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Intensive research subjected to the improvement of solubility and bioavailability of certain drugs has popularized the formation of cocrystals, wherein the desired drug is non-ionically bonded to a coformer by means of weak bonds. This paper addresses how crystal engineering of two compatible drug components can enhance the physicochemical and therapeutic properties of either or both of the drugs, resulting in drug-drug cocrystals, with pertinent examples. The paper also discusses the continuous screening processes which are replacing the traditional methods of crystallization due to numerous benefits to the producer as well as the products. Although faced with certain regulatory and scale-up constraints, cocrystals provide immense opportunities to the field of novel drug development. [Display omitted] • Various screening, manufacturing, and solid-state characterization methods concerning cocrystals have been discussed. • A comparative study between older and newer methods of manufacturing pertaining to ease of scale-up has been done. • Physicochemical and therapeutic advantages of drug-drug cocrystals over pure crystals have been elaborated with examples. • Cocrystals that have made their way to the market, in spite of the mentioned regulatory constraints, have been discussed. [ABSTRACT FROM AUTHOR]

Pyrazinamide (PZA) is a widely-used anti-tuberculosis pharmaceutical, but its poor solubility prompts us to optimize pharmaceutical performance. Cocrystallization is a promising technique to improve physiochemical properties of active pharmaceutical ingredient (API) by connecting it with cocrystal former (CCF) via intermolecular interactions. Even though a series of alkyl dicarboxylic acids are employed to form cocrystal structures, systematic understanding on the role of intermolecular interactions is still missing. Therefore, terahertz (THz) spectroscopy and quantum chemical calculation are combined to elucidate the behavior of ubiquitous supramolecular synthons, such as hetero-synthons of acid-pyrazine, acid-amide and homo-synthon of amide-amide, from energy's view. Potential energy is calculated to differentiate the stability within polymorphs of PZA-MA cocrystal and free energy is evaluated to compare the solubility of PZA-CCF cocrystals respectively. With regard to vibrational energy, THz spectral fingerprints are theoretically assigned to specific vibrations and attributed to the flexibility deformation of supramolecular synthons based on oscillation theory, where stretching and twisting modes dominate the collective vibrational behavior. It provides a promising tool to evaluate cocrystal performance from its driving force and insightful guidance to discover new pharmaceutical cocrystals. [Display omitted] • PZA-CCF cocrystals are studied by THz spectroscopy and theoretical calculations. • The collective vibrational behavior of supramolecular synthons is summarized. • Terahertz fingerprints are corresponded to specific collective vibrational modes. • Potential energy is calculated to evaluate the stability of cocrystal polymorphs. • Free energy is used to estimate the solubility difference of PZA-CCF cocrystals. [ABSTRACT FROM AUTHOR]

A series of four closely related 1,2,4-triazole-3-thione (1-4) compounds was obtained by heterocyclization of thiosemicarbazides under basic catalytic conditions. The crystal structures of the 4-alkyl-5-(substituted-phenyl)-2 H -1,2,4-triazole-3(4 H)-thione derivatives [4-alkyl = 4-ethyl-5-phenyl (1) , 4-hexyl-5-phenyl (2) , 4-hexyl-5-p-tolyl (3) , and 4-ethyl-5-(2,4,6-trimethoxyphenyl) (4) ] have been determined. PIXEL lattice energy calculations revealed that dispersion components make the major contributions, with the coulombic terms also contributing significantly to the total energy. Interaction energies for the inversion dimers involving N–H⋯S=C hydrogen bonds indicate a dominant contribution to packing stabilization coming from the coulombic energy component. Hirshfeld surfaces and 2D-fingerprint plots allowed us to visualize different intermolecular contacts and their relative contributions to the total surface in each compound. The comprehensive analysis of the crystal packing and the energetic features demonstrate the key role of the R 2 2 (8) supramolecular synthon of the type (···HNCS) 2 in the solid state structures of these 1,2,4-triazole-3-thiones. • Four 1,2,4-triazole-3-thione compounds are prepared. • Crystal and molecular structures were determined. • Intermolecular interactions and PIXEL lattice energy contributions were calculated. • Hirshfeld surfaces and 2D-fingerprint plots allowed visualizing different intermolecular contacts. • The R 2 2 (8) supramolecular synthon of the type (···HNCS) 2 was identified. [ABSTRACT FROM AUTHOR]

