William Jones

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Crystal engineering has advanced the strategies for design and synthesis of organic solids with the main focus being on customising the properties of the materials. Research in this area has a significant impact on large-scale manufacturing, as industrial processes may lead to the deterioration of such properties due to stress-induced transformatio...

Two new solvates of the widely used anthelminthic Praziquantel (PZQ) were obtained through mechanochemical screening with different liquid additives. Specifically, 2-pyrrolidone and acetic acid gave solvates with 1:1 stoichiometry (PZQ-AA and PZQ-2P, respectively). A wide-ranging characterization of the new solid forms was carried out by means of p...

This paper reports on the solution growth of carbamazepine dihydrate and discusses the relative development of the {h00} and {0k0} faces as a function of the crystallization conditions. While the overall shape of the obtained crystals remains lathlike, it is shown that from ethanol/water mixtures and at high water content (91 mol %) the dominant fa...

Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list o...

The inability to obtain a crystal form that has previously been reliably prepared is an important concern for industrial solid-state scientists. In the present study, we extend further the evidence that such a phenomenon also applies to cocrystals. Specifically, we report further on the apparent “disappearing polymorphs” of a cocrystal composed of...

Theophylline:2-pyrrolidone mono (1:1) and sesqui (2:3) solvates have been discovered through variable-amount liquid-assisted grinding (VALAG). The structures and stability of the solvates and the kinetics involved in their formation are investigated both experimentally and theoretically. Ex-situ studies reveal a delayed appearance of the sesquisolv...

Pharmaceutical salt-solvates (DMSO) of the drug triamterene (1) with the coformers (a) acetic, (b) succinic, (c) adipic, (d) pimelic, (e) azelaic, (f) nicotinic acid and (g) ibuprofen are prepared by liquid assisted grinding (LAG) and solvent evaporative crystallization (SEC). The modified ∆pKa rule as proposed by Cruz-Cabeza is in close agreement...

Pharmaceutical salt solvates (dimethyl sulfoxide, DMSO) of the drug triamterene with the coformers acetic, succinic, adipic, pimelic, azelaic and nicotinic acid and ibuprofen are prepared by liquid-assisted grinding and solvent-evaporative crystallization. The modified Delta pKa rule as proposed by Cruz-Cabeza [(2012). CrystEngComm, 14, 6362–6365]...

Chemical reactivity in the solid state is an important topic with regards to the exploitation of organic solids. The relatively immobile nature of the molecules in a crystal can lead to highly selective conversions and be exploited in the area of chemical synthesis. It can also, using crystal engineering methods, be used to provide chemical stabili...

Mechanochemistry has a long history and has recently undergone a surge in interest in many areas from metallurgy to chemical synthesis. It is frequently seen as a Green Chemistry approach since in many instances the volumes of solvent typically used (e.g. in synthetic organic chemistry) can be significantly reduced. The chapter reviews in particula...

Abstract: This study has demonstrated the use of crystallography, topology and graph set analysis in the description and classification of the complex hydrogen bonded network of triamterene. The aim is to give a brief overview of the methodology used to discuss the crystal structure of triamterene with a view to extending the study to include the s...

Within the pharmaceutical industry, and elsewhere, the screening for new solid forms is a mandatory exercise for both existing and new chemical entities. This contribution focuses on mechanochemistry as a versatile approach for discovering new and alternative solid forms. Whilst a series of recently published extensive reviews exist which focus on...

Nanoindentation and atomic force microscopy (AFM) are two surface techniques used to study mechanical and surface properties of solids. One area where these two approaches are not widely employed, however, is the discrimination of polymorphs, for which methods such as single crystal XRD, PXRD, spectroscopy, DSC and ss-NMR are more commonly used. Th...

Identifying as many polymorphs as possible for a molecular compound is important in the design of materials with desired properties. In this paper we demonstrate, using a simple experimental procedure, how the amount of liquid present during liquid-assisted mechanochemical reactions can be used to rapidly explore polymorph diversity. Through detail...

MKC and DKB gratefully acknowledge financial support from the UCL Faculty of Mathematical and Physical Sciences. DKB and WJ thank the Royal Society for a Newton International Fellowship and the Isaac Newton Trust (Trinity College, University of Cambridge) for funding. MA thanks the EPSRC for a studentship, while SAS acknowledges funding through the...

