Real-time monitoring of integrated continuous granulation/drying line system “LaVortex®” for the pharmaceutical manufacturing of acetaminophen oral dosage formulations using near-infrared spectroscopy

Abstract

Granules for tableting were continuously manufactured using a fully flow-type continuous wet-granulation and drying (CGD) line system, “LaVortex®.” The raw material powder containing standard excipients and 28.8 % acetaminophen was mixed with a binder liquid (pure water), continuously wet-granulated, and dried for 600 s under 20 different granulation/drying process conditions, and the process was monitored in real-time using near-infrared (NIR) spectroscopy. Twenty granulation/drying process conditions, varying across three parameters, namely added binding water rate, agitation blades and container rotational rates, and hot drying air flow rate, were applied. Training datasets from NIR spectroscopy stably measured during the CGD process were used to construct calibration models to predict the various critical quality attributes (CQAs) of granules, such as residual moisture content, median particle size, angle of repose, and tablet hardness, using partial least squares regression (PLSR). Optimal calibration models were validated using the NIR spectroscopy test dataset. The actual granule CQA profiles evaluated using the NIR/PLSR method were almost constant up to 600 s at the end of production depending on the critical process parameters (CPPs), except for fluctuations in the initial process. These results indicate that tableting granules with various pharmaceutical properties could be obtained continuously depending on CQAs, such as the rate of water addition. Additionally, changes in CQAs could be continuously monitored by the NIR/PLSR method. Furthermore, CGD granules with various characteristic CQAs can be continuously manufactured by controlling CPPs, such as agitation blades and tube rotation rates in the agitating granulation process and drying air flow rate in the drying process under NIR spectroscopy.