Methodology and Pitfalls when Calibrating a PBM: the Case of Twin-Screw Wet Granulation

Abstract

Abstract Traditional pharmaceutical processes comprise of a series of batch-wise operations. Nowadays, a shift is being made from these batch processes to continuous manufacturing, to cope with the inefficiencies and high cost involved in process development and manufacturing. Twin-screw wet granulation (TSWG) is an up-and-coming continuous granulation process that is being assessed for its performance in the solid dosage manufacturing. However, since these continuous processes are fairly new in the pharmaceutical industry, detailed process knowledge and understanding is still lacking. Application of mechanistic models can help in bridging this gap by assessing the experimental data and unravelling the underlying mechanisms. In this work, a compartmentalised Population Balance Model (PBM) is developed for predicting the granule size distribution inside the granulator starting from the pre-blend, up until the wet granules at the end of the process, also evaluating at intermediate positions in the barrel. Dedicated experiments were performed to collect sufficient data. Moreover, the PBM model was formulated in such a way that it is able to predict both the unimodal behaviour observed for high L/S ratios, as well as the bimodal behaviour observed at low L/S ratio using one set of kernel structures. This model-based approach provides significant insight in the driving mechanisms and operating conditions of the TSWG.