Introductory lecture: Mechanochemistry, a versatile synthesis strategy for new materials.

Mechanochemistry deals with reactions induced by the input of mechanical energy - for example by impacts within a vibratory ball mill. The technique has a long history with significant contributions from Ostwald, Carey Lea and, notably, Faraday. Mechanochemistry has subsequently seen application in a variety of areas of materials science including mechanical alloying in metallurgy, the synthesis of complex organic molecules and, more recently, the discovery and development of new solid forms of active pharmaceutical ingredients. This paper overviews the broad areas of application of mechanochemistry, some key features which make it a particularly attractive approach to materials synthesis and some mechanistic aspects highlighted within the literature. A significant part, however, will focus on recent applications in the area of pharmaceuticals and its important role in exploring the rich variety of solid forms available for small, drug-like, molecules.This is the final version. It was first published by RSC at http://pubs.rsc.org/en/Content/ArticleLanding/2014/FD/C4FD00162A#!divAbstrac

Highly unusual triangular crystals of theophylline: The influence of solvent on the growth rates of polar crystal faces

A noteworthy feature of the compound theophylline is that it forms crystals with a triangular habit, an extremely rare phenomenon for an organic molecule. Here, we investigate the formation of these crystals, comprised of the polymorph Form II (Pna21), and demonstrate that the triangles are obtained from solvents which are highly hydrophobic, or which have a hydrogen bond acceptor group and no hydrogen bond donor group. The formation of the triangular crystal habit is rationalized on the basis of the way such solvents interact with the inequivalent (001) and (00-1) polar crystal faces of Form II. Interactions are significantly stronger at one face than the other, inhibiting growth in one direction and limiting crystal growth to a single, triangle shaped, growth sector. This rationalization also enabled interesting surface features observed by atomic force microscopy to be interpreted. Furthermore, we report a second, previously unreported, type of triangular crystal of theophylline for which the angle at the tip of the triangle is obtuse rather than acute. These crystals are proposed, with the aid of transmission electron microscopy and crystal structure prediction, to be a new polymorphic form of theophyllin

Investigation of an amide-pseudo amide hydrogen bonding motif within a series of theophylline:amide cocrystals

The pharmaceutically active compound theophylline (T) was cocrystallised with the amides formamide (1), acetamide (2), N-methylformamide (3), N,N-dimethylformamide (4), benzamide (5) and pyrazinamide (6), with systems T:1, T:5 and T:6 displaying polymorphic behaviour. The cocrystals with formamide (T:1), acetamide (T:2) and benzamide (T:5), and one polymorph of the cocrystal with pyrazinamide (T:6-I), contain an R22(9) hydrogen bonding motif between the amide cocrystal formers and the HN-C-C=O moiety of the theophylline molecule (an amide-pseudo amide synthon). This motif was, however, absent from the other polymorph of the pyrazinamide cocrystal (T:6-II), and also from the N-methylformamide cocrystal (T:3) (and is not possible in the N,N-dimethylformamide cocrystal (T:4)). These observations are rationalised using hydrogen bond propensity calculations, although limitations of using such calculations for predicting cocrystallisation are noted. The amide-pseudo amide synthon is favoured when theophylline cocrystallises with both primary amides and with secondary amides which are locked in a cis configuration. On heating, all cocrystals were found to dissociate before melting due to loss of the amide, making stability to dissociation a more meaningful measure of cocrystal stability than melting point for these systems. On dissociation of the cocrystals, theophylline typically crystallises as the commonly observed polymorph Form II. In the case of the acetamide cocrystal (T:2), however, the rarely observed metastable polymorph, Form V, crystallises concomitantly with Form II suggesting that cocrystal dissociation on heating could be a strategy for generating novel polymorphic forms of compounds

Rationalization of the color properties of fluorescein in the solid state: a combined computational and experimental study

Fluorescein is known to exist in three tautomeric forms defined as quinoid, zwitterionic and lactoid. In the solid state, the quinoid and zwitterionic forms give rise to red and yellow materials respectively. The lactoid form has not been crystallized pure, although its cocrystal and solvate forms exhibit colors ranging from yellow to green. An explanation for the observed colors of the crystals is found using a combination of UV/Vis spectroscopy and plane-wave DFT calculations. In addition, the role of cocrystal coformers in modifying crystal color is established. Several new crystal structures are determined using a combination of X-ray and electron diffraction, solid-state NMR and crystal structure prediction (CSP). The protocol presented herein may be used to predict color properties of materials prior to their synthesis.M.A. thanks EPSRC for a PhD studentship. M.D.E. acknowledges support from the Interreg V “2 Mers Seas Zeeën” cross-border cooperation program. D.G.R. acknowledges financial support from the MRC. D.K.B. acknowledges University College London for an UCL Excellence Fellowship. A.J.M. acknowledges the support from the Winton Program for the Physics of Sustainability. G.M.D. thanks the Royal Society for funding. This work was performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/), provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England and funding from the Science and Technology Facilities Council.This is the final version of the article. It first appeared from Wiley via https://doi.org/ 10.1002/chem.20160134

The Plot Thickens: Gelation by Phenylalanine in Water and Dimethyl Sulfoxide

Phenylalanine (Phe) is an amino acid of great interest as coupling of an aromatic group with a chiral hydrophilic region imparts a number of unique properties. Recently there has been an increased interest in the crystalline and gel forms of this compound, part as a result of the complex and undetermined structures of the resulting materials and the relationship of the solid forms of Phe with the disease phenylketonuria. In this report, we highlight the relationship between gelation, crystallization, and the dynamics of self-assembly processes of Phe. We do this by describing the gelation of the amino acid, the gel to crystal relationship, crystal structure predictions for this relatively simple compound, and the dynamics of assembly as determined by NMR in both water and dimethyl sulfoxide. This will provide guidance to future research into Phe assemblies, possible treatments for phenylketonuria, and diseases related to formation of amyloid-like fibers

Nanocomposites of TiO₂/cyanoethylated cellulose with ultra high dielectric constants.

