We present an experimental and computational study of solid solution formation between structurally highly similar active pharmaceutical ingredients droperidol and benperidol in nonsolvates, dihydrates, and several solvates formed by these compounds. We demonstrate that the formation of solid solutions strongly depends on the crystal structure of the phase. In part of the structures almost complete replacement of benperidol with droperidol can be achieved, whereas in other structures the replacement is possible only up to a limited molar ratio. However, only limited replacement of droperidol with benperidol can be achieved and only in part of the structures. The solid solution formation is primarily determined by the change of intermolecular interaction energy resulted by the molecule replacement. Experimentally only structures where molecule replacement allows formation of efficient intermolecular interactions can be obtained. The results indicate that energetic requirements of intermolecular interaction changes to obtain solid solutions in nonsolvated phase are less strict than that for solvates.