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The symmetries of a crystal are notoriously uncorrelated to those of its constituent molecules. This symmetry breaking is typically thought to occur during crystallization. Here we demonstrate that one of the two symmetry elements of olanzapine crystals, an inversion centre, emerges in solute dimers extant in solution prior to crystallization. We combine time-resolved in situ scanning probe microscopy to monitor the crystal growth processes with all-atom molecular dynamics simulations. We show that crystals grow non-classically, predominantly by incorporation of centrosymmetric dimers. The growth rate of crystal layers exhibits a quadratic dependence on the solute concentration, characteristic of the second-order kinetics of the incorporation of dimers, which exist in equilibrium with a majority of monomers. We show that growth by dimers is preferred due to overwhelming accumulation of adsorbed dimers on the crystal surface, where it is complemented by dimerization and expedites dimer incorporation into growth sites. Crystal symmetry is notoriously uncorrelated to the symmetry of the constituent molecules that make up a crystal. Symmetry breaking is typically thought to occur during nucleation and growth, but a symmetry element of olanzapine crystals—an inversion centre—has now been shown to emerge in centrosymmetric dimers extant in solution prior to crystallization.

Silk is now making inroads into advanced pharmaceutical and biomedical applications. Both bottom-up and top-down approaches can be applied to silk and the resulting aqueous silk solution can be processed into a range of material formats, including nanoparticles. Here, we demonstrate the potential of microfluidics for the continuous production of silk nanoparticles with tuned particle characteristics. Our microfluidic-based design ensured efficient mixing of different solvent phases at the nanoliter scale, in addition to controlling the solvent ratio and flow rates. The total flow rate and aqueous : solvent ratios were important parameters affecting yield (1 mL min���1 > 12 mL min���1). The ratios also affected size and stability; a solvent : aqueous total flow ratio of 5 : 1 efficiently generated spherical nanoparticles 110 and 215 nm in size that were stable in water and had a high beta-sheet content. These 110 and 215 nm silk nanoparticles were not cytotoxic (IC50 > 100 ��g mL���1) but showed size-dependent cellular trafficking. Overall, microfluidic-assisted silk nanoparticle manufacture is a promising platform that allows control of the silk nanoparticle properties by manipulation of the processing variables.

The co-crystalline structure of the non-steroidal, anti-inflammatory indomethacin with the non-toxic, Generally Regarded As Safe (GRAS) sweetener component saccharin was investigated up to 6.33 GPa using a Diamond Anvil Cell (DAC). Single crystal X-ray diffraction measurements show that the co-crystal remains in the same triclinic, P-1, phase throughout the compression with a significant reduction in void space (155.69 to 55.61Å3). Information on the response of different types of intermolecular interactions to external force at the same time is enabled by the use of a co-crystal. We have rationalised that the length and compression rate of the saccharin amide dimer in the co-crystal is caused by the dimer sitting in a ‘pocket’ surrounded by the indomethacin framework. This framework reduces the effects of molecular packing on the dimer allowing for an ideal hydrogen bonding geometry.

Bacterial biofilm infections incur massive costs on healthcare systems worldwide. Particularly worrisome are the infections associated with pressure ulcers and prosthetic, plastic, and reconstructive surgeries, where staphylococci are the major biofilm-forming pathogens. Non-leaching antimicrobial surfaces offer great promise for the design of bioactive coatings to be used in medical devices. However, the vast majority are cationic, which brings about undesirable toxicity. To circumvent this issue, we have developed antimicrobial nanocellulose films by direct functionalization of the surface with dehydroabietic acid derivatives. Our conceptually unique design generates non-leaching anionic surfaces that reduce the number of viable staphylococci in suspension, including drug-resistant Staphylococcus aureus, by an impressive 4-5 log units, upon contact. Moreover, the films clearly prevent bacterial colonization of the surface in a model mimicking the physiological environment in chronic wounds. Their activity is not hampered by high protein content, and they nurture fibroblast growth at the surface without causing significant hemolysis. In this work, we have generated nanocellulose films with indisputable antimicrobial activity demonstrated using state-of-the-art models that best depict an "in vivo scenario". Our approach is to use fully renewable polymers and find suitable alternatives to silver and cationic antimicrobials.

