Experimental and computational investigation of benperidol and droperidol solid solutions in different crystal structures

We explored solid solution formation between structurally highly similar active pharmaceutical ingredients droperidol and benperidol in different crystal phases formed by these compounds. We crystallized samples having different compound molar ratio to evaluate the solid solution formation capabilities. Different crystallization conditions were used to evaluate solid solution formation in different crystal phases, including nonsolvates, dihydrates, and several solvates. We also explored the phase obtained in the desolvation of the obtained solvated products. Our results clearly demonstrate that the formation of solid solutions strongly depends on the crystal structure, as in part of the structures almost complete replacement of benperidol with droperidol was achieved but in other structures the replacement was possible only up to a limited molar ratio. Moreover, only limited replacement of droperidol with benperidol was achieved and only in part of the structures. We investigated change of intramolecular and intermolecular energy introduced by the molecule replacement using computational calculations. We show that experimentally we obtained only structures where molecule replacement allows formation of efficient intermolecular interactions, and energetic requirements of intermolecular interaction changes to obtain solid solutions in nonsolvated phase are less strict than that for solvates.