Liquid-assisted grinding (LAG) is a commonly used mechanochemical procedure, especially for polymorphic conversions. However, it is not understood what effect liquid additives actually have in driving mechanochemical polymorphic conversions, precluding our ability to control solid form transformations under mechanochemical conditions. We here present a time-resolved in situ (TRIS) synchrotron powder X-ray diffraction (PXRD) monitoring strategy that can track, with few-nanometer resolution, the evolution of crystallite size under liquid-assisted ball milling conditions. We apply this method to investigate the influence of liquid additives on the polymorphic conversion of the 1:1 cocrystal of theophylline and benzamide, with particular focus on the role that crystallite size plays in driving ball milling-induced polymorphic transformations. We found that the crystallite sizes achieved by ball milling are highly sensitive to the amount of liquid added to the reaction mixture. Liquid additives generally lead to larger crystallite sizes as compared with the neat grinding (NG) protocol, with our findings indicating that crystallite size reduction is not the main factor that causes polymorph conversion under liquid-assisted grinding conditions. The data presented clearly suggest the presence of an induction period before phase transformation begins with a minimum value in the crystallite size of the starting polymorph, marking the end of that induction period.

γ-Ba_3 CoNb_2 O_9 realizes a disordered simple-cubic spin-1/2 lattice in which Co^2+ ions randomly occupy one third of the sites, placing the system close to the site-percolation threshold for magnetic order. Specific-heat, susceptibility, neutron spin-echo, and muon spin-rotation measurements reveal a broad thermodynamic crossover, short-range magnetic correlations, and persistent fast spin dynamics down to at least 0.1 K, with no evidence for static order or conventional spin-glass freezing. Monte Carlo simulations yield a broad distribution of orphan spins, finite clusters, and an infinite network. The calculated orphan-spin fraction (≈ 8.8%) agrees well with the weakly correlated spin fraction inferred from magnetization (≈ 8.2%). Exact diagonalization of a diluted S = 1/2 Heisenberg model captures the broad magnetic specific-heat anomaly and supports the coexistence of weakly and strongly correlated spin environments. These results support a picture in which spin-1/2 quantum fluctuations, together with dilution and proximity to the percolation threshold, can support a disorder-driven dynamical state with short-range correlations in three dimensions, distinct from both classical spin glasses and geometrically frustrated quantum spin liquids.

We present the first known example of single crystal X-ray diffraction of small molecule crystals in a flow crystallisation environment via serial crystallography. Towards radiation damage mitigation, high-throughput screening and kinetic studies.

Layered crystal structures are commonly found across organic and inorganic material systems. When in-plane atomic arrangement remains (nearly) identical, a stacking variation of these layers may result in twinning, planar disorder, or polytypes, a form of polymorphism derived from altering stacking sequences. In this work, we use multi-dimensional electron diffraction (ED) modalities to explore the microstructure of xanthine, an archetypal purine base with a layered crystal structure. Firstly, we identify and characterise the twin operator relating domains of Form I xanthine. We then solve the structure of a new xanthine polymorph, revealing that it is a polytype of Form I. Finally, interfaces between twin and polytype domains are visualised, whilst streaking in the diffraction patterns reveals the presence of planar disorder. Given these observations in the xanthine system, this work suggests that disorder on the nanoscale may be a commonly occurring phenomenon in layered organic molecular crystals.

Three-dimensional (3D) electron diffraction (3D-ED) techniques can be used for structure determination, circumventing challenges posed to conventional and bulk X-ray diffraction techniques such as submicrometer-sized crystals, the strong effects of texture, the presence of defects, and polyphasic samples. Such challenges previously prevented the structure solution of xanthine, a purine base chemically similar to guanine that may also be found in organisms. In this work, we use 3D-ED to elucidate the crystal structure of xanthine. The electron diffraction data obtained from a single microcrystal is also of sufficient quality to determine hydrogen positions, confirming the presence of the 7H-tautomer, as expected. This study highlights the potential for the use of 3D-ED on biogenic nanocrystals, for example opening opportunities to understand the links between crystal anisotropy, birefringence, and organism characteristics.

Background There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder. Methods This is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18–65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles. Discussion This trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine. Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12622000235707). Registered on February 9, 2022.