A series of theophylline cocrystals involving fluorobenzoic acids was prepared and structurally characterised. The cocrystals display compositions and hydrogen-bond patterns that could not be predicted based on extensive literature/database surveys and the use of other tools. The study demonstrates that – without the use of first-principles crystal...

This chapter gives an overview of defects that may be present even when a crystal diffracts perfectly. It describes crystal defects more fully in terms of their nature and their potential physical and chemical consequences. Structural imperfections can be classified into three general types based on their geometry: point, line, and planar. The cons...

The importance of understanding the solid-state behavior of pharmaceutical compounds and formulations is universally recognized. This chapter introduces the main techniques that are used for studying crystal defects, and summarizes the range of information that these techniques can be expected to yield. It also outlines possible limitations of thes...

Despite the great interest that cocrystals are currently gaining for their application to the design of new supramolecular structures with desired functional properties, studies concerning new experimental strategies capable of controlling polymorphism phenomenon of a given system are scarcely reported. We propose herein the use of polymer-assisted...

The pharmaceutically active compound theophylline (T) was cocrystallized 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 behavior. The cocrystals with formamide (T:1), acetamide (T:2), and benzamide (T:5), and o...

Four new crystalline adducts of the Lawsone molecule (2-hydroxy-1,4-naphthaquinone) with 4,4′-bipyridine, 4-(2-pyridine-4-ethyl)pyridine, 1,3-di(4-pyridyl)propane and 2-hydroxy pyridine are reported. Adduct formation leads to colour shifts, which are characterised by UV/visible spectroscopy. Complementary quantum-chemical calculations are used to s...

Mechanochemistry is an effective method for the preparation of multicomponent crystal systems. In the present work, we propose an alternative to the established liquid-assisted grinding (LAG) approach. Polymer-assisted grinding (POLAG) is demonstrated to provide a new class of catalysts for improving reaction rate and increasing product diversity d...

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 wh...

The Faraday Discussion Mechanochemistry: From Functional Solids to Single Molecules which took place 21-23 May 2014 in Montreal, Canada, brought together a diversity of academic and industrial researchers, experimentalists and theoreticians, students, as well as experienced researchers, to discuss the changing face of mechanochemistry, an area with...

Ultrasound-assisted crystallization (sonocrystallization) was used to prepare a mixture of nano- and micrometer-sized crystals of the monoclinic form of paracetamol—a widely used analgesic known for its particularly problematic mechanical behavior under compression (i.e. poor tabletability). The nano- and micrometer-sized crystals yielded a powder...

Terahertz radiation is used to follow the solid state reaction to form cocrystals of theobromine and oxalic acid. The formation of an intermediate state is observed, and the cocrystal formation kinetics display a different reaction profile to the loss of the intermediate, thus supporting a moisture mediated reaction mechanism. We propose that THz-T...

A series of 9-X-acridizinium bromides (where X = F, Cl, Br, I, CH3, C(CH3)3) was synthesised, and their solid-state [4+4] photoreactivity was investigated using crystallographic and spectroscopic methods, while their thermal stability was studied using thermal gravimetry and differential-scanning calorimetry. The study aimed to identify how the nat...

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...

The dissociation at high humidity of cocrystals formed between caffeine and theophylline with a series of dicarboxylic acids is investigated and found to be driven by the partial dissolution of the acid, rather than by the formation of caffeine/theophylline hydrate. It is shown that partial dissociation occurs under all humidity conditions, and tha...

In previous studies, cocrystals have been shown to be susceptible to dissociation at high humidity because of differences in the solubilities of the two coformer molecules, especially when these molecules can form hydrates. Contrastingly, however, the propensity of the pharmaceutically active compound caffeine to hydrate formation is reduced by coc...

A polymorph screen on a new 1:1 co-crystal of caffeine, C8H10N4O2, with anthranilic acid, C7H7NO2, has revealed a rich diversity of crystal forms (two polymorphs, two hydrates and seven solvates, including two sets of isostructural solvates). These forms were prepared by liquid-assisted grinding and solution crystallization, and the crystal structu...

Looking in: The penetrating power of high-energy X-rays provides a means to monitor in situ and in real time the course of ball-milling reactions of organic pharmaceutical solids by detecting crystalline phases and assessing the evolution of their particle sizes. Upon switching from neat grinding to liquid-assisted grinding, cocrystal formation is...

