A Novel Continuous Method for Co-crystal Formation

Lead Research Organisation: University of Bradford
Department Name: Sch of Life Sciences


A high proportion of new drugs being discovered are extremely difficult to develop into viable dosage forms because of their inherently poor properties. Many of these drugs are poorly soluble and therefore the active ingredient is difficult to dissolve, for example in the stomach, which limits its ability to be transferred into the body. There are several potential routes to overcome problems such as poor solubility. These include reducing the size of the drug particles, forming salts or dissolving the drug in a soluble polymer by processes such as freeze-drying. These techniques are generally complex and costly, and are only suitable for some types of drugs.

Another potential method of improving the solubility of certain drugs is to form a co-crystal of the drug with another pharmaceutically accepted material, such as a sugar or vitamin. A co-crystal is a new crystalline structure produced from the two forming materials, which is a solid at room temperature. Recently, there has been an increased interest in co-crystal research, reflected by an exponential rise in the number of research publications and patents in this field over the last decade. However, the potential to use these materials has so far been limited by the methods by which co-crystals are produced. These have been restricted to manufacture on a laboratory scale of only a few grams, and have yielded a low purity of co-crystal, with typical conversion rates between 20 and 60%. Such methods include dissolving the two co-formers in a solvent and precipitating out the co-crystals, or grinding the two co-formers together with a small amount of solvent.

A new method to produce co-crystals has been developed by an inter-disciplinary team at the University of Bradford consisting of pharmaceutical scientists and process engineers. The technique is based on twin screw extrusion, a well-established process in the plastics industry which is increasingly being used in the pharmaceutical sector. The extrusion process relies upon a combination of high temperature and shearing forces to gradually convert the co-formers into co-crystals. This method has been found to yield co-crystal purities close to 100% in initial experiments with model drugs such as ibuprofen with nicotinamide acting as a co-former. The technique is continuous, readily scalable and solvent-free, and thus lends itself well to industrial scale manufacturing.

This research project led by the research team at Bradford aims to explore the underpinning science behind the formation of co-crystals in this innovative process. Using a selection of model drugs and co-formers, the optimum conditions at which co-crystals form will be determined. A range of analytical techniques will be used to characterise the state and structure of the crystalline materials, including novel in-process measurements to quantify the dynamics of formation during extrusion. The pharmaceutical properties of these new co-crystals, such as solubility, drug release rate and stability, will be assessed and suitable downstream processing methods to convert the materials into tablets or other suitable dosage forms will be investigated.

The findings of this project will significantly improve the potential for use of co-crystals in commercial drug delivery. Understanding the fundamental mechanisms behind co-crystal formation and subsequent optimisation of this process will accelerate industrial interest in this field, providing direct benefits to the UK pharmaceutical sector and wider long term benefits to public health through the availability of otherwise unusable drugs.

Planned Impact

Beneficiaries of this research will include both the public and private sectors, particularly areas associated with healthcare and therapeutics. In the short term, organisations involved in research and development of drug delivery systems will be the primary beneficiaries, together with associated industries such as nutraceutical, agro-chemical and foodstuffs. Manufacturers of continuous processing machinery and ancillary products will also benefit, as will companies specialising in process monitoring instrumentation. Outputs from the proposed research will inform regulatory bodies such as those operating within the food and drugs sector of emerging aspects of process monitoring and control. The research will have medium-term benefits to the UK and international pharmaceutical and associated sectors, and wider long-term benefits to the public through the possibility of novel therapeutic treatments.
The pharmaceutical research and manufacturing sectors will benefit from the availability of a new method to form co-crystals of active pharmaceutical ingredients. The continuous and scalable nature of the new technique will assist the development of novel co-crystal forms and subsequent translation into commercially viable products. The understanding of the mechanism and kinetics of co-crystal formation may enable the selection of new pairs of molecules and co-formers currently difficult or not possible to co-crystallise. Significant potential for intellectual property and commercial exploitation will benefit the healthcare sector of the UK economy by enhancing global competitiveness. Improved process understanding achieved through this project will support and facilitate regulatory monitoring processes, as will sensor development. The wider manufacturing and chemical industries will benefit from the development and commercialisation of new co-crystal forms and applications which result from the new manufacturing route. In the longer term (5-10 years) it is envisaged that the healthcare sector and public well-being will benefit from the new co-crystalline drug forms developed using this process.
Dissemination of the research and its findings will be actively promoted through communication with relevant academic and industrial contacts and through conference and journal publications reflecting the multidisciplinary nature of the research (details are provided in the Pathways to Impact). Key contacts from within the pharmaceutical sector have already provided advice on model co-crystal compounds, potential applications and the structure of planned research. A global pharmaceutical company has supported the proposal and this collaboration will provide access to drug candidates. An international extrusion and analytic company has also supported the project and will assist with equipment design and stands to benefit from the knowledge collaboratively gained during the design of novel components.
A patent application has been filed by the University to protect intellectual property concerning continuous co-crystallisation and preliminary non-confidential data has been discussed with potential collaborators. Exploitation of the research findings will be achieved initially through contract research activities focused in co-crystal screening and development. Commercial development of the project will be investigated by the University's Research and Knowledge Transfer Support unit. A business plan will be developed detailing service provision, routes to market, resource requirements and funding. Opportunities for further industry collaboration will be investigated throughout the duration of the project. The assembled project team have a strong track record in applied collaborative research and experience of successful commercialisation of leading academic research.