Abstract This work is the first, according to our knowledge, complete structural report on the solid-state supramolecular architecture of antidiabetic drug repaglinide. Here, we present a series of four crystal structures, namely: an un-solvated form of repaglinide (1), repaglinide hydrochloride (2), repaglinide monohydrate (3) and repaglinide methanol solvate (4), successfully determined and fully characterized by the single-crystal X-ray diffraction method (SC-XRD) at 100 K. The (1) and (2) crystallize in the orthorhombic P2 1 2 1 2 1 space group with Z = 1, while solvates exist in triclinic P-1 with Z = 2. The hierarchy and interplay of various intra- and intermolecular interactions in the creation of a 3-D supramolecular assembly using different finite groups (D), rings (R) and infinite chains (C) graph-set motifs are discussed in detail. A particular focus is put on unique halogen-bonded supramolecular synthons. Interestingly, in (2) structure, an intramolecular cyclic ring S (8) synthon was found as a consequence of the NH+ group. Solvent and water molecules play a significant role in the formation of supramolecular architectures in the context of large synthons, the so-called long-range synthon Aufbau modules (LSAM) at the higher level of the crystal organization. A qualitative and quantitative comparative investigation of intercontacts nature between the adjacent molecules in the crystal, govering the supramolecular assemblies, with respect to other members of the glinides family - nateglinide and also related antidiabetic benzoic acid derivatives, retrieved from the Cambridge Structural Database (version 5.39, update February 2018 release) was supported by 3-D Hirshfeld surface maps and the associated 2-D fingerprint plots analysis visualizing all intercontacts at once and contributing them to the total surface for each compound. It revealed numerous interactions mainly H⋯H, O⋯H, C⋯H (C H...π), but also Cl⋯H(O, C) C⋯C (π...π), N⋯H(O), C⋯O (π...lone pair), O⋯O (lone pair...lone pair) cooperatively participating in stabilization of the supramolecular structures of this class of APIs. Graphical abstract Image 1 Highlights • The first crystal structures of repaglinide were fully characterized. • The interplay of O H⋯O, N H⋯O, C H⋯O, C H⋯N, O(N, C) H⋯Cl, C H...π and π...π contacts create 3-D frameworks. • Solvents have a remarkable effect on the supramolecular architecture. • The intercontacts in antidiabetic agents were investigated. [ABSTRACT FROM AUTHOR]

Abstract 1,2,4-Triazolo[1,5-a]pyridines emerge as promising pharmacophores whose properties depend critically on 2- and 5-positioned substituents. We synthesized three new 1,2,4-triazolo[1,5-a]pyridine derivatives with different 2-substituents in combination with a morpholinomethylphenyl group at 5-position. Due to their unique electronic and intermolecular interactional characteristics, 2-substituents exert distinct influences on their crystal structures by forming diverse supramolecular synthons. Within the triazolopyridine cores, two non-conventional types of intermolecular hydrogen bonds are adopted by compound 1 , bifurcated hydrogen bond motifs are formed through the two faces of 2-amino group substituted compound 2 , and an anti-parallel self-complementary pairwise hydrogen bond motif is formed by 2-nitro group substituted compound 3. In the single crystal, compound 3 displays different conformational dynamics around the side chains compared to that of 1 and 2. The elucidating and understanding of their structural chemistry information is valuable for both their pharmaceutical development and application in crystal engineering. Graphical abstract Image 1 Highlights • Three 1,2,4-Triazolo[1,5-a]pyridines with special reactivity have been synthesized. • Various supramolecuar synthons resulting from 2-substituents have been revealed. • Different crystal packing and conformational dynamics are disclosed. • The crystal thermal stabilities parallel with the nature of supramolecular synthons. [ABSTRACT FROM AUTHOR]

