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The wide range of application possibilities of fluorene derivatives, due to their unique physical and chemical properties, has made this class of molecules important for various disciplines. The synthesis of these compounds and the study of their properties are, therefore, of great scientific interest. Due to their reactivity and sensitivity to oxidation, the 9-position of the fluorene skeleton is often double substituted, for example, to ensure the long-term stability of materials. Single crystal structure analysis, among other methods, plays a very important role in the development of various fluorene-based systems. In this paper, the crystal structures of three 9,9-disubstituted fluorene derivatives bearing methyl, hydroxymethyl or pyridinylmethyl groups are described (three solvent-free structures and one toluene solvate). A detailed evaluation of the intermolecular interactions, supported by Hirshfeld surface analysis, is the subject of this article. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Understanding how chemical modifications alter the atomic‐scale organization of materials is of fundamental importance in materials engineering and the target of considerable efforts in computational prediction. Incorporating covalent and noncovalent interactions in designing crystals while "piggybacking" on the driving force of molecular self‐assembly has augmented efforts to understand the emergence of complex structures using directed synthesis. In this work, microcrystalline powders of the silver 2‐, 3‐, and 4‐fluorobenzenethiolates are prepared and their structures are resolved by small‐molecule serial femtosecond X‐ray crystallography. These three compounds enable the emergence and role of supramolecular synthons in the crystal structures of 3D metal‐organic chalcogenolates to be examined. The unique divergence in their optoelectronic, morphological, and structural behaviors is assessed. The extent of CHF interactions and their influence on the structure and the observed trends in the thermal stability of the crystals are quantified through theoretical calculations and thermogravimetric analysis. [ABSTRACT FROM AUTHOR]

Purpose: The primary objective of this research work was to formulate crystal engineered multicomponent form of a BCS II drug, telmisartan (TEL) using crystal engineering approach to improve its aqueous solubility. Further, it was attempted to understand the co-crystallization specificity of TEL using a set of structurally similar coformers. Methods: Preliminary structural assessment and feasibility of cocrystal formation was done using Cambridge structural database (CSD) and molecular electrostatic surface potential (MESP). The formation of cocrystals was confirmed by different characterization techniques such as differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared spectroscopy (FTIR), and powder x-ray diffraction (PXRD). Solubility and dissolution studies were performed in phosphate buffer 7.5 and 0.1 N HCl. Results: TEL cocrystal with maleic acid (MA) was successfully obtained, and co-crystallization specificity was decoded at MESP. Cocrystal structure was also solved from PXRD data. A 4.27-fold and 2.8-fold improvement in the solubility was observed in phosphate buffer 7.5 and 0.1 N HCl. Conclusion: A significant improvement in the aqueous solubility and dissolution profile was observed for the prepared cocrystals over the pure TEL. The present study was a small initiative to serve as a guidance for the rationalized screening and preparation of novel multicomponent solids with desired properties. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 1H 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. [ABSTRACT FROM AUTHOR]

Abstract 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 1H 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.

Most of the Active Pharmaceutical Ingredients (APIs) are typically formulated and administered to patients in oral solid dosage forms due to ease of administration, patient compliance and cost effectiveness. Poor water solubility, low permeability and low bioavailability of APIs are major hurdles in development of oral solid dosage forms. In recent years, cocrystal development has evolved as a feasible approach for enhancing the solubility and bioavailability of poorly soluble drugs. Crystal engineering strategies have been asserted to enhance the likelihood of discovering new solid forms of an API. A pharmaceutical cocrystal is made up of two basic components, an API and a harmless material known as a coformer in stoichiometric ratio. Cocrystallization of an API with a pharmaceutically acceptable coformer can improve the physical characteristics of the API, such as solubility, hygroscopicity, and compaction behavior, without affecting the API's pharmacological efficacy. This review article offers a comprehensive overview of pharmaceutical cocrystals, their physiochemical characteristics, and methods of preparation, with an emphasis on cocrystal screening and cocrystal characterization. The review also included recent FDA and EMA guidance on pharmaceutical cocrystals as well as an outline of multidrug cocrystals. [ABSTRACT FROM AUTHOR]

Single crystals of two polymorphic forms of 4′-methyl-2,4-dinitrodiphenylamine were obtained by crystallization and characterized by X-ray diffraction analysis. One of the forms is non-centrosymmetric (space group P21212), while the second is centrosymmetric (space group P¯1) and contains two crystallographically independent molecules in the asymmetric unit. In both forms, the same supramolecular synthon, a dimer linked by bonding N-H···O, O···O, and C-H···O interactions were found. Despite nearly the same connectivity of the bonding interactions, the conformation of the supramolecular synthon is different, including its unavoidably different symmetry in two polymorphs. The comparison of the crystal packing of the orthorhombic polymorph with that of the related 2,4-dinitrodiphenylamine (space group P21/n) shows the quasi-isostructurality of the fragments, infinite π-stacks joined by weak non-directional intermolecular interactions. However, the fragments are linked by the supramolecular synthons via either a two-fold axis or an inversion center, which lead to only the partial isostructurality of the crystals. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

