A detailed study of molecular conformation and intermolecular interactions in the experimental crystal structures and general trends observed in the Cambridge Structural Database as well as theoretical calculations were performed to identify the reason for the formation of different crystal structures of two chemically very similar pharmaceutical molecules benperidol and droperidol. The most important difference between both molecules was the weak intermolecular interactions formed by the central ring which therefore was responsible for the formation of different crystal structures. Cross-seeding experiments were performed to check the possibility for the formation of mutually isostructural phases, and theoretical calculations were performed to compare the stability of experimentally observed phases and theoretical isostructural phases by therefore rationalizing the results of the cross-seeding experiments. In cross-seeding crystallizations, three new droperidol phases—an ethanol monosolvate, a dihydrate ...