• Synthesis of diaryl based pyridazine and triazine derivatives. • Amide-amide hydrogen-bonded synthons formation. • Hydrogen bonded synthons formation takes place by N-H⋯O interactions. • Hirshfeld surface analysis and interaction energy calculations. • Insilico studies for COX-2 selective inhibitor. Synthesis and characterization of diaryl fragment based pyridazine and triazine derivatives containing amide functional group have been carried out for the studies of amide-amide hydrogen-bonded synthons formation. The supramolecular synthons formations in solid state have been carried out by x-ray crystallography and Hirshfeld surface analysis. The crystal structure and Hirshfeld surface analysis have shown that synthons formation takes place by N-H⋯O interactions as well as some other interactions that stabilized the molecules. Further, insilico studies have been carried out for COX-2 selective Inhibitor. [ABSTRACT FROM AUTHOR]

• Self-assembly of the dithiophosphonate tectons generating supramolecular synthons via N H···S, N H···O, C H···S, C H···O, C H···π, and lp···π interactions. • Connection between molecular and supramolecular chirality in the crystalline state (chirogenesis). • NCI index analysis supports the proposition of P-stereogenic centers. • Chiral transference of the p atom to the supramolecular helical assembly. • Spontaneous resolution process to generate the homochiral crystal. The self-assembly of the dithiophosphonate tectons synthesized in this work generated novel supramolecular synthonsvia N H···S, N H···O, C H···S, C H···O, C H···π, and lp···π interactions. The reaction of the salts with chloro dithiastibocanes X(CH 2 CH 2 S) 2 SbCl (X = O , S) led to the formation of coordination compounds in which the crystal structures showed two new supramolecular synthons stabilized by C H···π and lp···π interactions. The theoretical study of the electronic density of the crystal and their synthons in the solid-state used the robust NCI index to confirm the nature of the interactions found. This study confirmed the connection between molecular and supramolecular chirality in the crystalline state. Three significant features unequivocally support the findings: the role of intramolecular interactions, the electronic density differences among diastereomers, and the nature of trans-annular bonds. The characterization of the salts: ammonium-menthoxy (4-methoxyphenyl) dithiophosphonate (1), triethylammonium-menthoxy (4-methoxyphenyl)-dithiophosphonate (2), triethylammonium-biphenyl-4‑methoxy (4-methoxyphenyl) dithiophosphonate (3), and the coordination compounds O(CH 2 CH 2 S) 2 Sb[S 2 P(biphenyl-4‑methoxy)(4-MeOC 6 H 4)] (4) and S(CH 2 CH 2 S) 2 Sb[S 2 P(biphenyl-4‑methoxy)(4-MeOC 6 H 4)] (5) was carried out by elemental analyses, IR, NMR (1H, 13C, 31P), and single-crystal X-ray diffraction analysis. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Metal complexes with Schiff base ligands are interesting for biological and pharmacological applications. • A new manganese complex (3) has been synthesized and characterized. • Interesting hydrogen-bonding supramolecular synthons are present in (3) • Intermolecular electrostatic interactions play a crucial role in building supramolecular metal complexes. • Complementary experimental and theoretical methods are used for the study of (3) • Schiff base of (3) has an interesting biological activity. MnII-based coordination compound [MnII(L) 2 (NO 3)(H 2 O) 3 ]NO 3 (3) has been synthesized with Shiff's base N2-benzylidenyl isonicotinic acid hydrazide (2) and (Mn(NO 3) 2 ⋅4H 2 O). The compound is new and has been fully characterized by FT-IR, UV–visible, 1H and 13C NMR spectroscopic techniques and single-crystal X-ray diffraction complemented with a quantum chemical study performed with DFT method. The compound crystallized in the monoclinic centrosymmetric P 2 1 /n space group. The crystal structure of (3) exhibits a nitrate anion and a non-centrosymmetric complex cation [MnII(L) 2 (NO 3)(H 2 O) 3 ]+. In the molecular packing, the different entities are held together through intermolecular strong, weak and non-conventional O/N/C H⋯O hydrogen bonds, that found to be effective in stabilizing the three-dimensional network. Furthermore, the crystal structure of (3) contains interesting cyclic supramolecular homo and heterosynthons. Moreover, π–π stacking and N lone-pair ...C H intermolecular electrostatic interactions play a crucial role in building a supramolecular layered network. To better understand the contribution of different intermolecular interactions to the supramolecular assembly, Hirshfeld surface analysis was performed. The obtained results indicate that the main contributions are attributed to O H⋯O, N H⋯O and C H⋯O interactions which are the primary giver the stabilisation in the crystal. The theoretical achievements were found in a good relation with the experimental structural analysis. The HOMO and LUMO energies and molecular electrostatic potential surface were derived from the same basis and the natural population Mulliken charge distribution analysis showed the different electron donors which coordinate with manganese. In addition to that, the molecular docking for (2) and (3) investigation with the 2X22 enzyme involved in Mycobacterium tuberculosis H37Rv have been conducted in order to check the biological activity of the Schiff base and its complex. [ABSTRACT FROM AUTHOR]