Objective: To compare the effects of consuming food-based versus supplement-based very low-energy diet (VLED) programs on gut microbiome composition in women with a high body mass index (BMI). Design: An investigator-initiated, single-blind, two-arm, parallel-group randomised controlled-feeding trial with computer-generated 1:1 randomisation. From May 2021 to February 2022, women aged 30-65 years with BMI 30-45 kg/m2 were recruited from southwest Victoria, Australia, and randomised to a three-week food-based or supplement-based VLED program. The primary outcome was between-group differential change in faecal microbiome alpha diversity (Shannon index) from baseline to week three, assessed using shotgun metagenomics. Outcome assessors, study investigators, and analysing statisticians were blinded to group allocation until analysis completion. Allocation concealment was managed by an independent researcher using a computer software system. Modified intention-to-treat (mITT) analyses using linear mixed-effects regression models estimated mean between-group differential changes, reported as beta-coefficient point estimates (β) and 95% confidence intervals (95%CI), adjusted for multiple comparisons. Results: Forty-seven participants were randomised (food-based: n=23, supplement-based: n=24). Of the 45 participants analysed, there was a between-group differential change in the Shannon index (mITT β: 0.37, 95%CI: 0.15 to 0.60) from baseline to week three, with a greater increase in the food-based group (mean change: 0.26, 95%CI: 0.09 to 0.44; n=23) versus supplement-based group (mean change: -0.10, 95%CI: -0.25 to 0.05; n=22). There were 27 non-serious adverse events (food-based: 8, supplement-based: 19), all non-serious. Conclusion: A food-based VLED, with more whole food components and fewer highly processed industrial ingredients, increases gut microbiome diversity more than a supplement-based VLED. ### Competing Interest Statement MML is Secretary for the Melbourne Branch Committee of the Nutrition Society of Australia (unpaid) and has received travel funding support from the International Society for Nutritional Psychiatry Research, the Nutrition Society of Australia, the Australasian Society of Lifestyle Medicine, and the Gut Brain Congress. AJM is immediate past Secretary for the International Society for Nutritional Psychiatry Research (unpaid) and is funded through the NHMRC supported CREDIT CRE, the Centre for Research Excellence for the Development of Innovative Therapies. MB is supported by a NHMRC Senior Principal Research Fellowship (1156072). MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier - all unrelated to this work. AL has received grant, research or travel support from Deakin University, The University of Melbourne, RMIT University, National Health and Medical Research Council, Australian Academy of Science, The Jack Brockhoff Foundation, Epilepsy Foundation of Australia, American Epilepsy Society and has received speakers' honoraria from European Space Agency, Swisse Australia - all unrelated to this work. AL is a named inventor on a patent relating to Prevotella. MM has received Grant/research support from the NHMRC, Deakin University School of Medicine, Deakin Biostatistics Unit, Institute for Mental and Physical Health and Clinical Translation, Stroke Foundation and Medibank Health Research Fund. WM is currently funded by an NHMRC Investigator Grant (#2008971). WM has previously received funding from the Cancer Council Queensland and university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University. WM has received funding and/or has attended events funded by Cobram Estate Pty. Ltd and Bega Dairy and Drinks Pty Ltd. WM has received travel funding from Nutrition Society of Australia. WM has received consultancy funding from Nutrition Research Australia and ParachuteBH. WM has received speakers honoraria from VitaFoods, The Cancer Council Queensland and the Princess Alexandra Research Foundation. FNJ has received: competitive Grant/Research support from the Brain and Behaviour Research Institute, the National Health and Medical Research Council (NHMRC), Australian Rotary Health, the Geelong Medical Research Foundation, the Ian Potter Foundation, The University of Melbourne; industry support for research from Meat and Livestock Australia, Woolworths Limited, the A2 Milk Company, Be Fit Food; philanthropic support from the Fernwood Foundation, Wilson Foundation, the JTM Foundation, the Serp Hills Foundation, the Roberts Family Foundation, the Waterloo Foundation and; travel support and speakers honoraria from Sanofi-Synthelabo, Janssen Cilag, Servier, Pfizer, Network Nutrition, Angelini Farmaceutica, Eli Lilly and Metagenics. FNJ has written two books for commercial publication. She is on the Scientific Advisory Board of the Dauten Family Centre for Bipolar Treatment Innovation and Zoe Limited. She is currently supported by an NHMRC Investigator Grant L1 (#1194982). The Food & Mood Centre has received Grant/Research support from the a2 Milk Company, Be Fit Food, Meat and Livestock Australia, and Woolworths Limited, and philanthropic support from the Fernwood Foundation, Wilson Foundation, the JTM Foundation, the Serp Hills Foundation, the Roberts Family Foundation, and the Waterloo Foundation. AO receives funding support from the National Health and Medical Research Council (#2009295). ### Clinical Trial ACTRN12620000301965 ### Funding Statement Aspects of this study (biochemical analyses) were funded by Be Fit Food. Investigational products were provided by Be Fit Food as in-kind support. The study was supported and sponsored by Deakin University. Both the study funders and sponsors were independent of the study design and oversight, had no role in study design, in the collection, analysis, and interpretation of data, in the writing of the report, and/or in the decision to submit the paper for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This trial received ethical approval from the Barwon Health (19/112) and Deakin University (2018/211) Human Research Ethics Committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes To access additional data from this study, the code and raw data can be found on GitHub and NCBI Sequence Read Archive, respectively. For further assistance or inquiries, please contact the corresponding author.

