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.