Recently, the pharmaceutical industry has undergone changes in the production of solid oral dosages from traditional inefficient and expensive batch production to continuous manufacturing. The latest advancements include increased use of continuous twin-screw wet granulation and application of advanced modeling tools such as Population Balance Models (PBMs). However, improved understanding of the physical process within the granulator and improvement of current population balance models are necessary for the continuous production process to be successful in practice. In this study, an existing compartmental one-dimensional PBM of a twin-screw granulation process was improved by altering the original aggregation kernel in the wetting zone as a result of an identifiability analysis. In addition, a strategy was successfully applied to reduce the number of model parameters to be calibrated in both the wetting zone and kneading zones. It was found that the new aggregation kernel in the wetting zone is capable of reproducing the particle size distribution that is experimentally observed at different process conditions as well as different types of formulations, varying in hydrophilicity and API concentration. Finally, it was observed that model parameters could be linked not only to the material properties but also to the liquid to solid ratio, paving the way to create a generic PBM to predict the particle size distribution of a new formulation.
Keywords: PAT; continuous manufacturing; formulation; granulation; granules; identifiability; particle size distributions; population balance modeling; process modeling and simulation; wet granulation.