3D electron diffraction (3DED) is increasingly employed to determine molecular and crystal structures from micro-crystals. Indomethacin is a well known, marketed, small-molecule non-steroidal anti-inflammatory drug with eight known polymorphic forms, of which four structures have been elucidated to date. Using 3DED, we determined the structure of a new ninth polymorph, σ, found within an amorphous solid dispersion, a product formulation sometimes used for active pharmaceutical ingredients with poor aqueous solubility. Subsequently, we found that σ indomethacin can be produced from direct solvent evaporation using dichloromethane. These results demonstrate the relevance of 3DED within drug development to directly probe product formulations.

The switching behavior of the novel hybrid material (FA)Na[Fe(CN) 5 (NO)].H 2 O ( 1 ) in response to temperature ( T ), light irradiation and electric field ( E ) is studied using in situ X-ray diffraction (XRD). Crystals of 1 display piezoelectricity, pyroelectricity, second and third harmonic generation. XRD shows that the FA + are disordered at room-temperature, but stepwise cooling from 273–100 K induces gradual ordering, while cooling under an applied field ( E =+40 kVcm −1 ) induces a sudden phase change at 140 K. Structural-dynamics calculations suggest the field pushes the system into a region of the structural potential-energy surface that is otherwise inaccessible, demonstrating that application of T and E offers an effective route to manipulating the crystal chemistry of these materials. Photocrystallography also reveals photoinduced linkage isomerism, which coexists with but is not correlated to other switching behaviors. These experiments highlight a new approach to in situ studies of hybrid materials, providing insight into the structure–property relationships that underpin their functionality.

Abstract The effects of post-hydration heating over a broad range of temperatures are evident in many Mighei-like carbonaceous (CM) chondrites as a variety of mineral transitions. To better understand these processes and how a CM chondrite’s starting composition may have affected them, we experimentally heated two meteorites with different degrees of aqueous alteration, Allan Hills 83100 and Murchison, at 25 °C temperature steps from 200 °C to 950 °C and 300 °C to 750 °C, respectively. During heating, synchrotron in situ X-ray diffraction patterns were collected. With the exception of calcite decomposition and its products, most mineral transitions were unaffected by starting composition. Key observations include: (1) partial decomposition of tochilinite at 200 °C, which indicates that tochilinite breakdown might be a two-stage process due to its intergrown layers of brucite/amakinite and mackinawite; (2) the breakdown of serpentine occurring at 300 °C with transitional phases appearing at 525 °C and 575–600 °C, while secondary olivine formed at 600 °C; (3) cronstedtite decomposing faster than lizardite, (4) the formation of secondary enstatite at 750 °C, and (5) calcite decomposition temperature differing significantly between meteorites, occurring at 725 °C and 575 °C in ALH 83100 and Murchison, respectively. The results for calcite are likely controlled by differences in its microstructure and chemical composition, related to the meteorite’s impact history and degree of aqueous alteration. The difference in calcite decomposition temperature also explains the contrasts in the observed breakdown products, with clinopyroxene occurring in both meteorites, and oldhamite only in ALH 83100. Mineral transitions due to post-hydration heating have been characterized with a high resolution XRD method, enabling a better understanding of processes occurring on the parent asteroids of CM chondrites. Graphical Abstract

