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

Abstract

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.

Mechanochemical Synthesis and Physicochemical Characterization of Previously Unreported Praziquantel Solvates with 2-Pyrrolidone and Acetic Acid

“…The diffraction peak positions of PZQ-AA and PZQ-2P are clearly different both from the known (starting) PZQ Form A, and from other known PZQ solid forms. However, the PXRD patterns of PZQ-AA and PZQ-2P are quite similar, which suggests that these two solvated forms should be isostructural [43]. The main reflections of PZQ-AA were at 6.21, 9.17, 14.90, 15 3).…”

Periodic DFT Calculations—Review of Applications in the Pharmaceutical Sciences

“…In some cases, the structural similarity between an original substance and its solvate, as well as thermodynamic stability of the emerging solvate polymorphs must be taken into account. This usually complicates the description of the process and the accurate determination of the stability as there emerges need to consider both pairwise intermolecular interaction energies and the lattice energies [103].…”

Various Molecular Arrangements Leading to Different Desolvation Rates: Research on the Stability of 2,7‐Dibromo‐9H‐carbazole Solvates

“…[ 1–7 ] Generally, solvates of the same compound could be different in either crystal cell parameters and spatial structures or stoichiometric ratio between solvent and solute molecules. [ 8–10 ] The formation of solvates could affect physicochemical properties of the materials such as melting point, particle size distribution, and dissolution rate, which in turn could significantly improve their practical application. [ 11,12 ] Solvates’ lower frequency of polymorphism makes them more predictable.…”

“…Generally, the formation of solvates is considered to rely on two main factors, [ 8,16,17 ] namely a) noncovalent interactions between molecules and b) the stacking modes. The engagement of the solvent molecules could compensate the original vacancy of interaction force such as the imbalance of hydrogen bonds, halogen bonds, and π–π stacking, etc., [ 9,18 ] while the incorporation of solvent molecule into the gaps of the crystals would also make a more efficient packing mode, thus further affecting the stability of solvate crystals.…”