Collisional depolarization of NO(A) by He and Ar studied by quantum beat spectroscopy

Zeeman and hyperfine quantum beat spectroscopies have been used to measure the total elastic plus inelastic angular momentum depolarization rate constants at 300 K for NO (A 2 σ+) in the presence of He and Ar. In the case of Zeeman quantum beats it is shown how the applied magnetic field can be used to allow measurement of depolarization rates for both angular momentum orientation and alignment. For the systems studied here, collisional loss of alignment is more efficient than loss of orientation. In the case of NO (A) with He, and to a lesser extent NO (A) with Ar, collisional depolarization is found to be a relatively minor process compared to rotational energy transfer, reflecting the very weak long-range forces in these systems. Detailed comparisons are made with quantum mechanical and quasiclassical trajectory calculations performed on recently developed potential energy surfaces. For both systems, the agreement between the calculated depolarization cross sections and the present measurements is found to be very good, suggesting that it is reasonable to consider the NO (A) bond as frozen during these angular momentum transferring collisions. A combination of kinematic effects and differences in the potential energy surfaces are shown to be responsible for the differences observed in depolarization cross section with He and Ar as a collider. © 2009 American Institute of Physics

Assessing the Spurious Impacts of Ice-Constraining Methods on the Climate Response to Sea-Ice Loss using an Idealised Aquaplanet GCM

Coupled climate model simulations designed to isolate the effects of Arctic sea-ice loss often apply artificial heating, either directly to the ice or through modification of the surface albedo, to constrain sea ice in the absence of other forcings. Recent work has shown that this approach may lead to an overestimation of the climate response to sea-ice loss. In this study, we assess the spurious impacts of ice-constraining methods on the climate of an idealised aquaplanet general circulation model (GCM) with thermodynamic sea ice. The true effect of sea-ice loss in this model is isolated by inducing ice loss through reduction of the freezing point of water, which does not require additional energy input. We compare results from freezing point modification experiments with experiments where sea-ice loss is induced using traditional ice-constraining methods, and confirm the result of previous work that traditional methods induce spurious additional warming. Furthermore, additional warming leads to an overestimation of the circulation response to sea-ice loss, which involves a weakening of the zonal wind and storm track activity in midlatitudes. Our results suggest that coupled model simulations with constrained sea ice should be treated with caution, especially in boreal summer, where the true effect of sea-ice loss is weakest but we find the largest spurious response. Given that our results may be sensitive to the simplicity of the model we use, we suggest that devising methods to quantify the spurious effects of ice-constraining methods in more sophisticated models should be an urgent priority for future work

Activation and Deactivation of a Robust Immobilized Cp*Ir-Transfer Hydrogenation Catalyst: A Multielement in Situ X-ray Absorption Spectroscopy Study

A highly robust immobilized [Cp*IrCl2]2 precatalyst on Wang resin for transfer hydrogenation, which can be recycled up to 30 times, was studied using a novel combination of X-ray absorption spectroscopy (XAS) at Ir L3-edge, Cl K-edge, and K K-edge. These culminate in in situ XAS experiments that link structural changes of the Ir complex with its catalytic activity and its deactivation. Mercury poisoning and “hot filtration” experiments ruled out leached Ir as the active catalyst. Spectroscopic evidence indicates the exchange of one chloride ligand with an alkoxide to generate the active precatalyst. The exchange of the second chloride ligand, however, leads to a potassium alkoxide–iridate species as the deactivated form of this immobilized catalyst. These findings could be widely applicable to the many homogeneous transfer hydrogenation catalysts with Cp*IrCl substructure

Gene Expression Profiling in Tibial Muscular Dystrophy Reveals Unfolded Protein Response and Altered Autophagy

Peer reviewe

The essential synergy of MD simulation and NMR in understanding amorphous drug forms

