STRUCTURAL STUDIES IN THE ORGANIC SOLID STATE
Organic crystalline materials play many important roles as pharmaceuticals, pigments, agrochemicals, organic conductors or non-linear optics, to name just a few. As the bulk properties of these crystalline solids are dictated by crystal and molecular structure, a knowledge of both is crucial so that the properties of these chemical systems are fully understood. The rationalisation of a structure-property relationship is even more vital when the design of solid state materials is required to fulfil a particular application.
Our research encompasses aspects from all these areas: from the design and synthesis of new molecular cocrystals, the investigation of polymorphic behaviour of pharmaceuticals to the development of new computational algorithms for the determination of crystal structure.
STRUCTURE SOLUTION FROM POWDER DIFFRACTION DATA
Many important crystalline materials cannot be prepared in the form of single crystals of sufficient quality for conventional single-crystal diffraction studies. It is therefore essential that reliable structural information can be obtained from other sources such as powder diffraction data or by crystal structure prediction on the basis of molecular structure. We are currently developing new more sophisticated approaches to the process of structure determination from powder diffraction data. This research involves both the development of structure solution software utilising powerful computational techniques and the application of this software to important structural problems including many taken from organic and biological chemistry. Our work on ‘direct-space’ structure solution methods has enabled the structural characterisation of relatively complex structures from powder diffraction data and opened up the field to a wider scientific community, initially through the use of global optimization techniques based on Monte Carlo methods, and more recently by the development of evolutionary algorithms.
Our research is also focussed on the complementary use of theoretical crystal structure prediction techniques and experimental diffraction methods. This combination of techniques is vital in cases where either structure determination from powder diffraction data is not possible, or there are many possible predicted structures that are not easily distinguished by theoretical methods.
EVOLUTIONARY ALGORITHMS IN CRYSTALLOGRAPHY
Evolutionary algorithms are powerful global optimisation techniques that can be used to solve complex multi-dimensional problems. These algorithms mimic natural evolutionary behaviour using the principles of mutation, mating and natural selection to evolve a population until the fittest and best individuals dominate the population and provide the optimal solution.
We develop and utilise the differential evolution technique to solve complex structural problems primarily from powder diffraction data. Our work has resulted in the development of other highly efficient algorithms such as cultural differential evolution which based on a hybrid of natural evolution and human social behaviour. The combination of these contrasting evolutionary dictates has resulted in efficiency gains of up to 50% over pure biological evolutionary computation. Our first paper on this work was highlighted as a ‘Hot Paper’ in Chem.Comm. and was the focus of highlights in Nature, MRS Bulletin and other RSC publications.
CRYSTAL ENGINEERING AND THE DESIGN OF MOLECULAR COCRYSTALS
An understanding of intermolecular interactions in the solid state and its utilisation in the design of new materials is one of the most important areas in chemistry. As such, crystal engineering continues to attract both academic and commercial attention. There are many examples of multi-dimensional aggregates that have been assembled through a perceptive use of hydrogen bonds and these have shown that the selectivity of such interactions can be employed in the deliberate design of reproducible structural motifs. The incorporation of specific structural units in the design of a crystal will result in materials with desirable chemical and physical properties.
Our research involves the study of systems in which the primary interest centres on the intermolecular aggregation of often well-defined molecular building blocks. The investigation of pure compounds teaches us much about strong intermolecular interactions that can then be applied to the design and synthesis of multi-component hydrogen-bonded materials such as molecular cocrystals. These materials are becoming increasingly important within the pharmaceutical industry as an alternative formulation source with optimal physical properties. We are investigating the predictability of synthon formation, the crystal structures and tunability of physicochemical properties of new molecular cocrystals using both single-crystal and powder diffraction techniques.
Powder diffraction and crystal structure prediction techniques are key to the study of materials that display polymorphism - the existence of more than one crystalline form of the same chemical compound. Compounds from a wide range of fields exhibit polymorphism, with different forms often obtained from only slight variations in reaction conditions (e.g. temperature or pressure, or by crystallisation from different solvents). Despite this, polymorphs often display distinct differences in their physical properties arising from their differing crystal structures. The phenomenon of polymorphism is still not fully understood and the occurrence of polymorphic behaviour still not predictable.
STRUCTURAL STUDIES OF PHARMACEUTICALS
The majority of pharmaceutical substances are processed in the form of crystalline powders and many exhibit polymorphism. This raises various problems as both physical properties such as stability, dissolution rate, and bioavailability of the substance, and processing properties such as crystal shape, compressibility and particle size, vary between polymorphs and formulations. Patenting and life cycle management of pharmaceuticals are also critical to the modern pharmaceutical and agrochemical industries, and recent cases have demonstrated the possibility of patenting known drugs in new formulations such as novel crystal forms. Detailed study of crystal structure and polymorphic behaviour of these materials is essential for a rational control of the crystallisation process and solid state properties, and for patenting and registration purposes. Our structure determination techniques and synthesis of new cocrystal materials can be used to investigate these rationalise these aspects.