Article:Nguyen, TTH, Hammond, RB, Roberts, KJ et al. (2 more authors) (2014) Precision measurement of the growth rate and mechanism of ibuprofen {001} and {011} as a function of crystallization environment. CrystEngComm, 16 (21). 4568 -4586. ISSN 1466-8033 https://doi.org/10.1039/c4ce00097h eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. acetonitrile. The crystal growth rates of the {001} and {011} faces of spontaneously nucleated crystals are precisely measured in-situ using optical microscopy revealing that their respective growth rates increase with increasing supersaturation to different extents, depending on the solvent type, with concomitant impact on the crystal habit. The measured aspect ratios, as a function of supersaturation, are generally higher at the 15 mL than the 0.5 mL scale size.Analysis of the growth rates versus supersaturation is consistent with a 2-D surface nucleation (Birth and Spread) model for both faces and at both scale sizes. The growth rates of the {001} and {011} faces exhibit much less growth rate dispersion when compared to literature data for a stirred batch crystallizer. 2The data is rationalized by examining the surface chemistry of the growing faces revealing, e.g. that polar protic solvents inhibit the growth rate of faces containing available binding sites for hydrogen bonding formation, such as carboxylic acid groups.

The key intermolecular (synthonic) interactions, crystal morphology and surface interfacial stability of the anti-inflammatory drug RS-ibuprofen are examined in relation to its bulk crystal and surface chemistry, and to rationalise its growth behaviour as a function of the crystallisation environment. The OH…O H-bonding dimers between adjacent carboxylic acid groups are calculated to be the strongest bulk (intrinsic) synthons, with other important synthons arising due to interactions between the less-polar phenyl ring and aliphatic chain. Morphological prediction, using the attachment energy model predicts a prismatic facetted shape, in good agreement with the shape of the experimentally grown crystals from the vapour phase. Crystals grown from solution are found to have higher aspect ratios, with t hose prepared in polar protic solvents (EtOH) producing less needle-like crystals, than those prepared in less polar and aprotic solvents (toluene, acetonitrile and ethyl acetate). Though the anisotropy factors of the {011} and {002} forms are relatively similar (39.5% and 43.4% respectively), examination of the surface chemistry reveals that the most important extrinsic (surface-terminated) synthons on the capping {011} surface involve H-bonding interactions, whilst those on the side {002} surfaces mostly involve van der Waal's (vdW) interactions. This suggests that a polar, protic solvent is more likely to bind to the capping {011} surface and inhibit growth of the long axis of the needle, compared to apolar and/or aprotic solvents. A previously unreported re-entrant face is found to appear in the external crystal morphology at higher supersaturations (in the range of = 0.66-0.79), not due to twinning, which is provisionally identified as being consistent with the {112} or {012} form. Analysis of the calculated surface entropy-factors suggest that the capping {011} faces would be expected to be least smooth on the molecular level, with a higher degree of unsaturated extrinsic synthons, in comparison to the

Crystallization of the active pharmaceutical ingredient Entacapone, which exhibits strong polymorphic behavior in aqueous/acetone solutions, is examined with and without the presence of a self-assembled molecular layer of Entacapone (SALE) on an Au (100) surface. SALE characterization by electrochemical and spectroscopic tools confirms the existence of a well-ordered layer structure. These surfaces are found to act as nucleation catalysts providing polymorph-specific templates which enable secondary nucleation through provision of oriented adsorption and molecular recognition at the SALE/solution interface. In particular, crystallization of the stable prismatic polymorphic form A is observed from aqueous/acetone solutions in the presence of an SALE compared to needle-shaped crystals of the metastable form D which usually form. The quiescent crystallization of Entacapone from the same aqueous/acetone solutions in the presence of an Au (100) surface produces an assembly of single crystals form A epitaxially grown at the surface with concomitantly form D being produced in the bulk solution confirming the surface-sensitive nature of the crystallization process. The research reveals the possibility of switching nucleation from uncontrolled nucleation sites toward a more directed crystallization process, and hence more stable polymorphic form, through the selective choice of adsorbed species. The future potential of this concept and methodology for larger scale size processes is discussed.

Sono-crystallisation has been used to enhance crystalline product quality particularly in terms of purity, particle size and size distribution. In this work, the effect of impurities and ultrasound on crystallisation processes (nucleation temperature, yield) and crystal properties (crystal size distribution determined by Focused Beam Reflectance Measurement (FBRM), crystal habit, filtration rate and impurity content in the crystal product by Liquid Chromatography-Mass Spectroscopy (LC-MS)) were investigated in bulk suspension crystallisation experiments with and without the use of ultrasound. The results demonstrate that ultrasonic intervention has a significant effect on both crystallisation and product crystal properties. It increases the nucleation rate resulting in smaller particles and a narrower Particle Size Distribution (PSD), the yield has been shown to be increase as has the product purity. The effect of ultrasound is to reduce the level acetanilide impurity incorporated during growth from a 2 mol% solution of the selected impurity from 0.85 mol% to 0.35 mol% and likewise ultrasound reduces the uptake of metacetamol from 1.88 mol% to 1.52 mol%.

SUMMARYNon-typhoidal Salmonella are an important but poorly characterized cause of paediatric diarrhoea in developing countries. We conducted a hospital-based case-control study in children aged <5 years in Ho Chi Minh City to define the epidemiology and examine risk factors associated with Salmonella diarrhoeal infections. From 1419 diarrhoea cases and 571 controls enrolled between 2009 and 2010, 77 (5·4%) diarrhoea cases were stool culture-positive for non-typhoidal Salmonella. Salmonella patients were more likely to be younger than controls (median age 10 and 12 months, respectively) [odds ratio (OR) 0·97; 95% confidence interval (CI) 0·94–0·99], to report a recent diarrhoeal contact (8·1% cases, 1·8% controls; OR 5·98, 95% CI 1·8–20·4) and to live in a household with >2 children (cases 20·8%, controls 10·2%; OR 2·32, 95% CI 1·2–4·7). Our findings indicate that Salmonella are an important cause of paediatric gastroenteritis in this setting and we suggest that transmission may occur through direct human contact in the home.