No abstract

The urea tape R-network of bifurcated N-H‚‚‚O hydrogen bonds is a common motif in diaryl ureas and their molecular complexes. We analyzed the X-ray crystal structures of N, N′-bis(3-pyridyl)urea 3 and some of its derivatives: hydrates of stoichiometry 3‚(4/3)H 2 O and 3‚2H 2 O, cocrystals 3‚SA and 3‚FA‚H 2 O with succinic acid and fumaric acid, bis pyridine N-oxide 8, and bis N-methylpyridinium iodide 9. Crystal packing in pyridyl urea structures is directed by N-H‚‚‚N pyridyl , N-H‚‚‚O water , N-H‚‚‚O acid , and N-H‚‚‚Ihydrogen bonds instead of the common one-dimensional N-H‚‚‚O urea tape. We postulated that the urea tape is absent in these structures because the CdO acceptor is weakened by two intramolecular C-H‚‚‚O urea interactions (synthon III) in a planar molecular conformation. Electrostatic surface potential (ESP) charges (DFT-B3LYP/6-31G*) showed that the C-H‚‚‚O interactions sufficiently reduce the electron density at the urea O, and so other electronegative atoms, such as pyridyl N, H 2 O, COOH, and I -, become viable hydrogen-bond acceptors for the strong NH donors. 1 H NMR difference nOe confirmed that the planar conformation of dipyridyl urea 3 in the solid-state persists in solution. Interestingly, even though the strong hydrogen-bond motifs changed in structures of 3, the C-H‚‚‚O interactions of synthon III (energy 4.6-5.0 kcal/mol) occurred throughout the family. In addition to dipyridyl urea, other electron-withdrawing diaryl ureas, e.g., those with phenylpyridyl and phenyl-nitrophenyl groups, also deviated from the prototype N-H‚‚‚O tape because of the interference from weak C-H‚‚‚O hydrogen bonds. Therefore, when one or both aryl rings have hydrogen-bond acceptor groups (e.g., pyridine, PhNO 2 ), the NH donor(s) preferentially bond to pyridyl N, nitro O, or solvent O atom instead of the urea CdO acceptor. We classify supramolecular organization in diaryl ureas into those with the R-network (twisted molecular conformation) or non-urea tape structures (stable, planar conformation) depending on the substituent group. Our results suggest a model to steer urea crystal structures toward the tape synthon (Ph and electrondonating groups) or with non-urea hydrogen-bond motifs and a high probability for urea‚‚‚solvent hydrogen bonding (electronwithdrawing groups) by appropriate selection of functional aryl and heterocyclic groups.

Cocrystals are long known yet recently applied molecular entities. In the past decade, a significant potential has been demonstrated by these novel solids in terms of modifying the physicochemical and pharmacokinetic properties of drugs. Thus far, publications have outlined various aspects of cocrystals at the molecular level concentrating on their design, growing techniques, and physicochemical characterizations. However, to take cocrystals from bench to bedside, they have to be incorporated into suitable formulations notwithstanding that the attention paid to cocrystal formulations is so diminutive. This is the first systematic review based exclusively on cocrystals formulation. In this contribution, the impact of cocrystals on essential pharmaceutical properties is glanced at before shining the spotlight on cocrystals formulation. The findings suggest that preformulation characteristics play a significant role, however, after which a number of approaches are desired in order to develop successful cocrystal formulations. It further highlights the main hurdles encountered with cocrystals formulation and other challenges to the transformation of cocrystals into viable medicines to have the full picture. There are marketed cocrystal products now, and it can be said it is only a matter of time before cocrystals are added to the main selection toolbox alongside salts for developing medicinal products.