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]

Supramolecular synthons are the smallest structural units that contain the information inherent in building large molecular assemblies. Here, we apply solid-state NMR methods for the identification of the synthon in a cocrystal of Azelaic acid [(CH2)7(COOH)2]– Isonicotinamide [C6H6N2O]. It is observed that the spin-lattice relaxation time of protons in the cocrystal is long, implying that the choice of experiments, particularly those that involve low-sensitivity nuclei, could be time consuming. It is noticed that the two dimensional 1H double quantum (DQ) – 1H single quantum (SQ) correlation experiment at very fast MAS (60 kHz) is able to provide information on proton-proton proximities that leads to an understanding of the synthon structure. Experiments such as the CP-Reverse CP and 1H–13C HETCOR have been used to obtain spectral assignment which was additionally confirmed by first-principle GIPAW NMR chemical shift calculations. Present study indicates the basic unit to be a heterosynthon in Azelaic acid (AZA) – Isonicotinamide (INIC) cocrystal formed by two different modes of intermolecular connectivity, viz. acid–pyridine and acid–amide hydrogen bonding interactions. The presence of a CH…O type bond involving a hydrogen of INIC is also indicated from the observation of a larger chemical shift of the corresponding proton. The experimental protocol presented in this paper is expected to be a useful tool for the estimation of the basic structural arrangement of the synthons in a rapid fashion.

Cocrystallization of the dithiadiazolyl (DTDA) radicals p‐XC6F4CNSSN (X=F, Cl, Br, I, CN) with TEMPO afforded the 2 : 1 cocrystals [p‐XC6F4CNSSN]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 [C6F5CNSSN]2[TEMPO] supramolecular motif from [C6F5CNSSN]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. [ABSTRACT FROM AUTHOR]

Single crystals of two polymorphic forms of 4′-methyl-2,4-dinitrodiphenylamine were obtained by crystallization and characterized by X-ray diffraction analysis. One of the forms is non-centrosymmetric (space group P21212), while the second is centrosymmetric (space group P¯1) and contains two crystallographically independent molecules in the asymmetric unit. In both forms, the same supramolecular synthon, a dimer linked by bonding N-H···O, O···O, and C-H···O interactions were found. Despite nearly the same connectivity of the bonding interactions, the conformation of the supramolecular synthon is different, including its unavoidably different symmetry in two polymorphs. The comparison of the crystal packing of the orthorhombic polymorph with that of the related 2,4-dinitrodiphenylamine (space group P21/n) shows the quasi-isostructurality of the fragments, infinite π-stacks joined by weak non-directional intermolecular interactions. However, the fragments are linked by the supramolecular synthons via either a two-fold axis or an inversion center, which lead to only the partial isostructurality of the crystals.

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. [ABSTRACT FROM AUTHOR]

The disposition of functional groups can induce variations in the nature and type of interactions and hence affect the molecular recognition and self-assembly mechanism in cocrystals. To better understand the formation of cocrystals on a molecular level, the effects of disposition of functional groups on the formation of cocrystals were systematically and comprehensively investigated using cresol isomers (o-, m-, p-cresol) as model compounds. Consistency and variability in these cocrystals containing positional isomers were found and analyzed. The structures, molecular recognition and self-assembly mechanism of supramolecular synthons in solution and in their corresponding cocrystals were verified by a combined experimental and theoretical calculation approach. It was found that the heterosynthons (heterotrimer or heterodimer) combined with O—H...N hydrogen bonding played a significant role. Hirshfeld surface analysis and computed interaction energy values were used to determine the hierarchical ordering of the weak interactions. The quantitative analyses of charge transfers and molecular electrostatic potential were also applied to reveal and verify the reasons for consistency and variability. Finally, the molecular recognition, self-assembly and evolution process of the supramolecular synthons in solution were investigated. The results confirm that the supramolecular synthon structures formed initially in solution would be carried over to the final cocrystals, and the supramolecular synthon structures are the precursors of cocrystals and the information memory of the cocrystallization process, which is evidence for classical nucleation theory.

