Robust S4 ⋠⋠⋠O Supramolecular Synthons: Structures of Radical-Radical Cocrystals [p-XC6 F4 CNSSN]2 [TEMPO] (X=F, Cl, Br, I, CN).

Cocrystallization of the dithiadiazolyl (DTDA) radicals p-XC6 F4 CNSSN (X=F, Cl, Br, I, CN) with TEMPO afforded the 2 : 1 cocrystals [p-XC6 F4 CNSSN]2 [TEMPO] (1-5) whose structures all reflect a common S4 ⋅⋅⋅O supramolecular motif. The nature of this interaction was probed by DFT calculations (M06/aug-cc-pVDZ) on 1 which revealed that the enthalpy of formation of the [C6 F5 CNSSN]2 [TEMPO] supramolecular motif from [C6 F5 CNSSN]2 and TEMPO is substantial (-54.0 kJ mol-1 ). Electronic structure calculations revealed a TEMPO-based doublet S= 1 / 2 configuration as the ground state with limited spin density on the DTDA rings (2.4 %). The corresponding spin quartet state is +78.9 kJ mol-1 higher in energy. An atoms-in-molecules analysis reveals four bond critical points (BCPs) between the TEMPO O and the DTDA S atoms as well as additional BCPs between selected DTDA S atoms and methyl H atoms of the TEMPO molecule. Herein, the structures of 2-5 are considered within the context of a hierarchical view of competing and complementary intermolecular interactions; in particular, the established supramolecular CN⋅⋅⋅S-S synthon is sacrificed in order to form the new S4 ⋅⋅⋅O interaction.

Heterosynthons, Solid Form Design and Enhanced Drug Bioavailability.

Starting from a molecular pharmacophore, which is a marker of drug action in medicinal molecules, we propose that the heterosynthon, a supramolecular synthon between unlike functional groups, plays an analogous role in the design and discovery of high bioavailability drugs. The heterosynthon could provide a more efficient and economical route to novel drugs.

Crystals at a Carrefour on the Way through the Phase Space: A Middle Path.

Multiple supramolecular functionalities of cyclic α-alkoxy tellurium-trihalides (including Te---O, Te---X (X = Br, I) and Te---π(C=C) supramolecular synthons) afford rich crystal packing possibilities, which consequently results in polymorphism or Z' > 1 crystal structures. Example of three crystal forms of cyclohexyl-ethoxy-tellurium-trihalides, one of which combines the packing of two others, affords a unique model to observe the supramolecular synthon evolution at the early stages of crystallization, when crystals on the way find themself at a carrefour between the evolutionally close routes, but fail to choose between two energetically close packing patterns, so taking the "middle path", which incorporates both of them (and results in two crystallographically independent molecules). In general, this allows a better understanding of the existing structures, and an instrument to search for the new polymorphic forms.

Synthetic Approaches to Halogen Bonded Ternary Cocrystals.

Higher cocrystal synthesis depends acutely on a knowledge of supramolecular synthons. We report three synthetic approaches towards ternary halogen bonded cocrystals that illustrate specificity and generality. Electrophilicity/nucleophilicity differences are needed among alternative sites of halogen bond formation. The two halogen bonds A⋅⋅⋅B and B⋅⋅⋅C in a halogen bonded ternary cocrystal ABC need to be of different strength. Interaction mimicry of hydrogen bonds by halogen bonds is a viable approach towards ternaries as illustrated with the pyrene structure. Finally, the crystal engineer should well be able to anticipate halogen bonds that are stronger than hydrogen bonds.

Non-Classical Synthons: Supramolecular Recognition by S⋠⋠⋠O Chalcogen Bonding in Molecular Complexes of Riluzole.