The current contribution aims to prepare a family of nitrofurantoin (NF) co-crystals and to investigate the ability of these co-crystals in enhancing the photostability and clinically relevant physicochemical properties of NF. Accordingly, supramolecular synthesis of the antibiotic drug NF with the coformers 3-aminobenzoic acid (3ABA), 4-aminobenzoic acid (4ABA), urea, 4-hydroxybenzamide (4HBAM), phenazine (PHEN), melamine (MELA), 4,4′-bipyridine (BIPY) and 1,2-bis(4-pyridyl ethane) (BIPE) have produced five co-crystals and three co-crystal hydrates. Solid-state physical characterizations have been conducted by powder X-ray diffraction (PXRD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM) and spectroscopy (Raman and 1 H NMR). Crystal structures have been analyzed based on homo-and heterosynthons. Six out of eight multicomponent crystals are primarily stabilized by heterosynthons, whereas the remaining two co-crystals (NF-4ABA and NF-UREA) contain homosynthons. Notably, thermal analysis of co-crystal hydrates showed high thermal stability (∼166 °C, NF-MELA-H 2 O) or upon dehydration provided new anhydrous co-crystals, NF-BIPY and NF-BIPE in a 2:1 molar ratio. Physicochemical properties such as aqueous solubility, intrinsic dissolution rate and photostability have been investigated for NF-3ABA, NF-4ABA, NF-UREA and NF-4HBAM. Co-crystals display enhanced physicochemical properties as compared to that of NF: NF-4HBAM > NF-3ABA > NF-4ABA > NF-UREA > NF (β-form). The results suggest that co-crystals can be a viable alternative for improving the biopharmaceutical properties of API.

No abstract

Analysis of phenyl-perfluorophenyl stacking synthon, C-H...F, C-F...pi interactions, and F...F tetramer in three closely related azine crystal structures shows the dominance of Ar-ArF synthon while other interactions are turned on/off depending on the H/F stoichiometry in the molecule.

The supramolecular synthon approach to crystal structure prediction (CSP) takes into account the complexities inherent in crystallization. The synthon is a kinetically favored unit, and through analysis of commonly occurring synthons in a group of related compounds, kinetic factors are implicitly invoked. The working assumption is that while the experimental structure need not be at the global minimum, it will appear somewhere in a list of computationally generated structures so that it can be suitably identified and ranked upward using synthon information. These ideas are illustrated with a set of aminophenols, or aminols. In the first stage, a training database is created of the 10 isomeric methylaminophenols. The crystal structures of these compounds were determined. The prototypes 2-, 3-, and 4-aminophenols were also included in the training database. Small and large synthons in these 13 crystal structures were then identified. Small synthons are of high topological but low geometrical value and are used in negative screens to eliminate computationally derived structures that are chemically unreasonable. Large synthons are more restrictive geometrically and are used in positive screens ranking upward predicted structures that contain these more well-defined patterns. In the second stage, these screens are applied to CSP of nine new aminols carried out in 14 space groups. In each space group, up to 10 lowest energy structures were analyzed with respect to their synthon content. The results are encouraging, and the predictions were classified as good, unclear, or bad. Two predictions were verified with actual crystal structure determinations.

The crystal structures and packing features of a family of 13 aminophenols, or supraminols, are analyzed and correlated. These compounds are divided into three groups: (a) compounds 1-5 with methylene spacers of the general type HO-C6H4-(CH2)n-C6H4-NH2 (n = 1 to 5) and both OH and NH2 in a para position; (b) compounds 1a, 2a, 2b, 2c, and 3a in which one or more of the methylene linkers in 1 to 3 are exchanged with an S-atom; and (c) compounds 2d, 1b, and 6a prepared with considerations of crystal engineering and where the crystal structures may be anticipated on the basis of structures 1-5,1a, 2a, 2b, 2c, and 3a. These 13 aminols can be described in terms of three major supramolecular synthons based on hydrogen bonding between OH and NH2 groups: the tetrameric loop or square motif, the infinite N(H)O chain, and the beta-As sheet. These three synthons are not completely independent of each other but interrelate, with the structures tending toward the more stable beta-As sheet in some cases. Compounds 1-5 show an alternation in melting points, and compounds with n = even exhibit systematically higher melting points compared to those with n = odd. The alternating melting points are reflected in, and explained by, the alternation in the crystal structures. The n = odd structures tend toward the beta-As sheet as n increases and can be considered as a variable series whereas for n = even, the beta-As sheet is invariably formed constituting a fixed series. Substitution of a methylene group by an isosteric S-atom may causes a change in the crystal structure. These observations are rationalized in terms of geometrical and chemical effects of the functional groups. This study shows that even for compounds with complex crystal structures the packing may be reasonably anticipated provided a sufficient number of examples are available.