Structural Characterization and Rationalization of Formation, Stability, and Transformations of Benperidol Solvates

Experimental and theoretical characterization and studies of phase transitions and stability of the solvates obtained in solvate screening of the pharmaceutical compound benperidol were performed to rationalize and understand the solvate formation, stability, and phase transitions occurring during their desolvation. The solvate screening revealed that benperidol can form 11 solvates, including two sets of isostructural solvates. The analysis of the solvate crystal structures and molecular properties indicated that benperidol solvate formation is mainly driven by the complications during packing of benperidol molecules in an energetically efficient way in the absence of solvent molecules, as well as by the compensation of an insufficient number of hydrogen bond donor moieties. Analysis of solvate structures, particularly those of isostructural solvates, revealed that both the possible interactions and the size and shape of the solvent molecules were important factors in solvate formation. Stability of the solvate was proved to be associated with the intermolecular interaction energies in the crystal structure. Desolvation studies of benperidol solvates identified two forces determining the polymorph obtained after desolvation: structural similarity with the solvate and the thermodynamic stability.