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 carboxylic 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, hydrochlorothiazide 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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Two polymorphic forms of a conformationally flexible molecule, 5-[(Diphenylphosphoryl)methyl]-4-(prop-2-en-1-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, were obtained by crystallization and characterized by X-ray diffraction analysis and differential scanning calorimetry. The relative stability of polymorphic forms was estimated with DFT calculations of crystal structures and isolated molecules. It turns out, that in the first more dense polymorph with higher cohesion energy and crystal lattice energy, the molecule adopts an energetically unfavorable conformation, and forms dimers with lower H-bond strength, as compared to the second polymorph. On the other hand, in the second polymorph, the molecule adopts almost the lowest-energy conformation and forms infinite chains via strong H-bonds. The first form that seems to be more thermodynamically stable at room temperature transforms into the second form via two endothermic phase transitions; the apparent irreversibility of the transition is due to high energy difference between the molecular conformations in crystals.

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]

The isocyanide trans‐[PdBr2(CNC6H4‐4‐X′)2] (X′=Br, I) and nitrile trans‐[PtX2(NCC6H4‐4‐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. [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]

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. Intermolecular chalcogen bonds involving relatively less polarizable sulfur atoms are found to form robust and directional supramolecular recognition units in a series of molecular complexes of the drug riluzole—indicating their potential utility in crystal engineering (see figure). [ABSTRACT FROM AUTHOR]

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.

The crystallization of 28 binary and ternary cocrystals of quercetin with dibasic coformers is analyzed in terms of a combinatorial selection from a solution of preferred molecular conformations and supramolecular synthons. The crystal structures are characterized by distinctive O—H...N and O—H...O based synthons and are classified as nonporous, porous and helical. Variability in molecular conformation and synthon structure led to an increase in the energetic and structural space around the crystallization event. This space is the crystal structure landscape of the compound and is explored by fine-tuning the experimental conditions of crystallization. In the landscape context, we develop a strategy for the isolation of ternary cocrystals with the use of auxiliary template molecules to reduce the molecular and supramolecular `confusion' that is inherent in a molecule like quercetin. The absence of concomitant polymorphism in this study highlights the selectivity in conformation and synthon choice from the virtual combinatorial library in solution.

The design of novel supramolecular synthons for functional groups relevant to drugs is an essential prerequisite for applying crystal engineering in the development of novel pharmaceutical cocrystals. It has been convincingly shown over the past decade that molecular level control and modulation can influence the physicochemical properties of drug cocrystals. Whereas considerable advances have been reported on the design of cocrystals for carboxylic acids and carboxamide functional groups, the sulfonamide group, which is a cornerstone of sulfa drugs, is relatively unexplored for reproducible heterosynthon-directed crystal engineering. The occurrence of synthons and isostructurality in sulfonamide–lactam cocrystals (SO2NH2...CONH hydrogen bonding) is analyzed to define a strategy for amide-type GRAS (generally recognized as safe) coformers with sulfonamides. Three types of supramolecular synthons are identified for the N—H donor of sulfonamide hydrogen bonding to the C=O acceptor of amide. Synthon 1: catemer synthon C21(4) chain motif, synthon 2: dimer–cyclic ring synthon R22(8)R42(8) motifs, and synthon 3: dimer–catemer synthon of R22(8)C11(4)D notation. These heterosynthons of the cocrystals observed in this study are compared with the N—H...O dimer R22(8) ring and C(4) chain motifs of the individual sulfonamide structures. The X-ray crystal structures of sulfonamide–lactam cocrystals exhibit interesting isostructurality trends with the same synthon being present. One-dimensional, two-dimensional and three-dimensional isostructurality in crystal structures is associated with isosynthons and due to their recurrence, novel heterosynthons for sulfonamide cocrystals are added to the crystal engineer's toolkit. With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.

Four new Zn(II) and Cd(II) picolinamide (pia) complexes with cyanate and azide, e.g. [Zn(OCN)2(pia)2] (1), [Cd(OCN)2(pia)2]n (2), [Zn(N3)2(pia)2] (3) and [Cd(N3)2(pia)2]n·nH2O (4), have been prepared and characterized by IR and NMR spectroscopy, and thermal (TG/DTA) methods. For the compounds 1 and 3 X-ray analysis revealed mononuclear molecular structure with octahedral N4O2 environment around the zinc(II) center with cis-arrangement of ligands. Only in 1 the amide head-to-head supramolecular motifs, represented by an R22(8) designator, are observed, while in 3 none of the typical amide motifs were found. While the IR data suggests the polymeric structures for 2 and 4 in the solid state, all the NMR spectra agree with the monomeric structure of the compounds in the solution.