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Pagire SK (2017) Thermodynamic Investigation of Carbamazepine-Saccharin Co-Crystal Polymorphs. in Journal of pharmaceutical sciences

Description Co-crystals typically contain two or more components, present at stoichiometric amounts, usually solid at ambient conditions. The main objective of exploring co-crystallisation of drugs is to modify physico-chemical properties such as solubility, stability, hygroscopicity, compressibility and dissolution rate. The crystallisation of co-crystal may be either through melt, solution or attrition routes. If the question is posed "What limits the transition for larger scale production, from laboratory to full production?" the response generally is that solution growth would be the first choice as this fits with current practice. However, the solvent used impacts on the crystallisation outcome due to the ternary nature of the phase diagram for co-crystal, components and solvent. Attrition routes such as milling are a possibility but issues such as energy consumption and scale-up difficulties limit its potential take-up.
Our innovative technology SFCC is based on use of twin screw melt extruder as a continuous, solvent-free technique to produce co-crystals. This would involve the application of both shear and mixing at or near to the melting point of the lowest melting component or between the eutectic temperatures. The process is deemed green, readily scalable and is capable of being used for screening and manufacture. The product obtained by SFCC is in the form of agglomerates of co-crystals.
Exploitation Route The patent has been published which is available for companies and other researchers to view. The information has been disseminated on Centre for Pharmaceutical Engineering Science website
Sectors Agriculture, Food and Drink,Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL http://www.bradford.ac.uk/research/rkt-centres/pharmaceutical-engineering/core-capabilities/process-development/
Description 1. The patent has been filed and is in the national stages in various countries. A lock out agreement has been signed in July 2014 for commercialisation of the technology. This solvent free technology will make green impact. 2. Two KTP awards based on EP/J00360/1: (Innovate UK with support from EPSRC) a. AstraZeneca (18 months), 1 job created and b. Health Innovation, Skipton (24months) , 1 job created. 3. A product patent published developed through knowledge from this project. (WO2016001681) 4. Support from company N4Pharma £18,000 (contract research) 5. Products have been launched based on the KTP 009978 5. Explore donated a new extruder for scale down operation (in kind support of about £100k. 6. KTP has been approved with Vitrition Ltd (KTP 010956)
First Year Of Impact 2019
Sector Agriculture, Food and Drink,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

