Understanding the Effect of Granulation and Milling Process Parameters on the Quality Attributes of Milled Granules

Abstract

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.