Mechanochemische Reaktionen werden durch mechanisches Mahlen ausgelöst oder in Gang gehalten. Sie sind durch eine besondere Einfachheit gekennzeichnet, trotzdem ist ihr Mechanismus kaum verstanden. In der Zuschrift auf S. 11752 ff. zeigen T. Friščić et al., wie eine kürzlich entwickelte Technik zur In‐situ‐Verfolgung von Reaktionen in einer Kugelmü...

The simplicity of mechanochemical reactions namely chemical reactions induced or sustained by mechanical milling or grinding, is contrasted by the poor level of understanding of their mechanisms. In their Communication on page 11538 ff., T. Friščić and co‐workers demonstrate how their recently developed technique for the real‐time and in situ monit...

AFM of cocrystals: Atomic force microscopy can be used to observe phase changes at crystal surfaces where the transformation is accompanied by a change in the spacing between layers of molecules. The conversion of a metastable polymorph of the caffeine-glutaric acid cocrystal to the thermodynamically stable form was analyzed continuously in situ us...

We demonstrate the utility of freeze-drying as a general method for cocrystal synthesis as well as for the preparation of new solid forms of drug–coformer cocrystal systems. Using this approach, several previously reported cocrystal phases containing pharmaceutical compounds were reproduced. In addition, a novel solid solution of caffeine and theop...

Cocrystals are modular multicomponent solids with exceptional utility in synthetic chemistry and materials science. A variety of methods exist for the preparation of cocrystals yet, some promising cocrystal phases have proven to be intractable synthetic targets. We describe a strategy for the synthesis of the pharmaceutically relevant (caffeine)(b...

Multi-component organic nanocrystals that are comprised of two or more supramolecular building blocks can be used to extend the design and assembly scope of solid molecular materials. Herein, we report the use of ultrasonication to prepare halogen-bonded stilbene-based nano-cocrystals that exhibit different photoemission properties, including one-...

While organic micro/nanostructures for optoelectronic applications have attracted increasing recent attention, the assembly of aligned micro/nanostructure arrays continues to be a challenge. Herein, a one-dimensional (1D) microbelt has been fabricated by a hydrogen bonding assembly strategy with guanidinium cations and stilbene-based sulfonate anio...

Electron diffraction offers advantages over X-ray based methods for crystal structure determination because it can be applied to sub-micron sized crystallites, and picogram quantities of material. For molecular organic species, however, crystal structure determination with electron diffraction is hindered by rapid crystal deterioration in the elect...

A new approach to crystal structure determination, combining crystal structure prediction and transmission electron microscopy, was used to identify a potential new crystal phase of the pharmaceutical compound theophylline. The crystal structure was determined despite the new polymorph occurring as a minor component in a mixture with Form II of the...

Mechanochemical cocrystallisation was utilised to prepare fluorescein cocrystals involving pyridyl-based cocrystal formers, which exhibit different crystal structures and optical properties than those obtained via solution-based crystallisation.

We have previously reported on hydrogen bond propensity calculations for the potential formation of adducts between pyrimethamine and dicarboxylic acids. Here we extend the range of potential synthon interactions using a variety of potential coformers. Specifically calculations were performed to predict the possibility of the formation of molecular...

The increasing use of high throughput methods, coupled with the need to develop approaches to anticipate long term stability issues, has necessitated the introduction of testing approaches whereby extremely small samples may be rapidly analysed. A novel method is described whereby the UV light-induced degradation of single particles of a model drug...

In this paper, we present an investigation of the polymorphism of griseofulvin. In addition to the only reported crystalline form (form I), two new polymorphic forms (II and III) have been identified and characterized by differential scanning calorimetry and powder X-ray diffraction. Reasons why these two polymorphs were isolated during the present...

We demonstrate how solution crystallization of lamotrigine with flexible alkane dicarboxylic acids with different chain lengths (adipic acid and pimelic acid) generates a series of four isostructural solvated three-component salts. The analysis of their crystal structures shows that isostructurality is achieved by the combination of robust hydrogen...

Adjusting and modifying the optical properties of organic fluorophores are of importance for the development of the next generation of luminescent materials. Herein, we report the tunable fluorescence of 2,4,5-triphenylimidazole (TPI) chromophore by the formation of multicomponent crystals with the supramolecular building blocks, 4-bromotetrafluoro...

