A formulation development strategy for dual-release bilayer tablets: An integrated approach of quality by design and a placebo layer.

Although dual-release mechanism bilayer tablets containing one drug in both immediate- and sustained-release layers are widely used to improve therapeutic efficiency, studies quantitatively analyzing the drug amount released from each layer and the mutual effect of each layer's mechanical properties on drug product quality are limited. Here, the formulation of a dual-release bilayer tablet containing sarpogrelate HCl was optimized with a placebo layer and quality by design (QbD) approach. The placebo layer was developed to replace the active pharmaceutical ingredient and its mechanical properties were evaluated. The formulation was developed using the placebo layer to quantitatively analyze the drug released from each layer. The mixture design and Monte Carlo simulation enabled robust design space identification. The mutual effect of each layer's mechanical properties on drug product quality was confirmed by multivariate analysis using the optimal settings in the design space. The optimized formulation was characterized by comparison with a reference drug for various quality attributes and in vivo pharmacokinetic parameters, which ensured the bioequivalence of the optimized bilayer tablet with the reference drug. This study shows that the integration of QbD and a placebo layer is an effective optimization strategy for dual-release bilayer tablets containing one drug in different layers.