Highlights: [•] Two three-dimensional supramolecular salts 1 and 2 have been prepared. [•] Robust hydrogen bonds generate interesting anionic substructures. [•] Thermal analysis showed they undergo an irreversible phase transition. [•] Dielectric studies suggested a low-frequency thermal fluctuation. [Copyright &y& Elsevier]

Abstract: The synthesis of Ni(dtc)2 [dtc=diethyldithiocarbamate] has been achieved by the interaction of NiL(ClO4)2 with sodium diethyldithiocarbamate. Although single crystal structure of this complex was already reported (R =10.6%), we were able to refine crystal structure up to R =2.99%. We also observed rare C–H⋯Ni anagostic interactions generally exhibited by d8 complexes which were overlooked previously. To investigate the structure of Ni(dtc)2 in solution, variable temperature NMR spectra in solution have also been recorded between 25 and −50°C. Ni(dtc)2 was also tested for antibacterial and antifungal activities. It showed higher activity against the bacteria and fungi than the known antibiotics. [ABSTRACT FROM AUTHOR]

Abstract: In the study of supramolecular synthons formed by the imide group, four polycyclic imides (2–5) with unsubstituted NH group have been synthesized. The parent compound (1), obtained previously, and its derivatives 2–5 have been characterized by an elemental analysis, FTIR, 1H NMR, 13C NMR and X-ray crystallography methods. The differences in supramolecular structure were discussed on the basis of the X-ray analysis and the solid-state IR spectra. Selected theoretical calculations of vibrational spectra and binding energies confirm the observations that follow from experiment. In particular, the observed splittings of bands corresponding to Cing vibrations in the solid-state IR spectra of 1, 2 and 5 are well predicted by quantum chemical calculations. The molecules 1–5, having chiral centers, crystallize in centrosymmetric space groups as racemic compounds. In the solid state the association motifs of the imide fragments seem to be related to the structure (molecular shape and substituents) of the interacting molecules. The strongest interactions are the Nimide–H…Oimide/epoxy hydrogen bonds. They stabilize cyclic dimers (1,2), infinite chains (3,5) and other patterns (4) in crystal architecture. Additionally, in the crystals electrostatic interactions involving Care observed; they form parallel (1) and anti-parallel (3,4) motifs. [Copyright &y& Elsevier]

Abstract: 1,2,3,4,5-Pentafluorodiphenyl disulfide (1) was synthesized from C6F5SCl and C6H5SSiMe3 in quantitative yield. The homo-crystals of disulfide 1 and co-crystals of 1,1′,2,2′,3,3′,4,4′,5,5′-decafluorodiphenyl disulfide (2) with naphthalene (stoichiometry 1:2, complex 4) and diphenyl disulfide (3) with octafluoronaphthalene (stoichiometry 2:1, complex 5) were prepared followed by XRD characterization. In the crystal lattice of 1, face-to-face and face-to-edge PhH/PhF orientations of neighboring rings were observed together with face-to-edge PhF/PhF orientations. For the face-to-face PhH/PhF orientation, the large offset of PhH and PhF groups excludes their π-stacking interaction which is very non-typical of the field. The crystal lattice of 4 reveals standard π-stacking interactions of the arene–polyfluoroarene type. While in the lattice of 4 each PhF ring interacts alternating with naphthalenes, in 5 two disulfides 3 are bridged by one octafluoronaphthalene with only one of the PhH rings of each disulfide interacting with the polyfluoroarene π-system. The large offset of neighboring molecules excludes however their π-stacking interactions in complex 5. An attempt to prepare 2/3 co-crystals failed. [Copyright &y& Elsevier]

