Pressure-Induced Nucleation for the Continuous Manufacture of supramolecular assemblies

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The organic solid state is at the centre of a number of key billion dollar industries from pharmaceuticals ($60 billion, 2009); pigments and dyes ($1.2 billion revenue, 2010), agrochemicals ($134 billion market, 2010), energetics (explosives and propellants; $0.5 billion revenue, 2012). Each of these industries suffers from attrition whereby the number of possible products that reach the marketplace is a fraction of those conceived and made in research labs. A stage at which materials are discarded is that of the physicochemical properties. A well-known example is in the pharmaceutical industry where it is estimated that it costs $1.6 billion to produce one drug compound which is due, in part, to the catastrophic attrition rates of drug products from bench to production line. Therefore if there was a method by which one could alter the physicochemical properties without changing the functionality of the molecules the cost for manufacture would decrease considerably. Crystal Engineering or co-crystallisation is one method by which one can alter the properties of materials by forming supramolecular assemblies. These assemblies contain more than one chemical entity but can enhance stability, solubility, colour and flow properties through the addition of the second inert component. The inclusion of a second component impacts on the three-dimensional arrangement of molecules which in turn changes the physical properties of materials. The beauty of this method is that the functionality of the molecule in question is not changed i.e. a pharmaceutical product still possesses the correct molecular geometry to bind to receptors to affect a response; the solubility of a pigment may be enhanced without the loss of its colour. Another method by which one can alter the three-dimensional structure of a material hence its physical properties is via the application of high-pressure (pressures of >1atm). High pressure has proven to be an extremely effective method for changing the 3-D structure and industrial high pressure methods are already in use for pasteurising foodstuffs e.g. chicken, shellfish, orange juice etc. One of the key disadvantages is that new high pressure forms of single-component materials, e.g. paracetamol, are not stable under normal working conditions. By coupling the two areas of science together, crystal engineering and high pressure, we will be able to create materials that are stable under normal working conditions. This proposal seeks to develop a novel manufacturing methodology by which we are able to form new materials at high pressure and feed these into an industrial scale process. This process of 'seeding' is used in industrial settings presently to ensure that a consistent product is formed from the crystallisation process, we will use this process to promote the growth of high-pressure materials under ambient conditions in both batch and continuous flow systems. The latter system would align our project to the outputs of the EPSRC Centre for Continuous Manufacture and Crystallisation. Furthermore, detailed analysis of the process and the resulting materials will be carried out so that improvements can be made in the process, such as the pressures and concentrations used, as well as the design of the assemblies themselves. The physical properties of the new materials will be investigated and will provide the feedback to improve upon the process.