Analytical quality by design-compliant retention modeling for exploring column interchangeabilities in separating ezetimibe and its related substances

•Computer-aided chromatographic method development for the separation of ezetimibe and its related substances.•Design space comparison - new approach for testing column interchangeability.•Mechanistic retention modeling and a 3D experimental design based approach via DryLab® software.•Baseline separation of the analytes achieved on nine different stationary phases with various chemistries.•Multivariate in silico robustness testing performed to identify the critical method parameters and to set up control strategy for routine applications.•General specification with suitable working point yielding similar results on six stationary phases.•Interchangeability of the columns proved in early phase method development.