Classical examples of supramolecular recognition units or synthons are the ones formed by hydrogen bonds. Here, we report the ubiquity of a S⋅⋅⋅O chalcogen bonded synthon observed in a series of supramolecular complexes of the amyotrophic lateral sclerosis drug riluzole. Although the potential of higher chalcogens such as Se and Te to form robust and directional chalcogen bonded motifs is known, intermolecular sulfur chalcogen bonding is considered to be weak owing to the lower polarizability of S atoms. Here, the robustness and electronic nature of a S⋅⋅⋅O chalcogen bonding non-classical synthon, and the origin of its exceptional directionality have been explored. Bond orders of the drug-coformer chalcogen bonding are found to be as high as one third of a single bond, and they are largely ionic in nature. The contribution of the S⋅⋅⋅O chalcogen bonded motifs to the lattice energies of a series of crystals from the Cambridge Structural Database has been analyzed, showing they can be indeed significant, especially in molecules devoid of strong hydrogen bond donor groups.

Four-Center Nodes: Supramolecular Synthons Based on Cyclic Halogen Bonding.

The isocyanide trans-[PdBr2 (CNC6 H4 -4-X')2 ] (X'=Br, I) and nitrile trans-[PtX2 (NCC6 H4 -4-X')2 ] (X/X'=Cl/Cl, Cl/Br, Br/Cl, Br/Br) complexes exhibit similar structural motif in the solid state, which is determined by hitherto unreported four-center nodes formed by cyclic halogen bonding. Each node is built up by four Type II C-X'⋅⋅⋅X-M halogen-bonding contacts and include one Type I M-X⋅⋅⋅X-M interaction, thus giving the rhombic-like structure. These nodes serve as supramolecular synthons to form 2D layers or double chains of molecules linked by a halogen bond. Results of DFT calculations indicate that all contacts within the nodes are typical noncovalent interactions with the estimated strengths in the range 0.6-2.9 kcal mol-1 .

Supramolecular Synthon Approach in Developing Anti-Inflammatory Topical Gels for In†Vivo Self-Delivery.

A new series of tertiary-butyl ammonium (TBA) salts of various nonsteroidal anti-inflammatory drugs (NSAIDs) have been synthesized and characterized. Nearly 90 % of the NSAID-derived primary ammonium monocarboxylate (PAM) salts displayed remarkable gelation ability with various solvents including methyl salicylate. Single crystal X-ray diffraction data (SXRD) revealed the existence of 1D PAM synthon in the gelator salts. Structure-property correlation studies based on SXRD and powder X-ray diffraction (PXRD) data established the presence of the 1D PAM synthon in the bulk salts as well as in the corresponding xerogels. A parallel series of salts derived from TRIS (2-amino-2-(hydroxymethyl)-1,3-propanediol) and the same set of NSAIDs displayed poor gelation ability; only 33 % of the salts in the series displayed gelation ability. A few selected gelator salts of both TBA and TRIS were found to be biocompatible (MTT assay with RAW 264.7 cell line) and two of the selected salts (FLR.TBA and FLR.TRIS) possessed anti-inflammatory properties equal to the parent drug FLR (flurbiprofen). Finally a methyl salicylate topical gel derived from FLR.TRIS was successfully delivered in a self-delivery fashion to treat inflamed skin conditions in the mice model. Histological studies of the dorsal tissues of the untreated and treated mice clearly demonstrated the effect of topical gels in such treatment.

Exploiting supramolecular synthons in designing gelators derived from multiple drugs.

A simple strategy for designing salt-based supramolecular gelators comprised of various nonsteroidal anti-inflammatory drugs (NSAIDs) and amantadine (AMN) (an antiviral drug) has been demonstrated using a supramolecular synthon approach. Single-crystal and powder X-ray diffraction established the existence of the well-studied gel-forming 1D supramolecular synthon, namely, primary ammonium monocarboxylate (PAM) synthon in all the salts. Remarkably five out of six salts were found to be capable of gelling methyl salicylate (MS)-an important ingredient in commercially available topical gels; one such selected biocompatible salt displayed an anti-inflammatory response in prostaglandin E2 (PGE2 ) assay, thereby indicating their plausible biomedical applications.

Combinatorial crystal synthesis: structural landscape of phloroglucinol:1,2-bis(4-pyridyl)ethylene and phloroglucinol:phenazine.

