This paper aims to determine key parameters that affect tablet quality and productivity in continuous tablet manufacturing. Experiments were performed based on design of experiments using a continuous high-shear granulator and ethenzamide as the active pharmaceutical ingredient. To guide a systematic and comprehensive parameter analysis, a parameter framework was defined that comprised five input parameters on raw material properties and process parameters, 11 intermediate parameters on granule properties, and 11 output parameters on tablet quality and productivity. The interrelationships were analyzed statistically and were described as matrix functions. The liquid/solid ratio was the key parameter that affected circularity, density, and flowability as the granule properties, and disintegration and dissolution as the tablet quality. The maximum acceptable manufacturing rate that governs productivity was also affected by the liquid/solid ratio. Circularity was found to affect disintegration and dissolution. This result was specific to the setup of the study, but suggested development opportunities for a new process analytical technology system/quality-by-design application based on circularity. In addition, practical findings were obtained as follows: (1) high-speed manufacturing favored a lower liquid/solid ratio, and (2) high circularity slowed down disintegration/dissolution. This obtained knowledge will enhance the applicability of continuous technology in an actual manufacturing environment.
Keywords: Circularity; Continuous manufacturing; Design of experiments; High-shear granulation; Liquid/solid ratio; Process design and operation.
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