. Steady-state determination for segregation-prone blends was refined using tracer pulse experiments. Impeller rotation direction was found to influence dead mass accumulation, with weir plates offering a better alternative for increasing fill levels. <br/> Pneumatic transport was generally feasible, though limitations were observed with micronized APIs and fine powders. Alternative transport methods were proposed. A scaling approach using geometric and dynamic principles proved effective for well-flowing and cohesive materials under various process conditions. <br/> Overall, this work establishes a systematic understanding of continuous dosing and blending, linking material attributes and process parameters from raw material to final tablet.