Ferroelectric materials, those that have a switchable spontaneous polarisation, have mainly been comprised of solely inorganic containing entities.Introducing organic components would likely introduce an increase in flexibility in the materials, with this a favourable property to obtain due to the cracking that can occur in ferroelectrics.

We present a charge density study of two linkage isomer photoswitches, [Pd(Bu4dien)(NO2)]BPh4·THF (1) and [Ni(Et4dien)(NO2)2] (2) using Hirshfeld Atom Refinement (HAR) methods implemented via the NoSpherA2 interface in Olex2. HAR is used to explore the electron density distribution in the photoswitchable molecules of 1 and 2, to gain an in-depth understanding of key bonding features and their influence on the single-crystal-to-single-crystal reaction. HAR analysis is also combined with ab initio calculations to explore the non-covalent interactions that influence physical properties of the photoswitches, such as the stability of the excited state nitrito-(η1-ONO) isomer. This insight can be fed back into the crystal engineering process to develop new and improved photoswitches that can be optimised towards specific applications.

Noncovalent interactions are essential in the formation and properties of a diverse range of materials. However, reliably identifying noncovalent interactions remains challenging using conventional methods such as X-ray diffraction, especially in nanocrystalline, poorly crystalline or amorphous materials which lack long-range lattice periodicity. Here, we demonstrate the accurate determination of deviations in the local structure and tilting of aromatic rings during the temperature-induced first order structural transition in the 1 : 1 adduct of 4,4 '-bipyridinium squarate (BIPY:SQA) from the low temperature form HAZFAP01 to high temperature HAZFAP07 by X-ray pair distribution function. This work demonstrates how pair distribution function analyses can improve our understanding of local structural deviations resulting from noncovalent bonds and guide the development of novel functional materials.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The visualization of chemical processes that occur in the solid-state is key to the design of new functional materials. One of the challenges in these studies is to monitor the processes across a range of timescales in real-time. Here, we present a pump-multiprobe single-crystal X-ray diffraction (SCXRD) technique for studying photoexcited solid-state species with millisecond-to-minute lifetimes. We excite using pulsed LEDs and synchronise to a gated X-ray detector to collect 3D structures with sub-second time resolution while maximising photo-conversion and minimising beam damage. Our implementation provides complete control of the pump-multiprobe sequencing and can access a range of timescales using the same setup. Using LEDs allows variation of the intensity and pulse width and ensures uniform illumination of the crystal, spreading the energy load in time and space. We demonstrate our method by studying the variable-temperature kinetics of photo-activated linkage isomerism in [Pd(Bu 4 dien)(NO 2 )][BPh 4 ] single-crystals. We further show that our method extends to following indicative Bragg reflections with a continuous readout Timepix3 detector chip. Our approach is applicable to a range of physical and biological processes that occur on millisecond and slower timescales, which cannot be studied using existing techniques.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

It is important to be able to identify the precise position of H-atoms in hydrogen bonding interactions to fully understand the effects on the structure and properties of organic crystals. Using a combination of near-edge X-ray absorption fine structure (NEXAFS) spectroscopy and density functional theory (DFT) quantum chemistry calculations, we demonstrate the sensitivity of core-level X-ray spectroscopy to the precise H-atom position within a donor-proton-acceptor system. Exploiting this sensitivity, we then combine the predictive power of DFT with the experimental NEXAFS, confirming the H-atom position identified using single-crystal X-ray diffraction (XRD) techniques more easily than using other H-atom sensitive techniques, such as neutron diffraction. This proof of principle experiment confirms the H-atom positions in structures obtained from XRD, providing evidence for the potential use of NEXAFS as a more accurate and easier method of locating H-atoms within organic crystals.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.