Examination of inequivalent wetting on the crystal habit surfaces of RS-ibuprofen using grid-based molecular modelling

Synthonic engineering tools, including grid-based searching molecular modelling, are applied to investigate the wetting interactions of the solute and four crystallisation solvents (ethanol, ethyl acetate, acetonitrile and toluene) with the {100}, {001} and {011} forms of RS-ibuprofen. The grid-based methods, in particular the construction of a crystal slab parallel to a given plane in a coordinate system with one axis perpendicular to the surface, are defined in detail. The interaction strengths and nature (dispersive, hydrogen bonding (H-bonding) or coulombic forces) are related to the crystal growth rates and morphologies. The solute is found to interact strongest with the capping {011}, then the side {001} and weakest with the top {100} habit surfaces. The solute interactions with the {100} and {001} surfaces are found to be almost solely dominated by dispersive force contributions, whilst the same with the {011} surfaces are found to have a greater contribution from H-bonding and coulombic forces. The increased surface rugosity, at the molecular level of the {011} surfaces, results in a favourable docking site in a surface 'valley', not present in the {100} and {001} surfaces. The H-bonding solvents ethanol, acetonitrile and ethyl acetate are found to strongly interact with the {011} surfaces and weakly with the {001} surfaces, with the {011} interactions having a much greater contribution from H-bonding and coulombic forces. The interaction energies of the apolar and aprotic solvent toluene, with the {011} and {001} surfaces, are found to be very close. Toluene is found having slightly stronger interactions with the {001} than the {011} surfaces, which are all dominated by dispersive interactions. The ratio of the average energy of the top 100 solvent interactions with the {001} surface divided by the average energy of the top 100 interactions with the {011} surface is compared to the ratio of the experimentally measured growth rates of the same forms. In general, the interaction energy ratio is found to have an inverse ratio with the growth rates, implying that the solvents which are calculated to interact strongly with a particular surface are impeding the growth of that surface and reducing the growth rate, in turn impacting upon the final morphology of the material

The integrated DL_POLY/DL_FIELD/DL_ANALYSER software platform for molecular dynamics simulations for exploration of the synthonic interactions in saturated benzoic acid/hexane solutions

Three separately developed software Molecular Dynamics packages at Daresbury Laboratory, namely DL_FIELD (DL_F), DL_POLY and DL_ANALYSER, have been integrated to form an efficient computational infrastructure to investigate the detailed solution chemistry of saturated benzoic acid in hexane solutions. These software capabilities are demonstrated, in combination with the Synthonic Engineering tools and density functional theory (DFT) calculations, to assess the extent that the solute-solute intermolecular synthonic interactions in solution mirrors the synthons in the crystal structure. The results show that the majority of the COOH groups are forming OH … O H-bonds, which are a combination of classic OH … O homo-dimers and three membered H-bonding clusters. The formation of pi-pi stacking interactions is observed, but in far fewer numbers than observed for the OH … O interactions. The DFT simulations of the IR spectra of the multiple benzoic acid aggregates extracted from the MD trajectories provides further in-depth analysis of previously published IR data, by matching simulated peaks to the experimental peaks, hence identifying the exact bonding modes that are responsible for such peaks. This study demonstrates the value of a multi-scale and multi-technique approach to exploring the molecular transition pathway from solution to crystal structure

A Digital Workflow Supporting the Selection of Solvents for Optimizing the Crystallizability of p-Aminobenzoic Acid

