(205b) Developing a Formulation Dependent Mechanistic Kernel to Predict the Granule Size Distribution in a Two Component High Shear Wet Granulation Process

Wet granulation process is often a complex multi-component unit operation in pharmaceutical industry. The complexity of this process lies in understanding the effects of process design, operating conditions and material properties on the granule product quality. A holistic understanding of the granulation rate processes will greatly help in predicting such granule product attributes. Although an actual pharmaceutical granulation process involves more than one solid component (Active Pharmaceutical Ingredient (API), binder, surfactant, disintegrant etc.) there were few models reported to evaluate the functional dependency of the constituent materials. Most of the population balance modeling studies were focused on the representation of granulation process with single solid component and granule product attributes were predicted using the effect of individual volumes of solid, liquid and gas ^[1,2,6,7].

The purpose of this study was to develop a formulation dependent mechanistic kernel and to provide an experimental basis for incorporating constituent material property such as contact angle. The preferential wetting of constituent materials with liquid binder was expected to be the governing factor for the dynamics of granulation process and hence, two materials (Ibuprofen and Micro crystalline cellulose (MCC-101)) with wide difference in contact angle were chosen. Other factors such as particle segregation during dry mixing ^[5] and drug migration during drying of granules ^[3] were avoided as Ibuprofen and MCC-101 were of similar particle size and both were insoluble.

This study was performed in a high shear wet granulator with percentage of formulation varying from 40% to 60% for a range of operating conditions (liquid to solid ratio and wet massing time), by face-centered central composite design. The analysis of variance study indicated a significant effect of percent API on the granule size distribution (GSD). Though, it was expected to have a narrow GSD with increase in hydrophobic material ^[4], it was observed that with the increase in hydrophobic material there was an increase in granule d50 as well as a wider GSD. Also a change from induction growth to steady growth was observed with increase in percentage composition of Ibuprofen. This provided an additional insight that apart from the availability of binder liquid around the granules other material properties like material yield strength and maximum pore saturation, that affect the granule deformation and uptake of powder into the liquid droplet, also play an important role in granulation rate processes. Finally, a composition dependent mechanistic kernel was proposed considering these findings and this was validated against the experimental results obtained.

References

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