A novel dielectric nanocomposite containing a high permittivity polymer, cyanoethylated cellulose (CRS) and TiO2 nanoparticles was successfully prepared with different weight percentages (10%, 20% and 30%) of TiO2. The intermolecular interactions and morphology within the polymer nanocomposites were analysed. TiO2/CRS nanofilms on SiO2/Si wafers were used to form metal-insulator-metal type capacitors. Capacitances and loss factors in the frequency range of 1 kHz-1 MHz were measured. At 1 kHz CRS-TiO2 nanocomposites exhibited ultra high dielectric constants of 118, 176 and 207 for nanocomposites with 10%, 20% and 30% weight of TiO2 respectively, significantly higher than reported values of pure CRS (21), TiO2 (41) and other dielectric polymer-TiO2 nanocomposite films. Furthermore, all three CRS-TiO2 nanocomposites show a loss factor <0.3 at 1 kHz and low leakage current densities (10(-6)-10(-7) A cm(-2)). Leakage was studied using conductive atomic force microscopy and it was observed that the leakage is associated with TiO2 nanoparticles embedded in the CRS polymer matrix. A new class of ultra high dielectric constant hybrids using nanoscale inorganic dielectrics dispersed in a high permittivity polymer suitable for energy management applications is reported.This work was supported by Dyson Ltd. NM is also grateful to the Cambridge Commonwealth Trust for financial support and Prof. William Jones, Department of Chemistry, University of Cambridge for providing additional laboratory facilities

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART) : a multicentre, prospective, randomised, open-label, blinded-endpoint trial

Funding Information: ISM reports research grants from Menarini, EMA, Sanofi, Health Data Research UK, the British Heart Foundation, and Innovative Medicines Initiative; institutional consultancy income from AstraZeneca outside the submitted work; and personal income from AstraZeneca and Amgen outside the submitted work. TMM reports grants from Menarini/Ipsen/Teijin and Merck Sharp & Dohme outside the submitted work, and personal income for consultancy from Novartis and AstraZeneca outside the submitted work, and is a trustee of the Scottish Heart Arterial Risk Prevention Society. AGB reports personal income from Novartis, Mylan, AstraZeneca, Bayer, Daiichi-Sankyo, Boehringer, Pfizer, Galderma, Zambon, and Novo-Nordisk outside the submitted work. ADS and the University of Dundee hold a European patent for the use of xanthine oxidase inhibitors in treating chest pain in angina pectoris. AW declares personal income for consultancy from AbbVie, Akcea, Albireo, Alexion, Allergan, Amarin, Apsara, Arena, Astellas, AstraZeneca, Autolus, Bayer, Biocryst, Biogen, Biomarin, Bristol Myers Squibb, Boehringer Ingelheim, Calico, Celgene, Chiesi, Daiichi Sankyo, Diurnal, Elsai, Eli Lilly, Ferring, Galapagos, Gedeon Richter, Gilead, GlaxoSmithKline, GW Pharma, Idorsia, Incyte, Intercept, Ionis, Ipsen, Janssen, Jazz, Jcyte, Kite Gilead, LEK, Leo Pharma, Les Laboratoires Servier, Lundbeck, Merck (Merck Sharp & Dohme), Merck-Serono, Mitenyi, Mundibiopharma, Mustang Bio, Mylan, Myovant, Norgine, Novartis, Novo Nordisk, Orchard, Paion, Pfizer, Pierre Fabre, PTC, RegenXBio, Rhythm, Sanofi, Santen, Sarepta, SeaGen, Shionogi, Sigmatec, SOBI, Takeda, Tanaya, UCB, and Vertex outside the submitted work. JST declares research funding from the UK National Institute for Health and Care Research (NIHR) and NHS England outside the submitted work and membership of a UK National Institute for Health and Care Excellence guideline committee on management of atrial fibrillation. All other authors declare no competing interests. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licensePeer reviewedPublisher PD

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research

Gastrointestinal decontamination in the acutely poisoned patient

ObjectiveTo define the role of gastrointestinal (GI) decontamination of the poisoned patient.Data sourcesA computer-based PubMed/MEDLINE search of the literature on GI decontamination in the poisoned patient with cross referencing of sources.Study selection and data extractionClinical, animal and in vitro studies were reviewed for clinical relevance to GI decontamination of the poisoned patient.Data synthesisThe literature suggests that previously, widely used, aggressive approaches including the use of ipecac syrup, gastric lavage, and cathartics are now rarely recommended. Whole bowel irrigation is still often recommended for slow-release drugs, metals, and patients who "pack" or "stuff" foreign bodies filled with drugs of abuse, but with little quality data to support it. Activated charcoal (AC), single or multiple doses, was also a previous mainstay of GI decontamination, but the utility of AC is now recognized to be limited and more time dependent than previously practiced. These recommendations have resulted in several treatment guidelines that are mostly based on retrospective analysis, animal studies or small case series, and rarely based on randomized clinical trials.ConclusionsThe current literature supports limited use of GI decontamination of the poisoned patient