A large number of crystal forms, polymorphs and pseudopolymorphs, have been isolated in the phloroglucinol-dipyridylethylene (PGL:DPE) and phloroglucinol-phenazine (PGL:PHE) systems. An understanding of the intermolecular interactions and synthon preferences in these binary systems enables one to design a ternary molecular solid that consists of PGL, PHE, and DPE, and also others where DPE is replaced by other heterocycles. Clean isolation of these ternary cocrystals demonstrates synthon amplification during crystallization. These results point to the lesser likelihood of polymorphism in multicomponent crystals compared to single-component crystals. The appearance of several crystal forms during crystallization of a multicomponent system can be viewed as combinatorial crystal synthesis with synthon selection from a solution library. The resulting polymorphs and pseudopolymorphs that are obtained constitute a crystal structure landscape.

Supramolecular synthons in hydrates and solvates of lamotrigine: a tool for cocrystal design.

The molecule of anti-epileptic drug lamotrigine [LAM; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine] is capable of the formation of multicomponent solids. Such an enhanced tendency is related to the diverse functionalities of the LAM chemical groups able to form hydrogen bonds. Two robust synthons are recognized in the supramolecular structure of LAM itself formed via N-H...N hydrogen bond: homosynthon, so-called aminopyridine dimer or synthon 1 [R22(8)] and larger homosynthon 2 [R32(8)]. The synthetic procedures for a new hydrate and 11 solvates of LAM (in the series: with acetone, ethanol: two polymorphs: form I and form II, 2-propanol, n-butanol, tert-butanol, n-pentanol, benzonitrile, acetonitrile, DMSO and dioxane) were performed. The comparative solid state structural analysis of a new hydrate and 11 solvates of LAM has been undertaken in order to establish robustness of the supramolecular synthons 1 and 2 found in the crystal structure of LAM itself as well as LAM susceptibility to build methodical solid state supramolecular architecture in the given competitive surrounding of potential hydrogen bonds. The aminopyridine dimer homosynthon 1 [R22(8)] has been switched from para-para (P-P) topology to ortho-ortho (O-O) topology in all crystal structures, except in LAM:n-pentanol:water solvate where it remains P-P. Homosynthon 2 [R32(8)] of the LAM crystal structure imitates in the LAM solvates as a heterosynthon by replacing the triazine nitrogen proton acceptor atoms of LAM with the proton acceptors of solvates molecules.

The supramolecular synthon behavior within cocrystals of pyrazinamide and alkyl dicarboxylic acids: A perspective from terahertz spectroscopy and quantum chemical calculation.

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.

Compounds Derived from 9,9-Dialkylfluorenes: Syntheses, Crystal Structures and Initial Binding Studies (Part II).

New representatives of 2,4,7-trisubstituted 9,9-dialkyl-9H-fluorenes were prepared and used for crystallographic investigations as well as initial binding studies towards metal ions and carbohydrates. The binding studies, which included 1 H NMR spectroscopic titrations and fluorescence measurements, demonstrated the ability of the tested fluorene-based compounds to act as complexing agents for ionic and neutral substrates. Depending on the nature of the subunits of the fluorene derivatives, "turn on" or "turn off" fluorescent chemosensors can be developed. Compounds composed of 4,6-dimethylpyridin-2-yl-aminomethyl moieties have the potential to be used as sensitive "turn-on" chemosensors for some metal ions.

Low-Molecular-Weight Organogelators Based on N-dodecanoyl-L-amino Acids-Energy Frameworks and Supramolecular Synthons.

Lauric acid was used to synthesize the low-molecular-weight organogelators (LMOGs), derivatives of two endogenous (L)-alanine, (L)-leucine, and three exogenous (L)-valine, (L)-phenylalanine, and (L)-proline amino acids. The nature of processes responsible for the gel formation both in polar and in apolar solvents of such compounds is still under investigation. Knowing that the organization of surfactant molecules affects the properties of nano scale materials and gels, we decided to elucidate this problem using crystallographic diffraction and energy frameworks analysis. The single crystals of the mentioned compounds were produced successfully from heptane/tBuOMe mixture. The compounds form lamellar self-assemblies in crystals. The energetic landscapes of single crystals of a series of studied amphiphilic gelators have been analyzed to explore the gelling properties. The presented results may be used as model systems to understand which supramolecular interactions observed in the solid state and what energy contributions are desired in the designing of new low-molecular-weight organic gelators.

