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

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

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

Impact of Structural Binding Energies on Dissolution Rates for Single Faceted-Crystals

This study investigates the effect of solid-state intermolecular binding energies on the dissolution rates of single faceted-crystals. The nonsteroidal anti-inflammatory drug ibuprofen is employed in a 95% v/v ethanol:water solution as a model system for single-crystal dissolution experiments in a dissolution cell at undersaturation ranging from 1.36% to 8.67%. In vitro dissolution of the ibuprofen crystals is quantified by capturing images during the dissolution process at fixed time intervals using a camera mounted on an inverted optical microscope. The regression rate of crystal faces with time is measured by an image analysis. VisualHabit software is used for a prediction of the crystal morphology and to characterize the intermolecular binding energies in the solid-state structure of the ibuprofen crystals to predict relative, face-specific dissolution rates. The relative face-specific dissolution rates of ibuprofen crystal calculated based on binding energies suggest that the face (011) dissolves faster than face (002). The experimental results on face-specific dissolution rates of single ibuprofen crystals reveal that the dissolution rates of faces (011) and (002) change nonlinearly as a function of undersaturation. The binding energy model is critically evaluated for performance as confronted with the experimental measurements. The binding energy model suggests a pathway to understand dissolution at the microscopic level and to design a crystal morphology for regulating bioavailability optimally during dissolution processes

Molecular Dynamics Simulation of the Salinity Effect on the n-Decane/Water/Vapor Interfacial Equilibrium

Low-salinity water flooding of formation water in rock cores is, potentially, a promising technique for enhanced oil recovery (EOR), but details of the underlying mechanisms remain unclear. The salinity effect on the interface between water and oil was investigated here using the molecular dynamics (MD) simulation method. n-Decane was selected as a representative oil component, and SPC/E water and all-atom optimized potentials for liquid simulations (OPLS-AA) force fields were used to describe the water/oil/ionic interactions for saltwater and n-decane molecules. Equilibrium MD simulations were first conducted to study the n-decane/vapor and saltwater/vapor interface systems at six different NaCl concentrations (0, 0.05, 0.10, 0.20, 0.50, and 1.00 M). The water/oil interface was then investigated by calculating bulk density distribution, radial distribution function, interface thickness, and water/oil interfacial tension (IFT). Sufficiently long MD simulations of water/n-decane/vapor were performed, followed by an analysis of the effect of salinity on the water/oil/vapor interface. The IFT values for the water/vacuum interface, n-decane/vacuum interface, and water/n-decane interface were obtained from the pressure tensor distribution after system equilibration, with values of 71.4, 20.5, and 65.3 mN/m, respectively, which agree well with experimental and numerical results reported in the literature. An optimal salinity of ∼0.20 M was identified corresponding to a maximum interfacial thickness between water and the oil phase, which results in a minimum water/oil IFT value and a maximum value for the oil/water contact angle, a condition beneficial for EOR

Comparison of m-mode echocardiographic left ventricular mass measured using digital and strip chart readings: The Atherosclerosis Risk in Communities (ARIC) study

BACKGROUND: Epidemiological and clinical studies frequently use echocardiography to measure LV wall thicknesses and chamber dimension for estimating quantitative measures of LV mass. While echocardiographic M-mode LV images have traditionally been measured using hand-held calipers and strip-chart paper tracings, digitized M-mode LV image measurements made directly on the computer screen using electronic calipers have become standard practice. We sought to determine if systematic differences in LV mass occur between the two methods by comparing LV mass measured from simultaneous M-mode strip chart recordings and digitized recordings. METHODS: The Atherosclerosis Risk in Communities study applied the latter method. To determine if systematic differences in LV mass occur between the two methods, LV mass was measured from simultaneous M-mode strip chart recordings and digitized recordings. RESULTS: We found no difference in LV mass (p > .25) and a strong correlation in LV mass between the two methods (r = 0.97). Neither age, sex, nor hypertension status affected the correlation of LV mass between the two methods. CONCLUSIONS: We conclude that digital estimates of LV mass provide unbiased estimates comparable to the strip-chart method

"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

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

Reading, Trauma and Literary Caregiving 1914-1918: Helen Mary Gaskell and the War Library

This article is about the relationship between reading, trauma and responsive literary caregiving in Britain during the First World War. Its analysis of two little-known documents describing the history of the War Library, begun by Helen Mary Gaskell in 1914, exposes a gap in the scholarship of war-time reading; generates a new narrative of "how," "when," and "why" books went to war; and foregrounds gender in its analysis of the historiography. The Library of Congress's T. W. Koch discovered Gaskell's ground-breaking work in 1917 and reported its successes to the American Library Association. The British Times also covered Gaskell's library, yet researchers working on reading during the war have routinely neglected her distinct model and method, skewing the research base on war-time reading and its association with trauma and caregiving. In the article's second half, a literary case study of a popular war novel demonstrates the extent of the "bitter cry for books." The success of Gaskell's intervention is examined alongside H. G. Wells's representation of textual healing. Reading is shown to offer sick, traumatized and recovering combatants emotional and psychological caregiving in ways that she could not always have predicted and that are not visible in the literary/historical record