Abstract: A set of six N-benzyl-3-spiro-succinimides with evaluated anticonvulsant activity has been crystallographically studied. In all crystals, in the absence of strong H-bond donors, only weak H-bonds of C–H…Oen found as intermolecular interactions. For six crystals, two main packing motifs of the strongest interactions of C(sp3)–H…Ormed two alternative supramolecular synthons. Additionally in all crystals, interactions with aromatic donors have been identified. The analogy in the chemical formulas of the studied species has been complemented by the similarity in the H-bonding patterns in the crystals. However, no relationship between molecular conformation and packing motif variations has been found. [Copyright &y& Elsevier]

Abstract: From X-ray diffraction data, the crystal lattice of 1,2,3,4-tetrafluoronaphthalene 1 is composed of infinite π-stacks revealing π–π interactions of the arene-arene, arene-polyfluoroarene and polyfluoroarene-polyfluoroarene types. On replacement of the C2-F fragment of 1 by a N atom (i.e. in going from 1 to 1,3,4-trifluoroisoquinoline 2) the enlarged offset of neighboring molecules within the stacks excludes their π–π interactions, and only the Fπ interaction of fluorine atom of the C1-F bond of one molecule with hydrocarbon ring of another is observed. Networks of shortened Ch xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si6.gif" overflow="scroll"> ⋯ Hld>1 and 2) and NHld>2) contacts also contribute to supramolecular tectonics of the crystals. Quantum chemical calculations at the PBE/cc-pVTZ level of theory on dimers of 1 and 2 result in geometries somewhat different from those observed in the solid state. [Copyright &y& Elsevier]

After making a comparison between inorganic pigments and quinacridone, several experimental results ensuing from 30 years of research are presented. Following this, the bridging hydrogen bond and crystal engineering are treated with some definitions, the pigment finishing is touched upon and the π…σ correlation is introduced. This is regarded as mesomerism between two non-covalent bond types, namely charge transfer and H bonds. It is compared with the lattice of the carbon blacks and thus used to explain the excellent stability of the quinacridones. In conclusion, Desiraju''s supramolecular synthons serve in the interpretation of the somewhat abstract π…σ correlation. Quinacridone crystals are made up solely of π…π charge transfer bonds and bridging hydrogen bonds i.e. they contain both of these non-covalent bonding types in compact form. This means that each and every quinacridone molecule is in itself a source of supramolecular mesomerism which encompasses the entire crystal lattice. [Copyright &y& Elsevier]

• A salt hydrate (4CA5SSA) was synthesized based on crystal engineering approach. • The crystal structure is stabilized by N H...O, O H...O and C H...O hydrogen bonding interactions. • The title crystal is thermally stable up to 239 °C. • The synthesized compound was evaluated for its antimicrobial activities. • Title crystal shows significant antioxidant activities comparison to the standard ascorbic acid. An organic molecular salt hydrate crystal, 4-chloroanilinium-5-sulfosalicylate monohydrate (4CA5SSA) was obtained in 2:2:1 ratio. A proton of SO 3 H group in 5-sulfosalicylic acid was transferred to nitrogen atom of 4-chloroaniline leading to form primary N H...O hydrogen bonding in its crystal structure. R 2 2(8) motif is also observed due to homo dimmer synthon of carboxylic acid. Further, the strong N H...O and O H...O hydrogen bonding interactions construct the supramolecular architecture whereas weak C H...O hydrogen bonds play the dominant role in controlling the interactions between layers in 4CA5SSA salt hydrate. The thermal stability of title crystal was determined by TG/DTA thermogravimetric analysis. The in vitro antimicrobial activity of 4CA5SSA crystal was investigated against bacterial and fungal pathogens. The title compound was also evaluated for its in vitro antioxidant susceptibilities through DPPH radical scavenging methods. [Display omitted] [ABSTRACT FROM AUTHOR]