We present a grid-based molecular modeling approach and software application for screening the solute–solvent and solute–solute interactions of organic molecules. This tool can provide a deeper understanding of solubilization of organic molecules, intended to guide scientists to intuitive conclusions about whether a solute/solvent pair may provide desired physical properties, such as crystallizability, solubility, and crystal polymorphism. This study focused on solutions of p-aminobenzoic acid in acetonitrile, ethanol, and water. Acetonitrile molecules are found to form the weakest interactions with the solute molecule, although they also form weak interactions with themselves. In contrast, water forms strong interactions with the solute molecule, with a strong preference to interact with the carboxylic acid group, although they also form strong self-interactions. Ethanol forms strong interactions with all of the solute molecules, along with reasonably strong interactions with itself. The looser solvation of the carboxylic acid group by acetonitrile is thought to drive the crystallization of the α polymorph, by lowering the crystallization kinetic energy barrier. In ethanol, the strong interactions of the solvent are thought to contribute to significant undercooling of ethanolic solutions observed in previous studies. Water’s strong interactions with the carboxylic acid of the solute may drive the self-assembly of the α-form by interactions of the phenyl groups and also contribute to the nucleation of the β-form from this solvent. This workflow can provide valuable guidance on the solvation properties of organic molecules and clusters, producing low-energy solvation shells of molecules and clusters to be utilized as starting points for more sophisticated simulations, such as molecular dynamics

Monitoring the Growth of an Orthotopic Tumour Xenograft Model: Multi-Modal Imaging Assessment with Benchtop MRI (1T), High-Field MRI (9.4T), Ultrasound and Bioluminescence

BACKGROUND: Research using orthotopic and transgenic models of cancer requires imaging methods to non-invasively quantify tumour burden. As the choice of appropriate imaging modality is wide-ranging, this study aimed to compare low-field (1T) magnetic resonance imaging (MRI), a novel and relatively low-cost system, against established preclinical techniques: bioluminescence imaging (BLI), ultrasound imaging (US), and high-field (9.4T) MRI. METHODS: A model of colorectal metastasis to the liver was established in eight mice, which were imaged with each modality over four weeks post-implantation. Tumour burden was assessed from manually segmented regions. RESULTS: All four imaging systems provided sufficient contrast to detect tumours in all of the mice after two weeks. No significant difference was detected between tumour doubling times estimated by low-field MRI, ultrasound imaging or high-field MRI. A strong correlation was measured between high-field MRI estimates of tumour burden and all the other modalities (p < 0.001, Pearson). CONCLUSION: These results suggest that both low-field MRI and ultrasound imaging are accurate modalities for characterising the growth of preclinical tumour models

Conformational and structural stability of the single molecule and hydrogen bonded clusters of para aminobenzoic acid in the gas and solution phases

The crystallographic structures of the α- and β- polymorphic forms of para aminobenzoic acid are deconstructed into their constituent hydrogen bonding molecular structural building blocks of monomers, dimers, tetramers and octamers, where they are analysed using ab initio quantum mechanical calculations of their conformation and cluster stability in solution. The molecular conformation found in the β-form is less stable than the same found in the α-form for both the gas and solution phases, suggesting that this causes a slight increase in the barrier to the crystallisation of the β-form in comparison to the α-form. The solution populations of the self-associated OH⋯O H-bonding ‘classic carboxylic acid dimer’, present in the α- and not the β-structure, is calculated to dominate in acetonitrile, dimethyl sulfoxide, ethanol, ethyl acetate, methanol, nitromethane and water. It is observed that this classic dimer is least stable in water, compared to the other PABA crystallisation solvents, with the OH⋯N H-bonding interaction present in the β-form being the second most stable dimeric interaction. These results are discussed in terms of the crystallisability and polymorphic behaviour of the α and β forms of PABA from the afore mentioned crystallisation solvents, whilst detailing how this approach could be reproducible for a range of polymorphic crystalline materials

Virtuality in human supervisory control: Assessing the effects of psychological and social remoteness

Virtuality would seem to offer certain advantages for human supervisory control. First, it could provide a physical analogue of the 'real world' environment. Second, it does not require control room engineers to be in the same place as each other. In order to investigate these issues, a low-fidelity simulation of an energy distribution network was developed. The main aims of the research were to assess some of the psychological concerns associated with virtual environments. First, it may result in the social isolation of the people, and it may have dramatic effects upon the nature of the work. Second, a direct physical correspondence with the 'real world' may not best support human supervisory control activities. Experimental teams were asked to control an energy distribution network. Measures of team performance, group identity and core job characteristics were taken. In general terms, the results showed that teams working in the same location performed better than team who were remote from one another