Fluorescent molecules included within a metal–organic framework (MOF) offer a new opportunity to develop luminescent host–guest materials. Two linear π-conjugated fluorescent molecules, 1,4-bis-p-cyanostyrylbenzene (bpcb) and 1,4-bis(5-phenyloxazol-2-yl)benzene (bpob), incorporated into MOF-5 systems are reported. The as-obtained bpcb@MOF-5 and bpo...

In recent years cocrystal formation has emerged as a viable strategy towards improving the solubility and bioavailability of poorly-soluble drugs. In this review the success of numerous pharmaceutical cocrystals for the improvement of the solubility and dissolution rates of poorly soluble drugs is demonstrated using various examples taken from the...

Three new cocrystals of 5-fluorouracil with acridine, phenazine and 4,4-bispyridylethene are reported, and analysed by transmission electron microscopy.

A comprehensive crystal form screen was performed on the phenazine:mesaconic acid system using a variety of techniques including solution based approaches, dry and liquid assisted grinding, thermal methods and sublimation. A novel approach to preparing pharmaceutical cocrystals involving crystallisation at a solvent–solvent interface was also emplo...

The formation of diastereomeric cocrystals of malic acid and tartaric acid was investigated by liquid-assisted grinding in the solid state. We demonstrate that racemic malic acid can be converted into two distinct diastereomeric cocrystal phases by grinding with a single enantiomer of tartaric acid.

In the past decade mechanochemical methodologies, such as neat grinding and liquid-assisted grinding, have been demonstrated to be a highly efficient means of both synthesising and screening for pharmaceutical co-crystals. This chapter provides an overview of these mechanochemical methodologies, their applications to date, an overview of mechanisti...

Here, we highlight recent research involving atomic force microscopy investigations of molecular crystals, and focus particularly on the latest relevant advances in our knowledge of crystal-growth mechanisms and structure-property relationships in organic crystals. This brief survey features the importance of incorporating AFM into solid-state rese...

Four new multi-component crystals of a carboxylic acid derivative of coumarin have been synthesised based on a hydrogen bond synthon approach.

Cocrystals of pyrazine with dicarboxylic acids were synthesised by mechanochemical methods. Crystal structure determination was performed by single crystal and powder X-ray diffraction (PXRD). The cocrystals consist of infinite 1D hydrogen-bonded chains exploiting the familiar pyridine-carboxylic acid synthon. The kinetics of dissociation of the py...

A new cocrystal containing caffeine and theophylline was found to dissociate on heating, with caffeine and theophylline molecules spontaneously demixing and recrystallizing as separate phases, in a solid-solid transition likely driven by an increase in entropy. The morphology and composition of the resulting crystals was determined by transmission...

The search for materials capable of storing small molecular species is experiencing a shift from solids with permanent porosity towards organic materials capable of the uptake and release of low-molecular-weight guests. We demonstrate that a solid mixture of the pharmaceutical compound lamotrigine with a range of saturated and unsaturated 1,4-butan...

An investigation into the predictability of molecular adduct formation is presented by using the approach of hydrogen bond propensity. Along with the predictions, crystallisation reactions (1a-1j) were carried out between the anti-malarial drug pyrimethamine (1) and the acids oxalic (a), malonic (b), acetylenedicarboxylic (c), adipic (d), pimelic (...

We describe a two-component cocrystal composition which appears in two stoichiometric variations exhibiting different supramolecular architectures: whereas one stoichiometric variation displays C-H center dot center dot center dot O hydrogen bonds, the second form exhibits short I center dot center dot center dot O halogen bonds alongside I center...

Atomic force microscopy (AFM) cantilevers were functionalized with particles of dicalcium phosphate dihydrate (DCP), and AFM, in force-displacement mode, was used to bring these probes into contact with aspirin (100) and (001) surfaces in order to investigate the effect of aspirin surface chemistry on the interaction between the two materials as a...

The development of modern pharmaceutical solid forms, including solvates, polymorphs, salts or cocrystals, is related to the design and control of molecular self-assembly processes. Mechanochemistry has emerged as an excellent experimental approach to rapidly and efficiently screen for and synthesise such pharmaceutical materials. This is particula...

We study synthon preferences in cocrystals of cis-carboxamides with carboxylic acids using a combination of database analyses, cocrystallisation experiments and theoretical calculations. We classify the cis-carboxamides into three families: primary amides, cyclic amides (lactams) and cyclic imides. Using crystal structure prediction calculations, w...