Crystal Structure Of Cocrystal Research Articles

Improving the Physicochemical and Biopharmaceutical Properties of Active Pharmaceutical Ingredients Derived from Traditional Chinese Medicine through Cocrystal Engineering.

Active pharmaceutical ingredients (APIs) extracted and isolated from traditional Chinese medicines (TCMs) are of interest for drug development due to their wide range of biological activities. However, the overwhelming majority of APIs in TCMs (T-APIs), including flavonoids, terpenoids, alkaloids and phenolic acids, are limited by their poor physicochemical and biopharmaceutical properties, such as solubility, dissolution performance, stability and tabletability for drug development. Cocrystallization of these T-APIs with coformers offers unique advantages to modulate physicochemical properties of these drugs without compromising the therapeutic benefits by non-covalent interactions. This review provides a comprehensive overview of current challenges, applications, and future directions of T-API cocrystals, including cocrystal designs, preparation methods, modifications and corresponding mechanisms of physicochemical and biopharmaceutical properties. Moreover, a variety of studies are presented to elucidate the relationship between the crystal structures of cocrystals and their resulting properties, along with the underlying mechanism for such changes. It is believed that a comprehensive understanding of cocrystal engineering could contribute to the development of more bioactive natural compounds into new drugs.

Molecular Structure, Spectral Investigations, Hydrogen Bonding Interactions and Reactivity-Property Relationship of Caffeine-Citric Acid Cocrystal by Experimental and DFT Approach.

The pharmaceutical cocrystal of caffeine-citric acid (CAF-CA, Form II) has been studied to explore the presence of hydrogen bonding interactions and structure-reactivity-property relationship between the two constituents CAF and Citric acid. The cocrystal was prepared by slurry crystallization. Powder X-ray diffraction (PXRD) analysis was done to characterize CAF-CA cocrystal. Also, differential scanning calorimetry (DSC) confirmed the existence of CAF-CA cocrystal. The vibrational spectroscopic (FT-IR and FT-Raman) signatures and quantum chemical approach have been used as a strategy to get insights into structural and spectral features of CAF-CA cocrystal. There was a good correlation among the experimental and theoretical results of dimer of cocrystal, as this model is capable of covering all nearest possible interactions present in the crystal structure of cocrystal. The spectroscopic results confirmed that (O33-H34) mode forms an intramolecular (C25 = O28∙∙∙H34-O33), while (O26-H27) (O39-H40) and (O43-H44) groups form intermolecular hydrogen bonding (O26-H27∙∙∙N24-C22, O39-H40∙∙∙O52 = C51 and O43-H44∙∙∙O86 = C83) in cocrystal due to red shifting and increment in bond length. The quantum theory of atoms in molecules (QTAIM) analysis revealed (O88-H89∙∙∙O41) as strongest intermolecular hydrogen bonding interaction with interaction energy −12.4247 kcal mol−1 in CAF-CA cocrystal. The natural bond orbital analysis of the second-order theory of the Fock matrix highlighted the presence of strong interactions (N∙∙∙H and O∙∙∙H) in cocrystal. The HOMO-LUMO energy gap value shows that the CAF-CA cocrystal is more reactive, less stable and softer than CAF active pharmaceutical ingredients. The electrophilic and nucleophilic reactivities of atomic sites involved in intermolecular hydrogen bond interactions in cocrystal have been demonstrated by mapping electron density isosurfaces over electrostatic potential i.e. plotting molecular electrostatic potential (MESP) map. The molar refractivity value of cocrystal lies within the set range by Lipinski and hence it may be used as orally active form. The results show that the physicochemical properties of CAF-CA cocrystal are enhanced in comparison to CAF (API).

