Towards continuous crystallisation of layered and disordered solid forms

Crystallisation is a vital step in the manufacture of many pharmaceuticals and fine chemicals, producing solids in a form ideal for downstream processes. Unlike others, these industries have not kept pace with advances in continuous production and for centuries industrial crystallisation has operated as a batch process, relying heavily on stirred tank reactors which bring batch to batch variations and limited control over particle attributes. Continuous crystallisation can offer improved product quality, less waste and access to new products more efficiently. One such particle attribute is the presence of molecular disorder in crystalline materials where different ratios of disordered components may show different physical properties [1]. However, disorder can be difficult to control and characterise so has not to date been widely exploited for achieving optimised properties. Multi-component crystallisation can be used to encourage orientational disorder and layering within the crystal lattice by appropriate choice of co-former and by utilising the principles of crystal engineering. The research being presented aims to systematically study disordered and layered materials. Systems that exhibit these characteristics will be discussed structurally, together with results from transferring production of these materials from evaporative to cooling crystallisation, frequently a key first step in achieving crystallisation in a continuous flow environment. In addition, the structural attributes of the particles produced will be correlated with different physical properties such as solubility and compressibility [2].

Single crystal synchrotron X-ray diffraction for imaging hydrogen bond evolution

Hydrogen bonding is a valuable intermolecular interaction in "engineering" solid-state materials. This is because of the directionality and relative strength (1) of these bonds. Hydrogen bonds enable charge and energy transfer, via H-bond evolution, in a range of biological and chemical systems (2). Recent work has demonstrated that single crystal X-ray diffraction can be used to image the evolution of hydrogen bonds, including variable temperature proton migration and proton disorder processes. In particular, in a recent study of the temperature dependent proton disorder in hydrogen bonded 3,5-dinitrobenzoic acid (3,5-DNBA) dimers, the proton disorder deduced from data collected on an X-ray laboratory source is in agreement with that found from neutron data (3). This work focuses on variable temperature single crystal synchrotron X-ray diffraction, for the imaging of evolving hydrogen bonds. The development of appropriate methodology is important here, particularly as previous studies have involved laboratory X-ray sources only. Results will be presented from variable temperature data collections on I19, at the Diamond Light Source, and on beamline 11.3.1, at the Advanced Light Source (ALS), on systems such as 3,5-DNBA and co-crystals of benzimidazole, both exhibiting proton disorder across hydrogen bonding interactions. Synchrotron X-ray diffraction measurements have also been used to follow the change in the position of a proton within an intramolecular [N-H···N]+ hydrogen bond across a range of proton-sponge molecular complexes. Importantly, it has been possible to visualise the evolving hydrogen atom position in Fourier difference electron density maps generated from the synchrotron data. In particular, for the 35-DNBA study, the clearest picture of the evolving hydrogen atom position is observed in those generated from data collected at the ALS; even clearer than that observed in X-ray laboratory and neutron measurements on the same system.

Stabilising peroxyacids in niche microenvironments

There has been dramatic evolution in the formulation of household cleaning products over the last decade, this is mainly due to the influence of social change, regulatory pressure and the need for new less toxic, safer formulations with increased performance. Due to their high chemical reactivity, peroxides are found in a wide range of bleaching agents, they are known for their instability which is a direct consequence of their high reactivity (in turn essential for function). Stabilising such materials for implementation in a range of product types is a significant target within the domestic products industry. Supramolecular approaches are already being explored to try stabilise other chemically reactive species such as explosives [1,2] thus illustrating the feasibility of this research. The work to be presented will deal with peroxyacids that include small model compounds such as m-chloroperbenzoic acid as well as a commericially relevant bleaching agent and their inclusion in both crystalline and amorphous hosting systems. Single crystal X-ray diffraction methods are used to elucidate the ordered crystalline structures and to confirm whether or not the peroxo group is still intact within the crystalline host environments. Simple reactivity tests are used to demonstrate whether or not the amorphous host-guest complexes contain the active peroxy acid within their host cavity. Other complementary analytical techniques such as powder X-ray diffraction, differential scanning calorimetry and thermogravimetry have also been used to characterise the newly-hosted peroxyacid materials. By hosting these molecules in microenvironments it is possible to prepare formulations that are less pH sensitive, thus making their storage safer while allowing their reactivity to be controlled and tuned.

Gas hydrates at high pressure

The behaviour of gas hydrates at high pressure is of wide interest and importance. Gas hydrates are stablised by water-gas repulsive interactions. Information on the effect of changing density on these water-gas interactions provides fundamental insight into the nature of the water potential. Gas hydrates are also widely found in nature and systems like the ammonia-water and methane-water systems form the basis of 'mineralogy' of planetary bodies like Saturn's moon Titan. Finally, gas hydrates offer the possibility of cheap environmentally inert transportation and storage for gases like carbon dioxide and hydrogen. We have been carrying out investigations of a range of gas hydrates at high pressure using neutron and x-ray diffraction as well as other techniques. Results from these studies including; the phase diagram of the ammonia water system, the occupancies of hexgonal clathrate structures, and new structures in the carbon dioxide water system, will be presented.

