| Summary: | In the pharmaceutical industry, the systematic optimization of process variables using a quality-by-design (QbD) approach is highly precise, economic and ensures product quality. The current research presents the implementation of a design-of-experiment (DoE) driven QbD approach for the optimization of key process variables of the green fluidized bed granulation (GFBG) process. A 3<sup>2</sup> full-factorial design was performed to explore the effect of water amount (X<sub>1</sub>; 1–6% <i>w</i>/<i>w</i>) and spray rate (X<sub>2</sub>; 2–8 g/min) as key process variables on critical quality attributes (CQAs) of granules and tablets. Regression analysis have demonstrated that changing the levels of X<sub>1</sub> and X<sub>2</sub> significantly affect (<i>p</i> ≤ 0.05) the CQAs of granules and tablets. Particularly, X<sub>1</sub> was found to have the pronounced effect on the CQAs. The GFBG process was optimized, and a design space (DS) was built using numerical optimization. It was found that X<sub>1</sub> and X<sub>2</sub> at high (5.69% <i>w</i>/<i>w</i>) and low (2 g/min) levels, respectively, demonstrated the optimum operating conditions. By optimizing X<sub>1</sub> and X<sub>2</sub>, GFBG could enhance the disintegration and dissolution of tablets containing a poorly water-soluble drug. The prediction error values of dependent responses were less than 5% that confirm validity, robustness and accuracy of the generated DS in optimization of GFBG.
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