Milling is an essential unit operation used for particle size reduction in solid oral dosage manufacturing. The breakage of particles in a comil is due to the intense shear applied on the particles between impeller and the screen. Breakage also occurs due to the impact from a rotating impeller. Particles exit the mill based on their size relative to the aperture size of the screen bores. This study was set up to understand the working of the comil better. A new CPP (Critical Process Parameter), in the form of batch loading was identified. It was found that there are two different regimes (quasi static regime and impact regime) in which a comil generally operates, and the effect of the CPP’s (batch loading and impeller speed) on these regimes was studied. Knowledge of the effect of upstream operations on a particular unit operation is of significant importance, especially for pharmaceutical industry. For this reason, the effect of granulation variables such as liquid-to-solid ratio, granulator impeller speed and the amount of binder in the formulation were analyzed. Milled particle size distribution and other critical quality attributes such as bulk density, friability, and porosity were studied. Batch loading and the interaction effect of batch loading with impeller speed are significant parameters that affect the quality attributes of the mill. Predictive regression models were developed for throughput of the mill, milled product bulk density and milled product tapped density (with an R² of 0.987, 0.953, 0.995 respectively) to enable their use in downstream process modeling.

Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing dynamics on the granule quality attributes (PSD, content uniformity, and microstructure). Mixing is an important dynamic process that simultaneously occurs along with the granulation rate mechanisms during the wet granulation process. An improved mechanistic understanding was achieved by identifying and quantifying the physically relevant intermediate parameters that affect the mixing dynamics in TSG, and then their effects on the granule attributes were analyzed by investigating their effects on the granulation rate mechanisms. The fill level, granule liquid saturation, extent of nucleation, and powder wettability were found to be the key physically relevant intermediate parameters that affect the mixing inside the twin-screw granulator. An improved geometrical model for the fill level was developed and validated against existing experimental data. Finally, a process map was developed to depict the effects of mixing on the temporal and spatial evolution of the materials inside the twin-screw granulator. This process map illustrates the mechanism of nucleation and the growth of the granules based on the fundamental material properties of the primary powders (solubility and wettability), liquid binders (viscosity), and mixing dynamics present in the system. Furthermore, it was shown that the process map can be used to predict the granule product quality based on the granule growth mechanism.