Tuning colour in multi-component complexes: Molecular disorder as a design tool

The key aim of multi-component crystallisation is modification of the physicochemical properties for a specific task.[1] Tuning colour using molecular components is a relatively unexplored area, which is surprising given the possible advantages in pigment development. In crystalline materials, the optical characteristics are not solely dependent on the molecules but also on the crystal packing;[2] it follows that the optical properties could be modified using crystal engineering techniques. We have systematically investigated co-crystallising haloanilines with dinitrobenzoic acids to build an understanding of the intermolecular interactions. Molecular disorder of one or more of the components tends to lead to layered crystal structures that include stacking interactions and therefore strong colour, indicating that molecular disorder is desirable. Defects in inorganic systems are routinely exploited as a route to enhancing or introducing physical properties but similar effects in organic systems are yet to be properly exploited. We will discuss the methods by which disorder can be designed into molecular complexes, and the local ordering effects which give rise to strong diffuse scattering. Additionally we have identified a pair of thermochromic molecular complexes, 2-iodoaniline/2-bromoaniline 3,4-dinitrobenzoic acid, where disorder appears to be crucial in lending the materials their properties. Both complexes undergo a temperature-induced colour change from red to yellow corresponding to a significant molecular rearrangement. The thermochromic transition is a single-crystal to single-crystal effect; the role of molecular disorder as a facilitator for the molecular rearrangement, maintaining the crystal integrity, will be discussed. Despite the complexes being isostructural, only the bromoaniline complex shows reversible thermochromic behaviour; subtleties in the manifestation of this disorder can explain the differences in the reversibility of the transition.

A novel open tubular continuous crystalliser: design and evaluation

The ability to continuously manufacture products can be of huge benefit to industry as it can reduce waste and capital expenditure. Continuous crystallisation has received tepid interest for many years but has come to the fore recently as it holds the potential for a radical transformation in the way crystalline products are manufactured, leading to the development method being embraced by major industries such as pharmaceuticals. In addition to the financial benefits offered by continuous crystallisation over conventional batch methods, a higher level of control over the crystallisation process can also be achieved - allowing improved, more consistent particle attributes to be obtained in the crystallisation process. This control is in part a consequence of the smaller volumes involved in continuous crystallisation, which also has the advantage of reducing any hazards associated with the materials being processed. By using smaller volumes, the mixing efficacy is inherently increased which reduces any disparity between local environments, thereby allowing kinetics to dictate the nature of the products. The EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC [1]) in the UK is a collaborative national initiative to further the knowledge base and understanding of all aspects relating to continuous crystallisation and its use in the manufacturing of crystalline particulate products. In this work we present the design and construction of a novel continuous crystalliser and its evaluation using various model systems such as calcium carbonate (polymorph control [2]) and Bourne reactions (mixing efficacy [3]). The crystalliser will then be used in the co-crystallisation of agrichemical and pharmaceutical compounds with co-formers in an effort to optimise the solid-state properties of these materials such as solubility. Various aspects of the evaluation of the design of the new crystalliser will be presented with reference to these trials, and assessed critically with respect to evolution of this design and potential implementation in manufacturing processes.

Experimental Charge Density studies of Ge(II) complexes using beamline I19

Interest in the p-block elements has recently been stimulated by the need for new reagents for materials and electronics applications, as well as the intrinsic interest in the unprecedented structures and properties observed. For germanium the development of low-valent compounds, organometallics, multiply bonded species, radicals and clusters is of significant importance. We have probed the coordination chemistry of Ge(II) with a range of neutral ligands, few examples of which were reported until recently. They exhibit many striking features including diverse structural motifs and highly variable coordination numbers (between 3 and 8) [1] suggesting the Ge centre does not to have a strong stereochemical preference and small differences in steric and electronic properties of the donor ligands have a significant role. Bonding models have been used to rationalise the observed structures with a Ge-based lone pair occupying the stabilised Ge 4s orbital. However these models are not entirely satisfactory and experimental charge density studies could provide valuable insights into the structures and chemistry of these compounds. [GeCl2(2,2'-bipyridine)], 1, and [GeCl2(1,2-bis(dimethylphosphino)benzene], 2, were selected as targets for initial experimental charge density studies and data have been collected using 3 different experimental configurations of the small molecule single-crystal diffraction beamline I19 [2] at Diamond Light Source. Using a Rigaku Saturn 724+ CCD detector on a 4-circle kappa-geometry CrystalLogic goniometer, data for 1 were collected at λ=0.6889Å without bimorph focussing mirrors in place, and for 2 data were collected at both λ=0.6889Å with bimorph mirrors and λ=0.4859Å without mirrors giving data to 0.48 and 0.38 Å resolution respectively. Details of the analysis of the topology of the electron density will be presented with the insights gained into the bonding in these unusual complexes.

Radiation Damage in Chemical Crystallography

Although crystals suffering radiation damage is a well-known and studied phenomena for macromolecular crystallography[1], as far as we are aware there appears to be no such published work relating to chemical crystallography. However, there are numerous anecdotal accounts of disintegrating crystals and resolution progressively dropping off that have been ascribed to radiation damage. Since the start of operations on the small molecule synchrotron beamline I19[2] at Diamond Light Source, there have been multiple comments from several users observing sample damage in the beam. The UK National Crystallography Service[3] handles a wide variety of samples and a number of these have experienced radiation damage. In order to understand the causes and symptoms of this effect in greater detail some controlled experiments were performed. A series of experiments were conducted on crystals that were known to undergo radiation damage in order to determine some quantification of the effect. Additionally the aim is to understand what one might be able to do to mitigate against the damage caused and determine whether the effects observed are similar to those of macromolecular crystallography. The effects of varying the collection temperature, overall dose, dose rate and wavelength of X-ray used were all tested and normalised for each sample. Samples where radiation damage has been observed were chosen and were also required to be air stable and preferably not suffer from solvent loss, in order to minimize problems of non-reproducibility. Those chosen to probe this effect were: 1. A gold complex - has potential to suffer heavily from absorption effects. 2. A nickel complex with significant solvent water - this could to some extent mimic the behaviour exhibited by proteins. 3. A small organic compound - an example of unexpected decay. The poster will summarise the results of these experiments and contrast them with data collected on a high intensity rotating anode laboratory source.