Oscillatory flow reactors (OFRs) are a new generation of tubular mixing and reaction equipment uniquely capable of combining continuous near plug flow with homogeneous particle suspension, yet the design of OFRs for liquid–solid and multi-phase flow processes relies on rules established during the past two decades from single, liquid-phase studies. A Design of Experiment (DoE) approach was herein implemented for establishing the relationship between four key geometrical parameters of the inner tube baffles and both the suspension of particles and the axial dispersion for liquid–solid continuous flows in 10 mm internal diameter (d) meso-scale tubes with periodic baffles. The parameters evaluated were the orifice open diameter, do = 0.35d–0.50d; the open cross section, α = 0.12d–0.25d, constriction spacing, l = 1.5d–3.0d, and baffle shape (sharp vs smooth edged). A total of ten tubes were tested, five consisting of smooth periodic constrictions (SPC) and the other five of sharp edged periodic constrictions (SEPC) according to a complete 2 × 2 factorial design with 1 central point. Each tube was experimentally evaluated via optical imaging of suspended monodispersed polyvinyl chloride (PVC) particles. Both SPC and SEPC meso-tubes were capable of delivering a near plug flow behaviour and the values of axial dispersion coefficient (Dc) estimated for the solids were in the range of 1.0–2.2 × 10−4 m2 s−1. In contrast, the minimum (critical) fluid oscillation conditions required for full suspension of particles varied significantly, in general with the SPC tubes requiring up to 50% lower amplitude for full particles suspension. Overall, α revealed the dominant parameter in controlling solids backmixing, and the inner tube geometry requiring the lowest energy input for homogenous particle suspension and minimum Dc (i.e. sharpest residence time distribution) presented a l/d = 3, do = 0.35d, α = 12% and SPC design. This study is believed to support the future design of optimised meso-scale OFR systems for continuous screening and manufacturing of value-added liquid–solid and multi-phase systems, such as catalytic and crystallisation processes.

A random forest model obtained from calculated physicochemical properties of solvents and observed crystallised structures of olanzapine has for the first time enabled the prediction of different types of 3-dimensional crystal packings of olanzapine solvates. A novel olanzapine solvate was obtained by targeted crystallization from the solvent identified by the random forest classification model. The model identified van der Waals volume, number of covalent bonds and polarisability of the solvent molecules as key contributors to the 3-D crystal packing type of the solvate.

A random forest model has for the first time enabled the prediction of the crystallisability (crystals vs. no crystals) of organic molecules with ∼70% accuracy. The predictive model is based on calculated molecular descriptors and published experimental crystallisation propensities of a library of substituted acylanilides.

Reported here is a rational approach for the selection of solvents intended for use in physical form screening based on a novel chemoinformatics analysis of solvent properties. A comprehensive assessment of eight clustering methods was carried out on a series of 94 solvents described by calculated molecular descriptors using the clusterSim package in R. The effectiveness of clustering methods was evaluated using a range of statistical measures as well as increasing efficiency of solid form discovery using a cluster-based solvent selection approach. Multidimensional scaling was used to illustrate cluster analysis on a two-dimensional solvent map. The map presented here is a valuable tool to aid efficient solvent selection in physical form screens. This tool is equally applicable to any scientific area which requires a solubility dependent decision on solvent choice.

A dataset consisting of structures and aqueous solubility and melting point data for 51 salt forms of the phenylethylamine base methylephedrine is presented. Analysis showed correlation between solubility and melting point and between melting point of the salt and melting point of the parent acid, but no correlation of salt solubility with solubility of the parent acid. Identification of associations was aided by examining chemically sensible subgroups of the dataset, and this approach highlighted significantly different relationships between solubility and melting point for these subgroups. Thus, for example, the expected negative correlation between solubility and melting point was found for 24 anhydrous benzoate salts, but a positive correlation observed for 8 halide salts. Hydrated forms were anomalous. Packing analysis identified groups of structures that were isostructural with respect to cation packing. Correlation between solubility and melting point was found to be greatest within these isostructural groups, implying a role for packing structure in determining solubility.

An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The crystal energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are respo...

Nine organotin fluorocarboxylates R n SnO 2 CR f (n = 3, R = Bu, R f = CF 3 , C 2 F 5 , C 3 F 7 , C 7 F 15 ; R = Et, R f = CF 3 , C 2 F 5 ; R = Me, R f = C 2 F 5 ; n = 2, R = Me, R f = CF 3 ) have been synthesized; key examples have been used to deposit fluorine-doped SnO 2 thin films by atmospheric pressure chemical vapour deposition. Et 3 SnO 2 CC 2 F 5 , in particular, gives high-quality films with fast deposition rates despite adopting a polymeric, carboxylate-bridged structure in the solid state, as determined by X-ray crystallography. Gas-phase electron diffraction on the model compound Me 3 SnO 2 CC 2 F 5 shows that accessible conformations do not allow contact between tin and fluorine, and that direct transfer is therefore unlikely to be part of the mechanism for fluorine incorporation in SnO 2 films. The structure of Me 2 Sn(O 2 CCF 3 ) 2 (H 2 O) has also been determined and adopts a trans-Me 2 SnO 3 coordination sphere about tin in which each carboxylate group is monodentate.