Tautomeric Equilibrium of an Asymmetric β-Diketone in Halogen-Bonded Cocrystals with Perfluorinated Iodobenzenes

In order to study the effect of halogen bond on tautomerism in β-diketones in the solid-state, we have prepared a series of cocrystals derived from an asymmetric β-diketone, benzoyl-4-pyridoylmethane (b4pm), as halogen bond acceptor and perfluorinated iodobenzenes: iodopentaflourobenzene (ipfb), 1,2-, 1,3- and 1,4-diiodotetraflorobenzene (12tfib, 13tfib and 14tfib) and 1,3,5-triiodo-2,4,6-trifluorobenzene (135titfb). All five cocrystals are assembled by I···N halogen bonds involving pyridyl nitrogen and iodoperfluorobenzene iodine resulting in 1:1 (four compounds) or 1:2 (one compound) cocrystal stoichiometry. Tautomer of b4pm in which hydrogen atom is adjacent to the pyridyl fragment was found to be more stable in vacuo than tautomer with a benzoyl hydroxyl group. This tautomer is also found to be dominant in the majority of crystal structures, somewhat more abundantly in crystal structures of cocrystals in which additional I···O halogen bond with the benzoyl oxygen has been established. Attempts have also been made to prepare an equivalent series of cocrystals using a closely related asymmetric β-diketone, benzoyl-3-pyridoylmethane (b3pm); however, all attempts were unsuccessful, which is attributed to more effective crystal packing of b3pm isomer compared to b4pm, which reduced the probability of cocrystal formation.

A series of cocrystals formed by 2,3-dimethylpyrazine bridging various aromatic acids through hydrogen bonds: Synthesis, structural characterization and synthon discussion

A family of aromatic acids containing different binding sites, including 5-chloro-2-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, salicylic acid, 3-nitrophthalic acid, 4,5-dichlorophthalic acid, 6-hydroxy-2-naphthoic acid and tetrafluorophthalic acid, were allowed to react with 2,3-dimethylpyrazine to assemble single molecule into diverse structures. Seven cocrystals were successfully synthesized and characterized by single crystal X-ray diffraction. Crystal structure analysis shows that OH⋯N H-bonds are involved in the formation of all 1D chains of the seven cocrystals. Moreover, CH⋯O H-bonds play a crucial role in the 3D supramolecular network. In the crystal structures of cocrystals 1, 2 and 4, noncovalent interaction π-π stacking can be considered as a significant influencing factor. In 2, the self-assembly of 3D tessellate-type supramolecular architecture in solution is driven mainly by π-π interactions, to a lesser extent, and by weak hydrogen bond. In 3, two carboxylic acid molecules link each other to form dimers [synthon V R22 (12)] but in 7 carboxylic acid molecules and water molecules are connected to afford tetramer [synthon XVII R44 (12)], further generating zig-zag chains via OH⋯N intermolecular H-bonds. What is worth mentioning, acid and alkali molecules constitute tape chains through the way of forming synthons VII R22 (14) and VIII R66 (30), XI R44 (24) and XII R22 (10) in crystals 4 and 5, respectively. The strong orthogonally directed CH···π interactions lie in the 2D architecture of 6. Meanwhile, solvent molecules make a significant part in preparation of supramolecular structures in 6 and 7. Results show that solvent molecules serve as H-bond donors/acceptors to complete the various motif.

Two-Dimensional Organic Brick-Wall Layers as Hosts for the Inclusion and Study of Aromatics Ensembles: Acid−Pyridine and Acid−Carbonyl Synthons for Multicomponent Materials

The compound trimesic acid (H3TMA) with 2,6-bis(4-pyridylmethylene)cyclohexanone (1) was shown to form two-/three-/four-component cocrystals or salts depending on the reaction conditions. Crystals of salt were obtained when crystallized H3TMA and 1 from MeOH alone, whereas the crystals of neutral components were obtained when crystallized from MeOH and phenol mixture. Both the structures (salt and cocrystal) exhibited huge cavities which are occupied by the self-interpenetration of the networks. This self-interpenetration of the networks found to be eschewed in favor of guest inclusion when the crystallization reactions are conducted in the presence of suitable aromatic guest molecules such as biphenyl, naphthalene, anthracene, phenanthrene, pyrene, triphenylene, and 1,4-hydroquinone. The crystal structures of cocrystals contain hydrogen-bonded layers with huge cavities, the self-interpenetrated layers have a honeycomb geometry with the cavity dimensions of 23 × 42 A2 and the guest included layers have a ...