Cracking the code: Spatial heterogeneity as the missing piece for modeling granular fluidized bed drying.

Pharmaceutical twin-screw wet granulation is a multifaceted and intricate process pivotal to drug product development. Accurate modeling of this process is indispensable for optimizing manufacturing parameters and ensuring product quality. The fluid bed dryer, an integral component of this granulation process, significantly influences the granular critical quality attributes. This study builds upon prior research by integrating experimental findings on granule segregation during fluid bed drying into an existing compartmental model, enhancing its predictive capabilities. An additional model layer on granule segregation behavior is composed and integrated into the existing model structure in this study. The added model compartment describes probability distributions on the vertical position of granules within each granule size class considered. To beware of overfitting, predictions of both the moisture content after drying and the granule bed temperature throughout drying are discussed in this study relative to experimental data from earlier published studies. These independent analyses demonstrated a marked improvement in prediction accuracy compared to earlier published model structures. The refined model accurately predicts the residual moisture content after drying for an untrained formulation. Moreover, it simultaneously makes accurate predictions of the granular bed temperature, which emboldens its structural correctness. This advancement makes it a powerful tool for predicting the behavior of the pharmaceutical fluid bed drying, which holds significant promise to facilitate pharmaceutical product development.

Validation of model-based design of experiments for continuous wet granulation and drying.

This paper presents an application case of model-based design of experiments for the continuous twin-screw wet granulation and fluid-bed drying sequence. The proposed framework consists of three previously developed models. Here, we are testing the applicability of previously published unit operation models in this specific part of the production line to a new active pharmaceutical ingredient. Firstly, a T-shaped partial least squares regression model predicts d-values of granules after wet granulation with different process settings. Then, a high-resolution full granule size distribution is computed by a hybrid population balance and partial least squares regression model. Lastly, a mechanistic model of fluid-bed drying simulates drying time and energy efficiency, using the outputs of the first two models as a part of the inputs. In the application case, good operating conditions were calculated based on material and formulation properties as well as the developed process models. The framework was validated by comparing the simulation results with three experimental results. Overall, the proposed framework enables a process designer to find appropriate process settings with a less experimental workload. The framework combined with process knowledge reduced 73.2% of material consumption and 72.3% of time, especially in the early process development phase.

Mechanistic modeling of semicontinuous fluidized bed drying of pharmaceutical granules by incorporating single particle and bulk drying kinetics.

In this work, a mechanistic fluidized bed drying model computing the granule moisture content in function of granule size, drying time, process settings and formulation properties is developed. Modeling the moisture content distribution concerning the granule size is essential for tabletability and drug product quality. This work combines a mechanistic bulk model and a single-particle drying kinetics model in a semicontinuous mode. The added model complexity allows physical approximations of drying phenomena at both the drying system level and the granular level. This includes quantifying the variations in moisture content by taking into account the specific dryer design and the variations in granule size. The model performance was quantified through industrially relevant case studies. It was revealed that the proposed model structure accurately predicts the drying behavior of the yield fraction. However, systematic model biases were observed for the fine and coarse fractions of the granule size distribution. In addition, discrepancies in the predicted outgoing air properties (relative air humidity and air temperature) were obtained. Further enhancement of the model complexity, e.g. complete incorporation of fluidization and segregation phenomena, is likely to improve the model performance. Notwithstanding, the developed model forms a step towards a formulation-generic fluidized bed drying model as interacting mechanisms on different levels of the drying system are considered.

A Colourful Way to Unravel the Important Fluidization-Related Granule Size Effect on Semi-Continuous Drying.

Continuous twin screw wet granulation (TSWG) systems are possible pathways for oral solid dosage manufacturing in the pharmaceutical industry. TSWG requires a drying step after granulation before the tableting process. Typically, semi-continuous fluidized bed dryers (FBDs) are used for this purpose. At the same time, the pharmaceutical sector is interested in mathematical prediction models to save resources during the early drug product development (DPD) stage or to control manufacturing. Several authors have already developed prediction models for semi-continuous drying processes. However, these model structures reported systematic prediction offsets, which could be related to the incomplete implementation of fluidization and granule segregation phenomena. This study evaluates the complex fluidization behavior of wet granules in industrially relevant semi-continuous FBDs. A transparent perspex version of the dryer was used for the analysis of bed height, pressure drop, porosity, segregation, and spatial heating patterns at varying process settings. The investigated behaviors of the fluidizing bed will be helpful to derive phenomenological (sub)models for the detailed description of segregation in the semi-continuous fluidized bed system. In this study, it was found that semi-continuous FBDs are characterized by a change in fluidization regime from plug flow to a bubbling bed at the moment that the granule bed slumps. Secondly, the presence of size-based vertical segregation phenomena as well as spatial temperature differences were proven. The experimental results suggest that larger granules are dried under more intense drying conditions than smaller granules.