A comprehensive, fully automated strategy is demonstrated for HPLC-UV chromatographic method development using ChromSword optimization software. The strategy involves: (1) the automated screening of various column and mobile phase combinations, (2) rational selection of the best starting conditions; and (3) subsequent automated method development to generate optimized separation methods. Pharmaceutical compounds were applied to solve problematic drug impurity separations. ChromSword software automates the screening, optimization, and documentation steps thus reducing the method development time. The strategy was compared to a manual method development approach showing the automated method strategy affords better selectivity in a shorter time.