• Adeninium derivatives are interesting for pharmaceutical and optical applications. • Two new adeninium-based hybrid materials have been synthesized and characterized. • Complementary experimental and theoretical approaches are used in this work. • DFT calculations confirm the inorganic organic charge transfer. • The 3D packings are controlled by hydrogen bonds and electrostatic interactions. In this paper, we report preparation and structure determination of two new adeninium-based hybrid compounds formed with selenious acid: adeninium hydrogen diselenite (I) and adeninium hydrogen selenite (II). Single crystals of (I) and (II) were obtained by slow evaporation and their X-ray structures are reported coupled with a quantum chemical density functional theory (DFT) studies. In the atomic arrangement, the different entities are held together through N/O—H ··· O, N—H ··· N and C—H ··· N/O hydrogen bonds on the Watson−Crick, Hoogsteen and sugar sites. Their overall three-dimensional architectures are mostly controlled by electrostatic interactions between the inorganic anion and organic cation frameworks and by hydrogen bonding. Furthermore, the crystal structures of (I) and (II) contain supramolecular homo and heterosynthons which are present in most similar structures. The similarities and subtle differences of the intermolecular interactions in the two crystal structures have been investigated and discussed using Hirshfeld surface analysis, fingerprint plots, and contact enrichment. The theoretical results are in good relation with the experimental structural analysis and confirm that the charge transfer occurs from inorganic anions to organic cations. Image, graphical abstract [ABSTRACT FROM AUTHOR]

The synthesis, analytical characterisation and four X-ray structures of aromatic sulfonester trimers featuring a meta -substitution are reported. The title compounds feature either resorcinol or a 1,3-benzenedisulfonyl moiety as a central unit; one of the trimers exists in two polymorphic forms. Depending on the C aryl -SO 2 -O-C aryl torsion angles two main conformations have been detected: U- and W-shape. Only little influenced by the molecular conformation the prevailing non-covalent interaction in the packing of all four title structures are C–H⋯O contacts. Thereby, aromatic H atoms in ortho position to oxysulfonyl groups serve as hydrogen bonding donor and S O units as hydrogen bonding acceptors. In all cases the structures contain cyclic supramolecular synthons featurin R 2 2 (10) g either graph- R 2 2 (12) set descriptor for the resorcinol trimers and for benzenedisulfonic acid derivatives respectively. One of the two supramolecular synthons is also present in most published sulfontriester X-ray structures uninfluenced from the aromatic substitution pattern. Image 1 • Aromatic sulfonester trimers exist in two main conformations: U- and W-shape. • Prevailing non-covalent interactions are C–H⋯O contacts. • Aromatic H atoms ortho to OSO 2 groups serve as H donor and S O units as H acceptors. • Cyclic supramolecular synthons of the type R 2 2 (X) (X = 10–12) are commons motifs. [ABSTRACT FROM AUTHOR]

The nature of bifurcated hydrogen bonds prompted us to analyze the energy of supramolecular motifs on the example of new structures of carboxylic acids salts with amines, which guarantee a multitude of such interactions. Experimental and theoretical studies of four dicarboxylic salts with primary amine: ethylammonium succinate hydrate (1), tartrate hydrate (2) phthalate hydrate (3) and terephthalate (4) has been investigated along with study of the strength of interactions between the anions and cations. The complete topological analysis of the charge density for all new structures allowed designation of the estimated Cumulative Dissociation Energy (eCDE). Image 1 • A traditional structure refinement based on a spherical atom model, was improved by the use of transferred multipolar charge density parameters. • Interactions in the solid-state have also been characterized and classified by means of their estimated cumulative dissociation energy. • The analysis carried out on new structures prove the usefulness of self-organization mechanisms description. [ABSTRACT FROM AUTHOR]