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]

An intriguing inorganic analog of ferrocene, pentaphosphaferrocene [CpRFe(η5-P5)] (R=Me, Et, CH2Ph, PhC4H9), has the ability to coordinate Cu(I) moieties resulting in giant superspheres of 2.1–4.6 nm in diameter. Smaller hollow supramolecules follow icosahedral C80 or C140 fullerene topology being constructed of adjacent pentagonal cyclo-P5 moieties and hexagonal Cu2P4 or P2Cu3Br rings. The same building units can also assemble to spherical and ellipsoid inorganic cores with different fullerene-related topologies. Larger supramolecules based on extended copper halide frameworks possess multilayered structures and form non-fullerene topologies. The size and solubility of the superspheres can be controlled through the variation of the steric demand of the cyclopentadienyl ligands at the pentaphosphaferrocene. The interconversion of supramolecules can be enabled in solution by changing the solvent mixtures. The quasi-spherical voids inside the supramolecules encapsulate various organic, inorganic, and organometallic guest molecules. Furthermore, the metallocene guests are involved in π-stacking with aromatic cyclo-P5 systems of the supramolecular host. The crystals of the obtained supramolecules consist of similar co-crystallized forms, in which different isomerism and porosity can occur. The mutual arrangement of the supramolecules in the crystals is essentially controlled by halogen–Cp* σ–π and Cp*–Cp* π–π stacking interactions. This allows to regard these interactions as the supramolecular synthons. Besides the expected structural motifs typical for close sphere packings, such superspheres form also unusual and low-dense packing motifs. [ABSTRACT FROM AUTHOR]

The packing interactions have been evaluated in the context of the self-assembly mechanism of crystal growth and also for its impacts on the aromaticity of the trimesate anion. The structure of ethylammonium trimesate hydrate (1) measured at 100 K and a charge density model, derived in part from theoretical structures, is reported. Theoretical structure factors were obtained from the geometry-optimized periodic wave function. The trimesic acid portion of 1 is fully deprotonated and participates in a variety hydrogen bonding motifs. Topological analysis of the charge density model reveals the most significant packing interactions and is then compared to a complementary analysis performed by the Hirshfeld surface method. The results presented herein demonstrate that in organic salt crystals the small structural motifs are most stable and once formed as stand-alone structures, may direct the self-assembly process. Moreover, when intermolecular interactions supported by the electrostatic forces are analyzed, the care must be taken with interpretation of the results of Hirshfeld surface analysis for organic salts crystals. [ABSTRACT FROM AUTHOR]

Crystal engineering approaches have been found to increase the possibility of discovering the new solid forms. Cocrystals are solids that are crystalline single-phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates/hydrates nor simple salts. Cocrystals may be binary, ternary and quaternary based on the number of components present and may be ionic or polymorphic in nature because of the presence of components (i.e. ions or polymorphs) in the crystalline structure. Cocrystals offer a unique advantage of preserving the pharmacological properties of the Active Pharmaceutical Ingredient (API), and strive to add the improved physicochemical properties of the coformers. The main challenging step during the design of pharmaceutical cocrystals is the screening of coformers which are suitable with the API. In the development process of cocrystal, one of the approaches for coformer selection is based on trial and error. Many researchers have used some theoretical and experimental approaches for the selection of effective coformers in crystal engineering, for the design of pharmaceutical cocrystals. This review article briefly explains various types of cocrystals reported in the literature and crystal design approaches (such as hydrogen bonding propensity, pKa Rule, Cambridge structure database (CSD), Fabian's method and Hansen solubility parameters, with examples) for the selection of coformers which may be more selective, time-efficient and cost-effective. [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]

