Transforming Industrial Crystallization by Sono-mechanical Manipulation of Crystal Surfaces

Lead Research Organisation: University of Strathclyde
Department Name: Chemical and Process Engineering

Abstract

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.

Planned Impact

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.
 
Description Research has confirmed the overall project hypothesis that ultrasound can reduce impurity incorporation during crystallization, it can increase yield and the processing time can be reduced to some extent. This finding is confounded by the role of ultrasound in modifying crystal size distribution and hence the role of filtration and washing is critical in establishing a proof for the hypothesis of the research. It is therefore essential to link the purification associate with the crystal growth process with the subsequent isolation steps (filtration, washing and drying). This aspect of the project is being addressed through a KTP with an SME Alconbury Weston Ltd and through the isolation aspects of CMAC. These points being there is now a body of evidence that application of ultrasound during growth does improve product purity. A further key challenge has been to establish a robust and acceptably accurate measure of the intensity of the ultrasonic intervention in organic solvent environments, this has been overcome by developing an approach using a needle hydrophone protected from the organic solution using a cott.
Exploitation Route The ultimate intention is for the ideas to be implemented by industrial partners and through publication by other researchers. Deployment is being explored with Pfizer, one of the project partners and may become a KTP project, they have already established a sonocrystalliztion capability at their UK research centre and the KTP would facilitate learning form the EPSRC funded program being deployed with the aim of accelerating the crystallization process without jeopardising product purity whilst simultaneously improving the bulk powder properties of problematic drug substances. One of the PhD students involved in this work has spent 4 months with Hoffman La Roche Ltd in Basel taking some of the project learnings and demonstrating their application in the company's polymorph screening work flow. Roche have also deployed the approach to ultrasound field quantification developed during the EPSRC funded research program.
Sectors Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL https://strathprints.strath.ac.uk/63406/1/Forbes_etal_PMA_2017_Elucidating_the_mechanism_of_paracetamol_sonocrystallization.pdf
 
Description The primary focus of the research cantered around demonstrating the utility of sonocrystallization as a purification tool in pharmaceutical manufacturing - deployment is being explored with one of the partner companies via a potential KTP. The methodology developed during the research to quantify ultrasound fields under realistic crystallization conditions has been deployed by Hoffman La Roche in their Basel R&D facility as a tool associated with their polymorphs screening approaches. A side benefit of the research focused on developing best practice in the isolation of crystals due to problems verifying the effectiveness of the ultrasound intervention. This led to an improved methodology of washing filter cakes. This expertise has been shared with an SME, Alconbury Weston Ltd., and through a KTP has been developed into a marketed product delivering automated continuous filtration, accurately controlled washing and drying for isolating pharmaceutical materials. This equipment fills a critical gap in the toolkit for continuous pharmaceutical development and small scale manufacturing, the first 3 commercial units have been manufactured and delivered to customers.
First Year Of Impact 2019
Sector Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description KTP
Amount £145,884 (GBP)
Funding ID KTP010280 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 04/2016 
End 03/2018
 
Title Data for: "Development of a novel continuous filtration unit for pharmaceutical process development and manufacturing" 
Description "This dataset comprises of one zip file which contains a number of folders containing spreadsheets, images text supporting experiments in paper named ""Development of a novel continuous filtration unit for pharmaceutical process development and manufacturing"" and for the proceeding of the Filtech 2016 conference. " 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact
 
Title Data for: "The impact of paracetamol impurities on face properties: investigating the surface of single crystals using TOF-SIMS" 
Description "AFM, TOF-SIMS, LC-TOF, optical microscope, raman microscopy, single crystal x-ray, SEM, solubility and UV-vis spectrometery data of paracetamol and 4-nitrophenol single crystals and on face impurities " 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact
 
Description Crystallizing and isolating pharmaceuticals: Addressing some of the remaining challenges 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation to Chemical and Process Engineering department focused on the use of ultrasound in crystallization
Year(s) Of Engagement Activity 2016
 
Description Developing Pharmaceutical Continuous Crystallization Processes: What we know and where are the gaps? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Communicating the challenges in crystallization process development and how these might be addressed by collaboration
Year(s) Of Engagement Activity 2016
 
Description Impurities: A neglected challenge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Running a workshop addressing the lack of academic work which addresses the critical role of impurities in continuous crystallization and isolation
Year(s) Of Engagement Activity 2016
 
Description Industrial Crystallization: Batch & Continuous 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presented to a group of industrialists and PhD students on the strategy for developing industrial crystallization processes and selecting whether these should be batch or continuous
Year(s) Of Engagement Activity 2017
 
Description Input to MAFuMA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Provide input to EPSRC project: Manufacturing Advanced Functional Materials. Presentation entitled: Industrial aspects of crystallization and isolation - what the pharmaceutical industry needs and ways to achieve this
Year(s) Of Engagement Activity 2016
 
Description Purification: Crystallization, isolation & rapid prototyping - linking API with drug product 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation on the role of continuous crystallization, ultrasound, isolation in controlling drug substance attributes and linking this to drug product performance
Year(s) Of Engagement Activity 2016
 
Description Talk to your crystallographer - Essential conversations and critical relationships for partners in Directed Assembly 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation at Directed Assembly Network Summer School
Year(s) Of Engagement Activity 2016
 
Description Using Ultrasound to Transform Pharmaceutical Crystallization Manufacturing Fellows presentation at Manufacturing the Future Cambridge 17/09/15 - 18/09/15 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Rapid fire communication of my research and its potential impact to a very broad community involved in all aspects of manufacturing
Year(s) Of Engagement Activity 2015
URL http://ukmanufacturing2015.eng.cam.ac.uk/proceedings/ChrisPricePechaKucha20sectransitions.pdf