The pharmaceutical industry has increasing interest in achieving more robust, efficient and controlled processing. Furthermore, the U.S. Food and Drug Administration (FDA) has mandated the implementation of Quality by Design (Qbd) toward the manufacturing of pharmaceutical processes. Granulation, for instance, is of one the key unit operations for the production of solid dosage forms such as tablets. Among the different types of granulation techniques, batch high shear granulation is one of the more frequently used techniques in the pharmaceutical industry. It has been recognized that the predictive modeling of granulation processes that incorporates the effect of key material properties and process parameters on granule critical quality attributes (CQAs) could potentially lead to a more science-based understanding of granulation operations leading to enhanced efficiency and product quality.
There are numerous mathematical models of high shear wet granulation (HSWG) present in the literature. Majority of these are represented by population balance models (PBM) and discrete element models (DEM) or a combination of both. PBMs in particular have been able to model the dynamics of the HSWG accurately firstly due to its ability to incorporate important material properties and process parameters into the PBM framework and secondly due to its relatively quick computation compared to the computationally more intense DEM. However, some gaps exist, namely accounting for any heterogeneities in the high shear granulator with respect to spatial location and the ability to model dry binder addition whereby solid binder is pre-mixed with active and excipient ingredients and water is added as the granulating liquid during the liquid addition stage. In this study, we present a novel compartment based PBM accounting for a spray and bulk zone and exchange of particles and liquid between the zones. We also account for a binder dissolution sub-model that computes the rate of dissolution of binder in water that subsequently governs the increase of viscosity in the system and the corresponding aggregation and breakage rates. Results will show that the developed model capture experimental trends of differences in particle growth rates for dry binder addition compared to wet binder addition.
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