Process analytical tools for monitoring, understanding, and control of pharmaceutical fluidized bed granulation: A review.

Fluidized bed granulation is a widely applied wet granulation technique in the pharmaceutical industry to produce solid dosage forms. The process involves the spraying of a binder liquid onto fluidizing powder particles. As a result, the (wetted) particles collide with each other and form larger permanent aggregates (granules). After spraying the required amount of granulation liquid, the wet granules are rapidly dried in the fluid bed granulator. Since the FDA launched its Process Analytical Technology initiative (and even before), a wide range of analytical process sensors has been used for real-time monitoring and control of fluid bed granulation processes. By applying various data analysis techniques to the multitude of data collected from the process analyzers implemented in fluid bed granulators, a deeper understanding of the process has been achieved. This review gives an overview of the process analytical technologies used during fluid bed granulation to monitor and control the process. The fundamentals of the mechanisms contributing to wet granule growth and the characteristics of fluid bed granulation processing are briefly discussed. This is followed by a detailed overview of the in-line applied process analyzers, contributing to improved fluid bed granulation understanding, modeling, control, and endpoint detection. Analysis and modeling tools enabling the extraction of the relevant information from the complex data collected during granulation and the control of the process are highlighted.