Optimization of Linagliptin and Valsartan Bilayer Tablets Using Quality by Design

Background and Objectives: The development of a bilayer tablet containing valsartan and linagliptin requires precise control of formulation and process variables to ensure consistent product quality. This study aimed to establish the design space of the bilayer tablet by applying a Quality by Design (QbD) approach, thereby optimizing key formulation and process parameters to meet predefined Critical Quality Attributes (CQAs). Materials and Methods: A 23+3 full-factorial Design of Experiments (DoE) was implemented to investigate the effects of formulation factors, including microcrystalline cellulose and crospovidone and the process parameter, main compression force. CQAs, including hardness, friability, disintegration time, assay, content uniformity, and dissolution rate, were evaluated using Design Expert software. Statistical analysis was performed through Analysis of Variance (ANOVA) to identify significant factors influencing each CQA. Results: ANOVA results indicated that the main compression force significantly affected tablet hardness, friability, disintegration time, and dissolution rate (p<0.05). Additionally, microcrystalline cellulose and crospovidone showed a significant impact on disintegration time of valsartan (p<0.05). The optimized formulation and process ranges that satisfied all CQAs were determined as follows: microcrystalline cellulose (7-40%), crospovidone (4-13%), and main compression force (1070-1570 kgf). Conclusion: Through the QbD-based DoE study, the optimal design space for the bilayer tablet of linagliptin and valsartan was successfully established. The findings demonstrate that systematic formulation and process optimization can effectively ensure the desired product quality and performance.