Polymorphism and Thermal Stability of Natural Active Ingredients. 3,3′-Diindolylmethane (Chemopreventive and Chemotherapeutic) Studied by a Combined X-ray, ¹H–¹⁴N NMR-NQR, Differential Scanning Calorimetry, and Solid-State DFT/3D HS/QTAIM/RDS Computational Approach

Abstract

The compound 3,3'-diindolylmethane, DIM, is a major in vivo product of digestion of indole-3-carbinol, I3C, (phytochemical from Brassicaceae family plants) and main mediator of its chemopreventive and chemotherapeutic effects. In our previous paper (Europ. J. Pharm. Sci. 2015) we have reported the impact of structural differences between DIM and I3C on their biological activity. In this paper, the co-influence of two factors: polymorphism and temperature, on the topology, nature (coulombic/polarization/dispersion/repulsion) and strength of interaction pattern in DIM are in the area of our interest. Upon polymorph screening it has been found that DIM crystallizes in two polymorphic forms, form I (already known) and form II (newly obtained). DSC indicated slightly lower melting point for form I than for form II (436 versus 440 K) and the lack of phase transitions in both polymorphs. The crystal and molecular structures of both polymorphs have been determined as a function of temperature by single-crystal X-ray diffraction. The structure of polymorph I is monoclinic,molecule adopts a twisted (both 1H-indole rings are aligned along the same direction, but they are twisted by about 61.5 o ) and a half-chair (the molecule is bent, both 1H-indole rings make an angle of 68.9 o ) conformation, respectively, in forms I and II, which remain almost unaffected by temperature changes. Despite different relative orientations of both 1H-indole moieties in forms I and II, the differences in the interaction patterns revealed by Quantum Theory of Atoms in Molecules (QTAIM), Reduced Density Gradient (RDS), Hirshfeld surfaces (3D HS) and 2D Molecular Fingerprints (2D MF) are relatively small. The distribution of intermolecular interactions in the crystal of form II is by 5% less balanced than in that of form I. The Manhattan and Euclidean distances between the interactions do not exceed 3.76% and 2.21%, respectively, while Bhattacharaya coefficient does not exceed 0.35.Solid state PDB/DPN calculations have revealed that in solid the twisted conformation of the molecule is less stable by 118.7 kJ/mol than that of the half-hair one, but despite this, polymorph I is more stable due to a greater number of weak intermolecular interactions stabilizing the crystalline packing. (In the gas phase the half-hair conformation of the molecule is less stable by 0.788 kJ/mol than the twisted one, which may be attributed to the existence of many weak interactions and crystal packing effects in the solid state, which are absent in the gas phase.) The key interaction stabilizing the twisted versus chair conformation and determining crystalline packing in both polymorphs of DIM is the NH···π one. The factor responsible for the locked conformation of DIM in both forms is the electrostatic potential complementarity of the regions of N-H···π, linking neighboring molecules, which permits easy overcoming of any repulsive interactions that may force rotation of the molecule. The commercial sample of DIM was found to contain approximately 50% of form I and...

The combination of polyphenols and phospholipids as an efficient platform for delivery of natural products

“…The intermolecular interactions are further analyzed using Bader’s QTAIM and the RDG methods. These analyses detect interactions that cannot be measured by experimental methods such as X-ray data analysis 60 . The obtained results from QTAIM and RDG calculations are summarized in Table 1 and Figs.…”

Synthesis and Crystal Structure of Adamantylated 4,5,6,7-Tetrahalogeno-1H-benzimidazoles Novel Multi-Target Ligands (Potential CK2, M2 and SARS-CoV-2 Inhibitors); X-ray/DFT/QTAIM/Hirshfeld Surfaces/Molecular Docking Study

“…The X-ray crystallography at usual resolution often fails to directly access the positions of light atoms, mainly because they show weak contribution to the diffraction; as a consequence, the proton positions are poorly identified. Therefore, the corrected (optimized) proton positions are routinely used by us in any analyses based on the electron density distribution [62][63][64][65][66].…”

“…The X-ray combined with modern approaches, including the Density Functional Theory (DFT) calculations augmented with an empirical dispersion, Bader's Quantum Theory of Atoms in Molecules (QTAIM) [55,56], Spackman's Hirshfeld surfaces [57,58], Politzier's Electrostatic Potential (ESP) [59], CLP (atom-atom) [60] and Pixel (quantum chemistry-based) [61], were used for investigation of the binding propensity in solid. They provide a deep insight into three-dimensional crystalline packing at the atomic and molecular levels and reveal the nature of the intermolecular interactions [62][63][64][65].…”

Crystallographic and Quantum Chemical Study of NH/π Interactions of Metal Ammine Complexes with Aromatic Rings in the Second Coordination Sphere

“…11 Also, NH/π interactions can participate in the self-assembly of the macrocyclic molecules. 12 Aromatic ring/ammonia dimers are well-studied systems. Monodentate benzene/ammonia structures (with one NH bond pointing toward the aromatic ring) are more stable than bidentate and tridentate ones.…”

“…There is an example of the polymorphs being stabilized to a different extent as a consequence of NH/π interactions . Also, NH/π interactions can participate in the self-assembly of the macrocyclic molecules …”