Optimization of Water Content in a High-Shear Wet Granulation Using an In-Line Rheometer

An in-line process analytical technology that measures drag force exerted by wet mass in a high-shear granulator on a thin cylindrical probe enabled real-time identification of distinct stages in high-shear wet granulation of acetaminophen. The technology known as Lenterra in-line rheometer outputs two parameters, the mean force pulse magnitude (MFPM) and the coefficient of variation of force pulse magnitude (CVFPM), that characterize granule densification and size uniformity in real time, providing a process fingerprint. The MFPM and CVFPM evolutions measured during granulation of acetaminophen formulations for varied amounts of added water were compared with the results of particle size distribution (PSD) analysis of the powder released after granulation and with the tablet dissolution tests. The comparison demonstrated a correlation between salient features of the MFPM and CVFPM evolutions and particle size distributions for different water amounts. Based on the measured process fingerprints, it was possible to identify the water amount optimal for best granulation output. In addition, MFPM and CVFPM evolutions allowed for the prediction of a granulation endpoint. The results indicate that in-line rheometry can be a useful tool for formulation development and scale-up of high-shear wet granulation processes.