(700a) Two-Dimensional Population Balance Model for Twin-Screw Wet Granulation: Model Development and Calibration Based on Particle Size Distribution and Porosity

In the pharmaceutical industry, there is a transition ongoing from conventional batch to novel continuous manufacturing. Twin-screw wet granulation (TSWG) is one of the emerging technologies in continuous manufacturing of solid oral dosages. Quite a few researchers have been working on mechanistic modeling of TSWG to predict granule quality attributes as well as to understand granulation mechanisms which occur spatially along the twin-screw granulation barrel. Among multiple types of mechanistic models, population balance models (PBMs) have been widely applied to TSWG for the computation of granule quality attributes, e.g., granule size distributions (GSDs).

One-dimensional (1D) PBM has been the most popular approach for the application to the pharmaceutical industry because of data availability. Existing studies reported that GSDs were successfully simulated by using 1D PBM^1–4. However, 1D PBM can only predict a single quality attribute, i.e., GSDs, and has difficulties in capturing some granulation phenomena, e.g., consolidation. With 1D PBM, it is impossible to simultaneously assess other quality attributes, e.g., porosity, whereas this is also important for the final product quality, e.g., tablet dissolution. This fact proves that the development of multi-dimensional PBMs is valuable to the industry.

One of the biggest challenges to develop multi-dimensional PBMs is the difficulty of obtaining sufficient and appropriate experimental data. Whereas multi-dimensional PBMs have been proposed by numerous authors^5–9, all of these models have yet to be calibrated for the formulations containing active pharmaceutical ingredients (APIs). Multi-dimensional PBMs mostly consider the items that require advanced and detailed measurements, e.g., liquid distribution.

Therefore, this work proposes a new two-dimensional (2D) PBM for TSWG focusing on GSD and granule porosity. Granulation experiments were performed for three formulations with different liquid-to-solid ratios using the TSWG of the ConsiGma^TM-25 (GEA Pharma Systems, Collette^TM, Wommelgem, Belgium), which consists of one wetting zone, two kneading zones, and size control elements. After each zone, granule porosity at five different size classes was characterized, in addition to GSDs. A 2D compartmental PBM was developed based on the experimental data. Pure aggregation was assumed for the wetting zone, where aggregation kernels were defined based on the kernels used in the 1D PBM^{1, 2}. In the kneading zones, three phenomena were taken into account for the model: aggregation, breakage, and consolidation. The simulation results using the developed PBM were compared with the experimental data.

From the experimental data, the impact of consolidation was observed in terms of reduced granule porosity after the kneading zones. This impact could be reflected in the developed PBM. In addition, model calibration of the wetting zone was successful for multiple settings of liquid-to-solid ratio. This means that the kernels developed for the 1D PBM can be applied to the 2D PBM because they already capture important phenomena sufficiently.

Overall, this work demonstrated the applicability of the 2D PBM for the pharmaceutical industry. The developed model can provide information of granule porosity as well as GSDs, which can increase the value of TSWG models. In the future, further calibrations with different formulations can make the developed 2D PBM more valid and generic.

Acknowledgment: The authors would like to acknowledge UCB for their financial support and fruitful collaboration in this project.

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