This study analyzes the similarity factor f2 within in vitro drug release profiles of modified-release (MR) dosage form. The Cubic Spline Interpolation (CSI) method is used to estimate the percentage drug release at intermediate time points; to reduce the difference between MR drug release profiles in the ex vivo environment. In this study, the cubic spline interpolation approach assesses the similarity factor f2 and a pair-wise comparative analysis between two different formulations of Quetiapine Fumarate MR tablets and one formulation of Venlafaxine HCl MR tablets. This analysis explains the interpretation and comparison of supplemental mediating timepoint observations. This method may aid industries in monitoring the characteristics of in vitro release studies with a few changes in timepoint selection and intensifying similarity factor f2 for early-stage drug dosage form preparation.