Molecular dynamics (MD) simulations and chemical shifts from machine learning are used to predict 15N, 13C and 1H chemical shifts for the amorphous form of the drug irbesartan. The molecules are observed to be highly dynamic well below the glass transition, and averaging over this dynamics is essential to understanding the observed NMR shifts. Predicted linewidths are consistently about 2 ppm narrower than observed experimentally, which is hypothesised to result from susceptibility effects. Previously observed differences in the 13C shifts associated with the two tetrazole tautomers can be rationalised in terms of differing conformational dynamics associated with the presence of intramolecular interaction in one tautomer. 1H shifts associated with hydrogen bonding can also be rationalised in terms of differing average frequencies of transient hydrogen bonding interactions

Designing lenalidomide cocrystals with an extended-release profile for improved pulmonary drug delivery †

Lenalidomide is a poorly soluble immunomodulatory drug that has been the subject of several cocrystal studies aiming to improve oral bioavailability by enhancing solubility. In contrast, for application in pulmonary fibrosis, reduced solubility may extend the retention time and reduce potential side effects of inhalable formulations. In this article, we present a proof-of-principle study on a low-solubility cocrystal of lenalidomide and melamine. The structure of the hydrated cocrystal was determined by single crystal X-ray diffraction and revealed a 3-dimensional hydrogen-bonding network between lenalidomide, melamine and channel-included solvent. The cocrystal has a lower maximum solubility than pure lenalidomide, making it more suitable for inhalable formulation approaches. A preliminary study shows that the cocrystal can be micronized with lactose as a model excipient with particle sizes in the appropriate order of magnitude for use in an inhalable formulation

Developing Multi-Component Solid Formulation Strategies for PROTAC Dissolution Enhancement.

PROTACs are an emerging class of beyond-rule-of-5 molecular drugs currently under clinical investigation for the treatment of malignant diseases and are capable of degrading previously "undruggable" protein targets. They are poorly crystallizable due to their structure, consisting of two ligands joined chemically by a flexible linker, yet the inherent insolubility of their amorphous phases hinders their development into sufficiently bioavailable medicines. Formulation approaches to improve the dissolution properties of PROTACs are required as a result, but research in this area is made even more challenging by the scarcity of available samples. In this work, amorphous solid dispersion (ASD) formulations of four cereblon-recruiting PROTACs 'AZ1-4' using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a polymer excipient are described. ASDs of AZ1 show up to a 2-fold increase in drug supersaturation compared to the pure amorphous API, observed up to a drug loading of 20% w/w. Preparing the ASDs by slurry conversion offers greater solubility enhancement over those prepared by solvent evaporation and maintains the dissolution advantage up to a higher drug load. Positive deviations from theoretical values coupled with a lack of spectral evidence of drug-polymer hydrogen-bond interactions suggest that the ASDs may differ from ideal mixtures via predominantly dispersive drug-polymer interactions. ASDs that provide a dissolution enhancement were stored at elevated temperature and humidity for one month and showed no sign of plasticization or loss of physical stability. Coamorphous formulations using low-molecular-weight excipients, by contrast, showed no dissolution advantage despite evidence of drug-coformer hydrogen-bonding interactions. This work demonstrates that ASDs may be an effective strategy for improving PROTAC bioavailability and producing commercializable solid forms for oral administration despite the lack of well-behaved solid phases of PROTACs. It also highlights the need for a deeper understanding of how to develop successful formulation approaches for bRo5 compounds