The equimolar reaction mixture of isoelectronic picolinic acid N-oxide (PAHNO) and/or 3-hydroxy picolinic acid (3-HPAH) with guanyl hydrazine bicarbonate (AgunH.HCO 3) in aqueous medium at room temperature produce 1:1 salt. Irrespective of the molar ratios (1; 1, 1:2 & 2:1) and reaction conditions maintained, invariably gives the same product in the form of polycrystalline nature except 1:1 ratio which yields a single crystal. The isoelectronic salts were characterized by spectroscopic, PXRD, thermal study and single crystal X-ray diffraction techniques. In general, most of the salts were crystallized in a centric space group rather than a non-centric, the prevailing factors are nature of the organic species and reaction conditions like pH, pKa, solvent effects, temperature and molar ratio etc ,. Surprisingly, in the present case, the isoelectric salt of [AgunH]+[PANO]- crystalized in centric (P2 1 /n), where in case of [AgunH]+[3-HPA]- crystalized in non-centric (Pca2 1) space group even though in the same reaction conditions. This may be due to the presence of the 3rd position of hydroxyl group and non-covalent interactions in [AgunH]+[3-HPA]- that facilitate non-centric space group. Both salts are stabilized by the variety of hydrogen bond features leading to intra- and intermolecular N-H⋯O, N-H⋯N, and C-H⋯N hydrogen bonds and π-π stacking interactions along with homo- and hetero ring motifs [two R 2 2 (8), R 1 1 (6), and two R 2 2 (9)]. These interactions render them an appropriate acid-base ion pair for the formation of sturdy hydrogen-bonded supramolecular synthons. Thermal studies on these salts reveal that the thermal degradation occurs via melting followed by complete loss of organic species. The solid-state emission spectra of free acids and its salts were recorded and compared. The materials exhibit a prominent luminescent character towards red shift than the starting compounds. Further, these materials show enhanced secondary antioxidant and antimicrobial activities, this is due to the crucial role of hydrazine species in guanyl hydrazinium cation. The structure of starting compounds (free acids and base), detailed experimental procedure and reaction conditions are shown in Scheme. [Display omitted] • New isoelectronic salts of [AgunH]+[PANO]- (1) & [AgunH]+[3-HPA]- (2) were synthesized and investigated. • As synthesized compounds have been analyzed by various spectral characterizations including single crystal analysis. • To understand and compare the structural and thermal properties of these salts. • The antioxidant, antimicrobial and emission studies of the free acids, base and its salts were studied. [ABSTRACT FROM AUTHOR]

This article is a personal account of the author, who serendipitously entered the field of supramolecular gels nearly two decades ago. A supramolecular synthon approach in the context of crystal engineering was utilized to develop a working hypothesis to design supramolecular gelators derived from simple organic salts. The activity not only provided a way to occasionally predict gelation, but also afforded clear understanding of the structural landscape of such supramolecular materials. Without waiting for an ab initio approach for designing a gel, a large number of supramolecular gelators derived from organic salts were designed following the working hypothesis thus developed. Organic salts possess a number of advantages in terms of their ease of synthesis, purification, high yield and stability and, therefore, are suitable for developing materials for various applications. Organic salt-based gel materials for containing oil spills, synthesizing inorganic nanostructures and metal nanoparticles, sensing hazardous gas and dissolved glucose, adsorbing dyes, and facilitating drug delivery in self-delivery fashion have been developed. The journey through the soft world of gelators which was started merely by serendipity turned out to be rewarding, despite the challenges and frustrations in the field.

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. [ABSTRACT FROM AUTHOR]

Poor aqueous solubility and low oral bioavailability of an active pharmaceutical ingredient are the major constraints during the development of new product. Various approaches have been used for enhancement of solubility of poorly aqueous soluble drugs, but success of these approaches depends on physical and chemical nature of molecules being developed. Cocrystallization of drug substances offers a great opportunity for the development of new drug products with superior physicochemical such as melting point, tabletability, solubility, stability, bioavailability and permeability, while preserving the pharmacological properties of the active pharmaceutical ingredient. Cocrystals are multicomponent systems in which two components, an active pharmaceutical ingredient and a coformer were present in stoichiometric ratio and bonded together with non-covalent interactions in the crystal lattice. This review article presents a systematic overview of pharmaceutical cocrystals. Differences between cocrystals with salts, solvates and hydrates are summarized along with the advantages of cocrystals with examples. The theoretical parameters underlying the selection of coformers and screening of cocrystals have been summarized and different methods of cocrystal formation and evaluation have been explained. [ABSTRACT FROM AUTHOR]

Strong hydrogen bonds play a significant role in crystal packing. In particular, the involvement of interactions involving fluorine in controlling the crystal packing requires appropriate attention, especially in the presence of other strong hydrogen bonds. In the present study, a detailed quantitative assessment has been performed of the nature, energetics and topological properties derived from the electron density in model compounds based on fluorinated benzamides (a total of 46 fluorine-substituted benzamides containing multiple fluorine atoms) in the solid state. The primary motivation in the design of such molecules is to enhance the acidity of the interacting H atoms in the presence of an increasing number of F atoms on the molecular scaffold, resulting in increased propensity towards the formation of intermolecular interactions involving organic fluorine. This exercise has resulted in the identification of new and frequently occurring supramolecular synthons involving F atoms in the packing of molecules in the solid state. The energetics associated with short and directional intermolecular C sp2-H...F-C sp2 interactions with significantly high electrostatic contributions is noteworthy, and the topological analysis reveals the bonding character of these ubiquitous interactions in crystal packing in addition to the presence of C sp2-F...F-C sp2 contacts. [ABSTRACT FROM AUTHOR]