A method is developed for determining feasible sequences for separating mixtures with binary azeotropes and optimizing each column in every sequence (including two-column subsequences for azeotropic distillation and solvent recovery) to determine which sequence has the lowest overall cost. This method can be applied automatically for different feed mixtures and feed compositions, which permits screening of process alternatives including different feed compositions. The results are illustrated using two case study systems: a five-component mixture with three binary azeotropes and one distillation region and a four-component mixture with one binary azeotrope and two distillation regions.