Boron-π interactions in two 3-(dihydroxyboryl)anilinium salts analyzed by crystallographic studies and supported by the noncovalent interactions (NCI) index theoretical approach.

In the title compounds, 3-(dihydroxyboryl)anilinium bisulfate monohydrate, C6H9BNO2+·HSO4-·H2O (I), and 3-(dihydroxyboryl)anilinium methyl sulfate, C6H9BNO2+·CH3SO4- (II), the almost planar boronic acid molecules are linked by pairs of O-H...O hydrogen bonds, forming centrosymmetric motifs that can be described by the graph-set R22(8) motif. In both crystals, the B(OH)2 group acquires a syn-anti conformation (with respect to the H atoms). The presence of the hydrogen-bonding functional groups B(OH)2, NH3+, HSO4-, CH3SO4- and H2O generates three-dimensional hydrogen-bonded networks, in which the bisulfate (HSO4-) and methyl sulfate (CH3SO4-) counter-ions act as the central building blocks within the crystal structures. Furthermore, in both structures, the packing is stabilized by weak boron-π interactions, as shown by noncovalent interactions (NCI) index calculations.

Molecular duplexes featuring NH···N, CH···O and CH···π interactions in solid-state self-assembly of triazine-based compounds.

Synthetic supramolecular structures constructed through the cooperative action of numerous non-covalent forces are highly desirable as models to unravel and understand the complexity of systems created in nature via self-assembly. Taking advantage of the low cost of 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) and the sequential nucleophilic substitution reactions with almost all types of nucleophiles, a series of six structurally related novel s-triazine derivatives 1-6 were synthesized and structurally characterized based on their physical, spectral and crystallographic data. The solid-state structures of all the six compounds showed intriguing and unique molecular duplexes featuring NH···N, CH···O and CH···π interactions. Careful analysis of different geometric parameters of the involved H-bonds indicates that they are linear, significant and are therefore responsible for guiding the three-dimensional structure of these compounds in the solid state. The prevalence of sextuple hydrogen bond array-driven molecular duplexes and the possibility of structural modifications on the s-triazine ring render these novel triazine derivatives 1-6 attractive as a platform to create heteroduplex constructs and their subsequent utility in the field of supramolecular chemistry and crystal engineering.

Unlocking the potential of drug-drug cocrystals - A comprehensive review.

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.

Salts of purine alkaloids caffeine and theobromine with 2,6-dihydroxybenzoic acid as coformer: structural, theoretical, thermal and spectroscopic studies.

The study of various forms of pharmaceutical substances with specific physicochemical properties suitable for putting them on the market is one of the elements of research in the pharmaceutical industry. A large proportion of active pharmaceutical ingredients (APIs) occur in the salt form. The use of an acidic coformer with a given structure and a suitable pKa value towards purine alkaloids containing a basic imidazole N atom can lead to salt formation. In this work, 2,6-dihydroxybenzoic acid (26DHBA) was used for cocrystallization of theobromine (TBR) and caffeine (CAF). Two novel salts, namely, theobrominium 2,6-dihydroxybenzoate, C7H9N4O2+·C7H5O4- (I), and caffeinium 2,6-dihydroxybenzoate, C8H11N4O2+·C7H5O4- (II), were synthesized. Both salts were obtained independently by slow evaporation from solution, by neat grinding and also by microwave-assisted slurry cocrystallization. Powder X-ray diffraction measurements proved the formation of the new substances. Single-crystal X-ray diffraction studies confirmed proton transfer between the given alkaloid and 26DHBA, and the formation of N-H...O hydrogen bonds in both I and II. Unlike the caffeine cations in II, the theobromine cations in I are paired by noncovalent N-H...O=C interactions and a cyclic array is observed. As expected, the two hydroxy groups in the 26DHBA anion in both salts are involved in two intramolecular O-H...O hydrogen bonds. C-H...O and π-π interactions further stabilize the crystal structures of both compounds. Steady-state UV-Vis spectroscopy showed changes in the water solubility of xanthines after ionizable complex formation. The obtained salts I and II were also characterized by theoretical calculations, Fourier-transform IR spectroscopy (FT-IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and elemental analysis.

