Sierra-Vega, Nobel Osvaldo

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    Real-time monitoring of pharmaceutical formulations within continuous process units for tablet manufacturing
    (2021-03-18) Sierra-Vega, Nobel Osvaldo; Méndez-Román, Rafael; College of Engineering; Acevedo-Rullán, Aldo; Romañach, Rodolfo J.; Lorenzo-González, Edgardo; Department of Chemical Engineering; Sundaram, Paul A.
    This dissertation describes the advancements in Process Analytical Technology (PAT) through developing and implementing strategies for real-time monitoring of drug concentrations in flowing powder blends, analyzing the powder flow behavior within continuous process units, and understanding the relationships among materials properties and process parameters. Three continuous process units for tablet manufacturing were studied in this dissertation: the tablet press feed frame, a transitional chute, and an innovative sampling interface. The feed frame was the first process unit studied. The feed frame is designed to feed the powder blends into moving dies using paddle wheels. In Chapter 3 of this dissertation, NIR spectroscopy was used to quantify the concentration in 3.0% w/w acetaminophen powder blends and track the powder flow dynamic within the feed frame. This study found that paddle wheel speed can be increased by up to 30% and the die disc speed can be decreased by up to 10% without affecting NIR spectroscopic model predictions. Likewise, the results demonstrated that paddle wheel speed has a significant effect on the powder wave behavior but does not affect the mass hold-up within the feed frame, while the die disc speed does not affect powder wave behavior, but significantly affects the mass hold-up. In Chapter 4, the drug concentration was evaluated at three-points of a continuous tablet manufacturing line via direct compaction: the feed frame, a transitional chute, and the tablets. The transitional chute was the second process unit studied. The chute consists of a stainless-steel pipe partially flattened to form a rectangular interface. This process unit was connected at the discharge of the continuous blender. This study demonstrated that the drug concentration of tablets could be predicted, with high accuracy, from the drug concentration of the powder blends within the feed frame. The mixing effect within the feed frame contributes to a 60% decrease in the relative standard deviation of the drug concentration compared to the chute. Variographic analysis demonstrated that the chute presents total sampling and analytical errors approximately five times higher than the feed frame. Chapter 5 presents the design, development, and characterization of a novel sampling interface for blend uniformity. The sampler device was designed based on the powder flow behavior within the tablet press feed frame, following the principles laid down in the Theory of Sampling. Two near-infrared (NIR) spectroscopic models were developed using powder blends with compressibility values less than 6% v/v. The NIR models were able to quantify drug concentration as low as 0.76% w/w and showed excellent results in linearity, accuracy, precision, and robustness. This study demonstrates that the sampler device presents low analytical and sampling errors while handling throughputs up to 45 kg/h, without significantly affecting the physical properties of powder blends. In Chapter 6, the sampler device was tested to monitor cohesive formulations with Carr’s Index higher than 35%. The sampler device was operated in combination with NIR spectroscopy to quantify ibuprofen concentrations between 1.5 and 4.5% w/w. NIR spectra also provided essential information to study the process dynamics within the sampler. The test blends were within specifications according to the requirements of European Pharmacopeia. Variographic analysis demonstrated that an increase in the blend compressibility leads to a slight rise in sampling errors within the sampler device. This study confirms that the device offers statistical robustness in evaluating blend uniformity with low analytical and sampling errors. This doctoral dissertation demonstrates the suitability of NIR spectroscopy as part of a PAT system to monitor blend uniformity in flowing powder. Likewise, this dissertation contributes to the understanding of the powder flow dynamics within three continuous process units. The results obtained from these studies can help in the design, development, implementation, and optimization of control strategies to ensure the critical quality attributes of the tablets.