Isopropyl-thiazole ((iPr)Th) represents a new addition to the building blocks of nucleic acid minor groove-binding molecules. The DNA decamer duplex d(CGACTAGTCG)(2) is bound by a short lexitropsin of sequence formyl-PyPy(iPr)Th-Dp (where Py represents N-methyl pyrrole, (iPr)Th represents thiazole with an isopropyl group attached, and Dp represents dimethylaminopropyl). NMR data indicate ligand binding in the minor groove of DNA to the sequence 5'-ACT(5)AG(7)T-3' at a 2:1 ratio of ligand to DNA duplex. Ligand binding, assisted by the enhanced hydrophobicity of the (iPr)Th group, occurs in a head-to-tail fashion, the formyl headgroups being located toward the 5'-ends of the DNA sequence. Sequence reading is augmented through hydrogen bond formation between the exocyclic amine protons of G(7) and the (iPr)Th nitrogen, which lies on the minor groove floor. The B(I)/B(II) DNA backbone equilibrium is altered at the T(5) 3'-phosphate position to accommodate a B(II) configuration. The ligands bind in a staggered mode with respect to one another creating a six base pair DNA reading frame. The introduction of a new DNA sequence-reading element into the recognition jigsaw, combined with an extended reading frame for a small lexitropsin with enhanced hydrophobicity, holds great promise in the development of new, potentially commercially viable drug lead candidates for gene targeting.

Three novel crystalline solvates of the antiepileptic compound carbamazepine were obtained by targeted crystallisation from solvents identified by a Random Forest classification of solvent properties, experimental conditions and known crystallisation outcomes.

The sequence selectivity of small molecules binding to the minor groove of DNA can be predicted by "in silico footprinting". Any potential ligand can be docked in the minor groove and then moved along it using simple simulation techniques. By applying a simple scoring function to the trajectory after energy minimization, the preferred binding site can be identified. We show application to all known noncovalent binding modes, namely 1:1 ligand:DNA binding (including hairpin ligands) and 2:1 side-by-side binding, with various DNA base pair sequences and show excellent agreement with experimental results from X-ray crystallography, NMR, and gel-based footprinting.

Perfluoroalkytin compounds R((4-n))Sn(R-f)(n) (R = Me, Et, Bu, R-f = C4F9, n = 1; R = Bu, R-f = C4F9, n = 2, 3;R = Bu, R-f = C6F13, n = 1) have been synthesized, characterized by H-1, C-13, F-19 and Sn-119 NMR, and evaluated as precursors for the atmospheric pressure chemical vapour deposition of fluorine-doped SnO2 thin films. All precursors were sufficiently volatile in the range 84-136 degrees C and glass substrate temperatures of ca 550 degrees C to yield high-quality films with ca 0.79-2.02% fluorine incorporation, save for Bu3SnC6F13, which incorporated < 0.05% fluorine. Films were characterized by X-ray diffraction, scanning electron microscopy, thickness, haze, emissivity, and sheet resistance. The fastest growth rates and highest quality films were obtained from Et3SnC4F9. An electron diffraction study of Me3SnC4F9 revealed four conformations, of which only the two of lowest abundance showed close F center dot center dot center dot Sri contacts that could plausibly be associated with halogen transfer to tin, and in each case it was fluorine attached to either the gamma- or delta-carbon atoms of the R-f chain. Copyright (c) 2005 John Wiley P Sons, Ltd.

The nicotinamide (NA) mol-ecules of the title compound, 2C(6)H(6)N(2)O·C(2)H(3)F(3)O, form centrosymmetric R(2) (2)(8) hydrogen-bonded dimers via N-H⋯O contacts. The asymmetric unit contains two mol-ecules of NA and one trifluoroethanol molecule disordered over two sites of equal occupancy. The packing consists of alternating layers of nicotinamide dimers and disordered 2,2,2-trifluoro-ethanol mol-ecules stacking in the c-axis direction. Intra-molecular C-H⋯O and inter-molecular N-H⋯N, O-H⋯N, C-H⋯N, C-H⋯O and C-H⋯F inter-actions are present.

High-resolution STM imaging of the structures formed by carbamazepine molecules adsorbed onto a pseudo-ordered carbamazepine monolayer on Au(111) shows the formation of previously unreported 1-dimensional supramolecular assemblies.