Structural variety of heterosynthons in linezolid cocrystals with modified thermal properties.

In a search for new crystalline forms of linezolid with modified thermal properties five cocrystals of this wide range antibiotic with aromatic acids were obtained via mechanochemical grinding and analyzed with single crystal X-ray diffraction, solid-state NMR spectroscopy, powder X-ray diffraction and DSC measurements. The coformers used in this study were benzoic acid, p-hydroxybenzoic acid, protocatechuic acid, γ-resorcylic acid and gallic acid. In each of the cocrystals distinct structural features have been found, including a variable amount of water and different heterosynthons, indicating that there is more than one type of intermolecular interaction preferred by the linezolid molecule. Basing on the frequency of the observed supramolecular synthons, the proposed hierarchy of the hydrogen-bond acceptor sites of linezolid (LIN) is C=Oamide > C=Ooxazolidone > C-O-Cmorpholine > C-N-Cmorpholine > C-O-Coxazolidone. In addition, aromatic-aromatic interactions were found to be important in the stabilization of the analyzed structures. The obtained cocrystals show modified thermal properties, with four of them having melting points lower than the temperature of the phase transition from linezolid form II to linezolid form III. Such a change in this physicochemical property allows for the future application of melting-based techniques of introducing linezolid into drug delivery systems. In addition a change in water solubility of linezolid upon cocrystalization was evaluated, but only in the case of the cocrystal with protocatechuic acid was there a significant (43%) improvement in solubility in comparison with linezolid.

The Influence of Solvent on the Crystal Packing of Ethacridinium Phthalate Solvates.

The synthesis, structural characterization and influence of solvents on the crystal packing of solvated complexes of ethacridine with phthalic acid: 6,9-diamino-2-ethoxyacridinium phthalate methanol solvate (1), 6,9-diamino-2-ethoxyacridinium phthalate ethanol solvate (2), 6,9-diamino-2-ethoxyacridinium phthalate isobutanol solvate (3), and 6,9-diamino-2-ethoxyacridinium phthalate tert-butanol solvate monohydrate (4) are described in this article. Single-crystal XRD measurements revealed that the compounds 1-4 crystallized in the triclinic P-1 space group, and the 6,9-diamino-2-ethoxyacridinium cations, phthalic acid anions and solvent molecules interact via strong N-H···O, O-H···O, C-H···O hydrogen bonds, and C-H···π and π-π interactions to form different types of basic structural motifs, such as: heterotetramer bis[···cation···anion···] in compound 1 and 2, heterohexamer bis[···cation···alcohol···anion···] in compound 3, and heterohexamer bis[···cation···water···anion···] in compound 4. Presence of solvents molecule(s) in the crystals causes different supramolecular synthons to be obtained and thus has an influence on the crystal packing of the compounds analyzed.

Supramolecular synthon hierarchy in sulfonamide cocrystals with syn-amides and N-oxides.

Sulfonamide drugs are well known antibacterial and antimicrobial molecules for pharmaceutical development. Building a library of suitable supramolecular synthons for the sulfonamide functional group and understanding their crystal structures with partner coformer molecules continues to be a challenge in crystal engineering. Although a few sulfonamide cocrystals with amides and N-oxides have been reported, the body of work on sulfonamide synthons is limited compared with those that have carb-oxy-lic acids and carboxamides. To address this structural gap, the present work is primarily focused on sulfonamide-lactam and sulfonamide-syn-amide synthons with drugs such as celecoxib, hydro-chloro-thia-zide and furosemide. Furthermore, the electrostatic potential of previously reported cocrystals has been recalculated to show that the negative electrostatic potential on the lactam and syn-amide O atom is higher compared with the charge on carboxamide and pyridine N-oxide O atoms. The potential of sulfonamide molecules to form cocrystals with syn-amides and lactams are evaluated in terms of the electrostatic potential energy for the designed supramolecular synthons.