Crystal chemical analysis of eight polymorphs of flufenamic acid (FFA, C14H10NO2F3)the current record-holder of the number of structurally characterized polymorphic modificationswas carried out using the method of molecular Voronoi–Dirichlet polyhedra. It was proved that every polymorph of FFA, as every polymorph of the previous record-holder ROY (C12H9N3O2S), has a unique set of types of intra- and intermolecular noncovalent interactions.

Aripiprazole (APZ) is a highly polymorphic chemical compound with nine structurally characterized modifications. Using the method of molecular Voronoi–Dirichlet (VD) polyhedra and the k–Φ criterion, we showed that each of the APZ polymorphs is characterized by unique combinations of types of intra- and intermolecular noncovalent contacts. Descriptors of the three-dimensional geometric image of an interatomic interaction of any kind were calculated to quantitatively characterize crystal structures of all the available APZ polymorphs. The identification of differences in interatomic interactions in polymorphic modifications of APZ is important mainly for the pharmaceutical industry (drugs design), as well as for fundamental science to establish the desired relationship between observed types of interactions and certain features of polymorphic modifications, such as relative stability or physicochemical properties. A comparison of calculations performed using molecular VD polyhedra and Hirshfeld surface approach highlights the importance of interactions with low partial contributions for distinguishing polymorphs.

A method for clear visualization of the variation of noncovalent interactions in crystal structures of conformational polymorphs is developed and introduced. The first stage of the method establishes the characteristics of all, without exception, noncovalent interactions in all crystal structures under discussion. This is possible using a strict and objective method of construction of Voronoi-Dirichlet polyhedra within the framework of the stereoatomic model of crystal structures. The second stage of the method then involves plotting of diagrams, showing the relation between parameters characterizing interatomic interactions and chosen geometric parameters of molecules. Application of the title method to highly polymorphic systems of ROY and flufenamic acid allows several imperceptible features of real crystal structures to be revealed and determines the value of different types of interactions in their conformational polymorphs. The method is universal as it can be readily adapted to any system of crystal structures in which noncovalent interactions change as a function of any parameters. Employment of the title method along with quantum chemical calculations offers opportunities for the correlation of potential energy of crystalline materials with noncovalent interactions in their structures, which is a giant step forward towards a more complete understanding of the relationship between the structure and properties of compounds.

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