(129c) Analysis of Fluidization and Particle Temperature in Semicontinuous Fluid Bed Drying of Pharmaceutical Granules

The fluidization dynamics and spatial heterogeneity in semicontinuous drying of pharmaceutical granules are still a black box in the understanding and mechanistic modeling of this process. Therefore, this work investigates the dominating phenomena in the fluid bed dryer of a continuous pharmaceutical wet granulation line, which are acting on the fluidization regime and heat transfer between the gas and solid phase. The gained knowledge about these phenomena will, in a later phase of the research, be used to calibrate and validate a three-phase computational fluid dynamics (CFD) model. A thorough and novel experimental data collection campaign is performed to create spatial temperature profiles considering the process features. Simultaneously, the effect of the most influential process settings on the fluidization features is also evaluated. Along with that, the effect of the observed phenomena on the obtained key product quality, the residual moisture content and granule size distribution, is taken into account. In this way, additional information needed to translate pharmaceutical fluidization processes into predictive models is provided, which makes model-based process analysis for the application of continuous manufacturing in the pharmaceutical industry, more concrete.

The fluidization regime and heat transfer are investigated in a ConsiGma‑1™ semi-continuous fluid bed dryer, which is fed with wet granules from a twin-screw granulator through gravimetric transport. The Perspex wall of this drying system makes it possible to accurately capture the fluidization behavior through a video recording system followed by image processing. Supplemented with several other sensors such as temperature, pressure, and relative air humidity loggers, it was possible to cover the spatial effects of the majority of the influential factors on the phenomena under investigation.

39 different drying experiments were performed with continuous filling of wet granules, which were supplemented with experiments on dry granules to improve the process understanding. 27 of the wet granule experiments were performed to characterize the fluidization regime and to link this regime with the product quality. For those experiments, the liquid to solid ratio was varied between 6.36 and 9.78 wt%, and the dryer inlet air flow rate between 50 and 84 m³/h. The filling time of the dryer cell, governing the cell load, was varied between 60 and 180 seconds. To investigate the energy transfer between the inlet air and the drying granules, 12 experiments were performed with a formulation that was enriched with a thermo-sensitive colored component (LCR Hallcrest Ltd, Flintshire, UK). These components induce a change in color of the granules in function of their temperature, making the spatial temperature distribution in the bed observable. [1] For this set of experiments, the granulation settings were kept constant while the following drying settings were varied: the incoming air temperature between 35 and 60°C and the dryer inlet air flow rate between 50 and 66 m³/h. The total drying time was always at least two times the filling time, ensuring that a stabilized fluid bed was achieved during the experiment.

An obvious observation can be made that, during the filling time, the fluidization regime will transition from a turbulent regime to a bubbling bed. Due to the very low cell loading and the constant inlet air flow rate, a high bed height is observed at the beginning of the loading period. This will result in efficient heat exchange between the solid and gas phase, inducing a high evaporation rate. As evaporation consumes the energy supplied by the fluidizing air, the granules’ temperature does not increase significantly in the early drying stage. [2] Proportional to the filling time, the loading of the drying cell increases, which causes an increase in the total bed weight. Henceforth, the bed transitions from a turbulent to a bubbling fluidization regime. Through the reduced bed height, the contact surface between the solid and the air diminishes. Consequently, the energy exchange efficiency and average evaporation rate over the bed decrease.

However, not only does the fluidization behavior determine the evaporation rate during fluid bed drying, the newly gathered experimental data also indicates segregation effects depending on the granule size distribution. Together with the observed preferential granule flow patterns in the bubbling bed, this phenomenon results in a heterogeneous evaporation behavior of the granules. Spatially, different granule sizes and granule temperatures are observed during one experiment, more specifically the relative distance of a granule to a bubble will have a large influence on the temperature of that granule.

In addition to the new insights, this work also provides a wealth of data to calibrate and validate predictive models to, supplying an abundance of quantitative data in different conditions to build an accurate model. Specifically, the spatial nature of the data is used to provide a qualitative three-phase computational fluid dynamics (CFD) model, which will help to create a new generation of highly predictive models that capture the effect of process settings and granule and material properties on the drying dynamics.

References:

[1] Lakio, S., Heinämäki, J., & Yliruusi, J. (2010). Colorful drying. AAPS PharmSciTech, 11(1), 46–53.

[2] D.M. Parikh, J.A. Bonck, M. Mogavero, Batch fluid bed granulation, in: D.M. Parikh (Ed.), Handbook of Pharmaceutical Granulation Technology, Marcel Dekker Inc., New York, 1997, pp. 227-302.