Nonmimetic Gels Direct Novel Crystallization Behavior of Lenalidomide

Crystallization within supramolecular gels can yield distinct solid-state outcomes compared with conventional solution-phase methods, including the formation of novel crystal forms or selectively crystallizing one crystal form from a concomitant mixture. In several cases, tailoring the molecular structure of a gelator to mimic a pharmaceutical substrate has facilitated crystallization control, where nonmimetic gelators had no influence on the crystallization outcome compared to the solution phase. In this study, we investigate the crystallization behavior of lenalidomide within both mimetic and nonmimetic gels. Crystallization in a cyclopentanone gel using a nonmimetic gelator led to the discovery of a novel cyclopentanone hemisolvate, inaccessible via solution-phase crystallization. Additionally, an ethanol gel of the same gelator promoted selective crystallization of metastable Form 4 in ethanol, in contrast to the thermodynamically favored Form 1 obtained from solution. Gel-phase crystallization using a drug-mimetic gelator produced no deviation from the solution-phase polymorphic outcomes, in contrast to previously reported examples. Solution-state NMR studies showed no evidence of strong interactions between lenalidomide and either gelator, suggesting that the spatial arrangement of the nonmimetic gel fibers and/or possible confinement effects, rather than solution association, plays a critical role in directing crystallization behavior

Crystallizing the Uncrystallizable: Insights from Extensive Screening of PROTACs

PROTACs are new drug molecules in the beyond Rule of Five (bRo5) chemical space with extremely poor aqueous solubility and intrinsically poor crystallizability due to their structure, which comprises two distinct ligands covalently linked by a flexible linker. This makes PROTACs particularly challenging to understand from a solid-state preformulation perspective. While several X-ray structures have been reported of PROTACs in ternary complexes, to date no structures have been published of single component densely packed PROTACs, from which an understanding of PROTACs’ intermolecular interactions, and therefore physical properties, can be developed. An extensive crystallization protocol was applied to grow single crystals of a cereblon-recruiting PROTAC “AZ1” resulting in structures of an anhydrous form and a nonstoichiometric p-xylene solvate using 3D electron diffraction and synchrotron X-ray crystallography, respectively. The lattice energies are dominated by dispersive interactions between AZ1 molecules despite the presence of multiple hydrogen-bond donors and acceptors and planar aromatic groups, and both structures are built on similar intermolecular interactions. Thermal and spectral characterization revealed another solvate form containing dichloromethane. Amorphous solids produced by mechanochemical grinding of anhydrous AZ1 crystals also differed in dissolution characteristics from an amorphous solid produced by desolvating the dichloromethane solvate crystals, indicating that AZ1 may demonstrate pseudo-polyamorphism. This study paves the way for solid form screening and understanding in pharmaceutical systems that are far bRo5

Genome Sequencing and Comparative Transcriptomics of the Model Entomopathogenic Fungi Metarhizium anisopliae and M. acridum

Metarhizium spp. are being used as environmentally friendly alternatives to chemical insecticides, as model systems for studying insect-fungus interactions, and as a resource of genes for biotechnology. We present a comparative analysis of the genome sequences of the broad-spectrum insect pathogen Metarhizium anisopliae and the acridid-specific M. acridum. Whole-genome analyses indicate that the genome structures of these two species are highly syntenic and suggest that the genus Metarhizium evolved from plant endophytes or pathogens. Both M. anisopliae and M. acridum have a strikingly larger proportion of genes encoding secreted proteins than other fungi, while ∼30% of these have no functionally characterized homologs, suggesting hitherto unsuspected interactions between fungal pathogens and insects. The analysis of transposase genes provided evidence of repeat-induced point mutations occurring in M. acridum but not in M. anisopliae. With the help of pathogen-host interaction gene database, ∼16% of Metarhizium genes were identified that are similar to experimentally verified genes involved in pathogenicity in other fungi, particularly plant pathogens. However, relative to M. acridum, M. anisopliae has evolved with many expanded gene families of proteases, chitinases, cytochrome P450s, polyketide synthases, and nonribosomal peptide synthetases for cuticle-degradation, detoxification, and toxin biosynthesis that may facilitate its ability to adapt to heterogenous environments. Transcriptional analysis of both fungi during early infection processes provided further insights into the genes and pathways involved in infectivity and specificity. Of particular note, M. acridum transcribed distinct G-protein coupled receptors on cuticles from locusts (the natural hosts) and cockroaches, whereas M. anisopliae transcribed the same receptor on both hosts. This study will facilitate the identification of virulence genes and the development of improved biocontrol strains with customized properties