Pressure-Induced Nucleation for the Continuous Manufacture of supramolecular assemblies

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.

The intended beneficiaries of this research are the pharmaceutical and other chemical industries. In addition we will capitalise on our novel techniques and use 3D printing to engage a much wider audience of school children and the general public with this research.

It is estimated that it costs a pharmaceutical company in the region of $1.6 billion to produce one marketable drug compound. Part of this huge cost is due to the catastrophic attrition or 'drop-out' rates of drug products from bench to production line. In some areas of pharmaceutical production there are high levels of wastage in terms of cost, time and human effort. A key reason for attrition is when it is apparent that the experimental compound is unsuitable or unstable and therefore cannot be reproduced reliably in large enough quantities for commercial use. The fine-tuning of properties such as colour, stability, solubility, and flow could be the difference between whether a product is taken forward to manufacture or left the shelf.

This proposal seeks to scale-up and accelerate the production of groups of molecules under high-pressure conditions. This research develops a different route to the marketplace for poorly performing functional materials and re-uses them in supramolecular assemblies for enhanced properties. I have already demonstrated that other properties of materials can be altered, by the assembly of a co-crystal or supramolecular material that contains more than one molecular component, under ambient conditions.

The pharmaceutical industry is only one of a number of key billion dollar revenue industries supporting world economic growth, which have the same problem in that the number of possible products reaching the marketplace is a fraction of those conceived and made in research labs. These include pigments and dyes ($1.2 billion revenue, 2010), agrochemicals ($134 billion market, 2010), energetics explosives and propellants ($0.5 billion revenue, 2012). In the long term, any production improvements in attrition rates should transfer to other sectors where the modelling of crystalline compounds will help to identify stable physicochemical states, leading to significant cost savings and a faster route to market.

We have detailed plans to engage the public and schools throughout the research project, through well-established links between the University of Strathclyde and the Glasgow Science Centre, and through the 3D printing labs on campus. The ethos of the University of Strathclyde is to take every opportunity to make our research accessible and interesting to a wide range of external audiences.