Ji Eun Kim¹, Shugeng Cao², Jae Sung Pyo¹ , Kang Min KIm³

Abstract

Purpose: To identify the optimized region of formulation using quality by design for pitavastatin calcium (PTV) and ezetimibe (EZE) immediate-release fixed-dose combination tablets Methods: Hardness, friability, disintegration time, content, content uniformity, and dissolution rate were critical quality attributes (CQAs). Through the initial risk assessment, microcrystalline cellulose (MCC), sodium starch glycolate (SSG), the amount of water in the wet granulation part, and the main compression force were identified to affect the CQAs, and a full factorial design of the experiment (DoE) was applied. Results: Parameters in all the batches were significantly influenced based on the analysis of variance (p < 0.05). MCC affected content (p = 0.0002), content uniformity (p = 0.0002), and dissolution rate (p = 0.0131) while SSG affected friability (p = 0.0004), disintegration time (p < 0.0001), and dissolution rates (pH 4.5 for pravastatin: p = 0.0227, 0.5 % SLS (pH 4.5) for ezetimibe: p < 0.0001, and 0.5 % SLS (pH 6.8) for ezetimibe: p = 0.0434, respectively). The amount of water in wet granulation part and main compression were the main factors affecting hardness (p = 0.0143) and disintegration time (p = 0.0005). Optimized ranges included MCC (10 – 18 %), SSG (7.86 – 15 %), amount of water in the wet granulation part (38 – 43.52 %), and main compression (954 – 1133 kgf). Conclusion: The optimized region ranges of MCC, SSG, compression force, and the amount of water in the wet granulation for manufacturing process development have been successfully achieved by the design of experiments (DoE) approach.