Simultaneous optimization of mobile phase composition and pH using retention modeling and experimental design.

•A new 3 dimensional design with 18 input runs was presented to model mobile phase influence on the chromatographic selectivity, as a function of gradient time (tG), pH and ternary eluent composition (tC).•DryLab4 (U)HPLC method modeling software was used to discover multifactorial solvent- and instrument-dependent influences, allowing stage 1 (development phase) robustness integration of the method.•The study outlines the missing systematic concept for practical- and life-cycle aspects of method robustness in current guidelines.