Transforming Industrial Crystallization by Sono-mechanical Manipulation of Crystal Surfaces

Purification is a vital process in chemical manufacture that ensures only the desired product is obtained and unwanted or hazardous impurities are effectively removed. Many every day materials are purified by crystallization. It is the principal purification technique in the pharmaceutical, fine chemical, paint, pigment and agrochemical sectors. The UK chemical industry turnover is £55 billion or 11% of the value of UK manufacturing. The UK pharmaceutical sector generated a trade surplus of £5.5 billion in 2012 with exports of £20.9 billion. (UK Manufacturers' Sales by Product (PRODCOM) 2011 (ONS December 2012) & HMRC UK Trade Information June 2013).
During crystallization molecules assemble together to form crystals with a regular 3D packing arrangement known as a lattice. Purification occurs by molecular recognition at the solution - lattice interface. At some sites on the crystal surface the mismatch between the impurity molecule and the lattice is so large that the impurity is rejected. At other sites the lattice mismatch is small enough for the impurity to attach to the crystal face. The portion of the impurity molecule facing away from the crystal face may differ so much from the adjacent molecules that it disrupts and slows the subsequent growth on that crystal face. Increasing the crystallization driving force results in the impurity being overgrown and incorporated into the product. Typical feed streams to industrial crystallizations contain several % of impurities so these interactions are very frequent and have serious consequences. Sometimes the product is so impure it has to be re-crystallized. Impurity poisoning of crystal growth increases processing time slowing the approach to equilibrium so much that some product has to be left in solution and lost in the waste stream. Improving crystal purity and increasing efficiency through improved yield and accelerating crystallization processes are amongst the major challenges identified by the European Federation of Chemical Engineering Working Party on Crystallization, (Biscans Industrial Crystallization Challenges and Scientific Issues Sept 2011).
Intervening to remove impurities from the growing crystal surface during crystallization will overcome this problem increasing product purity and productivity, reducing waste and delivering crystals with improved performance. Ultrasound is uniquely suited to this task as sound propagates through media by interaction with every molecule present. Frequencies in the KHz to MHz range are high enough to intervene as each molecular layer is added to the growing crystal. The proposed mechanisms involve increased molecular motion adjacent to the growing crystal improving transport to and from the crystal faces. Highly localised perturbations caused by cavitation events lead to momentary local temperature fluctuations. When these occur close to strained regions of the lattice where impurities are attached they favour release of the impurity molecules. Although there has been previous work sonocrystallization this is a new area of application that will develop new understanding and lead to a new process capability. The approach benefits batch processes but will be especially valuable in continuous processes where accelerating crystallization will reduce residence time in what is usually the longest process step. This is strategic for the pharmaceutical sector where batch processing dominates but there is a strong drive to switch to continuous operation for financial, quality and sustainability reasons. Undertaking this project at Strathclyde University aligns it with major national manufacturing research activities including the EPSRC Centre for Innovative Manufacturing and Doctoral Training Centre in Continuous Manufacturing and Crystallisation (CMAC) and dedicated facility within the £89M University of Strathclyde Technology and Innovation Centre (TIC) designed to promote continuous processing, particularly crystallization.

Academic Impact
Bringing a new approach to an established problem demonstrates the value of looking for a transformational solution as a proactive alternative to measuring, understanding but choosing to live with a problematic phenomenon. The approach encourages a culture change within the discipline, simultaneously promoting scientific advancement and translation of new knowledge into industrial practice. Because crystallization is ubiquitous in the chemical sector, the approach is likely to catch the attention of researchers both within the UK and internationally and hence to impact academic research in the area. Ideally this will boost the development of a holistic approach to the design of novel functional particles. The research is cross-disciplinary drawing on crystallography, particle science, process and ultrasonic engineering with the potential to impact synthetic chemistry, product design and formulation science. The project will strengthen links between these disciplines and will produce highly skilled new researchers experienced in cross functional team work.
Economic and societal impact
This project can contribute to quality of life, health, well-being, and to social cohesion through increased economic activity and by reducing the cost of pharmaceutical manufacture improving access to medicines. High value manufacturing is important to the UK economy and UK industrial policy reflects this, for example in the Government's vision in establishing the patent box. The project will support evidence based policy-making, successful implementation across the chemical sector will strengthen its competitive position and a good RoI will provide evidence to justify future investment in the field. The research will have an impact at a regional level in the North West, North East, Yorkshire & Humber and Scotland where the chemical sector is concentrated; by boosting industrial vitality thereby bringing regeneration and economic development.
This economic impact will be through cost savings of up to 10% in the manufacture of crystalline products. As crystallization is ubiquitous this represents a substantial sum, many times the fellowship cost, perhaps as much as £1bn enhancing business revenue across the chemical sector. If used to fund future innovations it will contribute to wealth creation, company growth and employment. This is a priority area with potential to attract R&D investment from global business exemplified by the companies providing letters of support.
When implemented the project will contribute to delivering the UK's environmental sustainability targets. Increasing yield uses less input material and produces less waste. Eliminating recrystallization preserves yield and cuts solvent use. Reduced cycle time and process foot print favour more sustainable manufacturing and facilitating continuous manufacturing will increase the impact. Commercial exploitation will be achieved by translation into industrial practice via a spin out company working in partnership with an existing equipment supplier.
An industrialisable solution to the undesirable impact of impurities on crystal growth will liberate industrial practitioners to address other aspects of crystallization with more vigour eg to focus on delivering functionally designed particles. Taking a different approach to a long standing industrial problem challenges the classical organisational culture and will help promote a culture of innovation.
Crystallization is a very visual science which is frequently taught in schools, it is a great topic to engage young people in science. Describing this approach to crystal purity and its contribution to the economic and sustainable manufacture of every day products is an excellent way to communicate the value of science and engineering to young people. The project will deliver a number of highly skilled researchers who through extensive industrial partnership in the project are likely to make their careers in industry.