"Particle Informatics": Advancing Our Understanding of Particle Properties through Digital Design

We introduce a combination of existing and novel approaches to the assessment and prediction of particle properties intrinsic to the formulation and manufacture of pharmaceuticals. Naturally following on from established solid form informatics methods, we return to the drug lamotrigine, re-evaluating its context in the Cambridge Structural Database (CSD). We then apply predictive digital design tools built around the CSD-System suite of software, including Synthonic Engineering methods that focus on intermolecular interaction energies, to analyze and understand important particle properties and their effects on several key stages of pharmaceutical manufacturing. We present a new, robust workflow that brings these approaches together to build on the knowledge gained from each step and explain how this knowledge can be combined to provide resolutions at decision points encountered during formulation design and manufacturing processes

Parenting in a warming world: thermoregulatory responses to heat stress in an endangered seabird

This is the final version. Available on open access from Oxford University Press via the DOI in this recordThe frequency of extreme weather events, including heat waves, is increasing with climate change. The thermoregulatory demands resulting from hotter weather can have catastrophic impacts on animals, leading to mass mortalities. Although less dramatic, animals also experience physiological costs below, but approaching, critical temperature thresholds. These costs may be particularly constraining during reproduction, when parents must balance thermoregulation against breeding activities. Such challenges should be acute among seabirds, which often nest in locations exposed to high solar radiation and predation risk. The globally endangered bank cormorant Phalacrocorax neglectus breeds in southern Africa in the winter, giving little scope for poleward or phenological shifts in the face of increasing temperatures. Physiological studies of endangered species sensitive to human disturbance, like the bank cormorant, are challenging, because individuals cannot be captured for experimental research. Using a novel, non-invasive, videographic approach, we investigated the thermoregulatory responses of this seabird across a range of environmental temperatures at three nesting colonies. The time birds spent gular fluttering, a behaviour enhancing evaporative heat loss, increased with temperature. Crouching or standing birds spent considerably less time gular fluttering than birds sitting on nests (ca 30% less at 22°C), showing that postural adjustments mediate exposure to heat stress and enhance water conservation. Crouching or standing, however, increases the vulnerability of eggs and chicks to suboptimal temperatures and/or expose nest contents to predation, suggesting that parents may trade-off thermoregulatory demands against offspring survival. We modelled thermoregulatory responses under future climate scenarios and found that nest-bound bank cormorants will gular flutter almost continuously for several hours a day by 2100. The associated increase in water loss may lead to dehydration, forcing birds to prioritize survival over breeding, a trade-off that would ultimately deteriorate the conservation status of this species.National Research FoundationDST-NRF Centre of Excellence fund at the FitzPatrick Institute of African OrnithologyLeiden Conservation Foundatio

3D Characterisation of Dry Powder Inhaler Formulations: Developing X-ray Micro Computed Tomography Approaches.

Carrier-based dry powder inhaler (DPI) formulations need to be accurately characterised for their particle size distributions, surface roughnesses, fines contents and flow properties. Understanding the micro-structure of the powder formulation is crucial, yet current characterisation methods give incomplete information. Commonly used techniques like laser diffraction (LD) and optical microscopy (OM) are limited due to the assumption of sphericity and can give variable results depending on particle orientation and dispersion. The aim of this work was to develop new powder analytical techniques using X-ray computed tomography (XCT) that could be employed for non-destructive metrology of inhaled formulations. α-lactose monohydrate powders with different characteristics have been analysed, and their size and shape (sphericity/aspect ratio) distributions compared with results from LD and OM. The three techniques were shown to produce comparable size distributions, while the different shape distributions from XCT and OM highlight the difference between 2D and 3D imaging. The effect of micro-structure on flowability was also analysed through 3D measurements of void volume and tap density. This study has demonstrated for the first time that XCT provides an invaluable, non-destructive and analytical approach to obtain number- and volume-based particle size distributions of DPI formulations in 3D space, and for unique 3D characterisation of powder micro-structure