Description Knowledge Transfer Partnership
Amount £137,000 (GBP)
Funding ID KTP009978 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 11/2015 
End 10/2018
Description Knowledge Transfer Partnership
Amount £105,000 (GBP)
Funding ID KTP009991 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 07/2015 
End 12/2016
Description KTP Partnership on melt granulation for thermosensitive nutraceuticals (KTP No KTP009978) 
Organisation Health Innovations
Country United Kingdom 
Sector Private 
PI Contribution Health Innovations is a leading manufacturer of vitamins, minerals & nutritional supplements. The company has identified that it is not competitive in certain solid dosage product categories and in order to retain and grow its manufacturing activities changes in the manufacturing process need to be evaluated and implemented. The partnership is essential because - development of tablet involves an intermediate granulation stage. - conventional/wet granulation involves aqueous systems and drying at high temperature and is not suitable for temperature and moisture sensitive NS. It is relatively easy to develop in-house wet granulation technology with selection of suitable granulator available on the market and trained operators. But development and embedding of alternative granulation technology such as melt/dry granulation, which will provide granules with required flowability and compressibility is not easy as it requires understanding of molecular chemistry, physics of compression, knowledge about excipients, fundamentals of granulation and process development and proper mechanism of embedding the technology. - It is also essential to have clear understanding on new techniques such as melt granulation, solvent free and high shear processing and intellectual property scenario in that area. This knowledge and expertise is not available in the company. The required bespoke granulation capability embedded and via the KTP cannot be bought 'off the shelf' or by accessing consultancy support. The KTP addresses a variety of challenges including, • introduction of new granulation technologies • enhancement of manufacturing and development skills, transfer of molecular knowledge implementation and embedding of new processes • increased raw material knowledge, increased procurement opportunity on raw materials • increased formulation opportunities with improved raw material compatibility/consistency. • The knowledge and learning repository Material Properties- Product Processing (MPPP) database, ANN modelling will simplify product processing for other active molecules once technology is embedded in the company.
Collaborator Contribution KTP contribution in -cash and in kind. Apart from this it led to a technology licence deal.
Impact Licence deal for EfferShield Technology
Start Year 2015
Description Knowledge Transfer Partnership in continuous PAT enabled melt extrusion technology with AstraZeneca (KTP No KTP009991) 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution A significant proportion of drugs in pharmaceutical pipelines have challenging physical properties such as low aqueous solubility. Poor solubility can lead to low and variable drug bioavailability and failure to achieve the therapeutic target. Among the formulation technologies that have emerged to address this problem, hot melt extruded amorphous solid dispersions is Application: 1013353 - AstraZeneca UK Ltd & University of Bradford Adviser: (Fiona Nightingale) Page 4 Senior Staff Member Jon Paul Sherlock one of the most promising approaches. AZ has the aspiration to establish hot melt extrusion (HME) as a core "advanced" manufacturing technology aimed at the development of poorly soluble drugs and other products where HME / twin screw processing, (eg melt-granulation) is applicable. To realise this goal in an acceptable timescale, access is urgently required to a skill/knowledge-base that is currently not available in house. A KTP partnership with the University of Bradford is viewed as an optimal solution to address the HME capability-gap at AZ, for the following reasons: This project aligns well with KTP principles of close academic/industry collaboration to address an unmet need and leverage the ability of the Associate to spend majority of his/her time at AZ, with the benefits that this brings for both parties. AZ have previously participated in successful collaborations with Bradford, thereby promoting the likelihood of further success in this project AZ recently invested in identical HME equipment to that already at Bradford. This will enhance the ease of transfer of knowledge and skills
Collaborator Contribution This partnership provided an opportunity for the Knowledge Base team to understand the expectations of a global pharmaceutical company such as AstraZeneca and allow the opportunity to work on real applications. It also provided the opportunity for the academics to interact with the research team at the company on issuessuch as regulatory frameworks, future strategies of the company in the area of poorly soluble drugs, which was helpful inhelping to formulate future strategies for CPES and enhance employability of their graduates.The University of Bradford offers post graduate programs in the areas of pharmaceutical technology and chemical engineering. This partnership led to at least two postgraduate research projects in the area of hot melt extrusion and PAT. Hot melt extrusion and process analytics is relatively new field and we expect to generate at least one strong publication on the application of process analytics in a peer reviewed journal such as Pharmaceutical Research.
Impact This is a multidisciplinary collaboration across life sciences (pharmaceutical sciences) and chemical engineering.
Start Year 2015
Description Knowledge Transfer Partnership:KTP 010956 
Organisation Vitrition UK Ltd
Country United Kingdom 
Sector Private 
PI Contribution We are Knowledge Base Partner providing technology Solvent free process chemistry to address challenges in formulations
Collaborator Contribution Company partner, Vitrition Limited
Impact This is a multidisciplinary project involving Polymer and process Engineering and Pharmaceutical Sciences
Start Year 2018
Description Melt processed delivery systems research funding 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution The partnership is for investigation of injection moulding a downstream operation to melt extrusion
Collaborator Contribution Financial contract sponsoring 1 year PDRA ($100,000). It will start from April 2017
Impact Not yet
Start Year 2017
Description The present invention relates to a method useful for forming products which are useful in a pharmaceutical context, and products formed by such a method. The invention relates particularly, but not exclusively, to methods of forming a metastable polymorph using screw extrusion, whereby temperature and shear induce transformational changes, and products obtained or obtainable via such methods. 
IP Reference WO2013171484 
Protection Patent application published
Year Protection Granted 2013
Licensed Commercial In Confidence
Impact Spin-out opportunity in progess
Description The present invention relates to effervescent compositions which are resistant to water vapour in the atmosphere and to methods of preparing such compositions. In particular, the invention relates to an effervescent composition comprisinga co-crystal. The co- crystal comprises an acidic component and a basic component is separate. The co-crystal comprising the acidic component is resistant to water uptake avoiding initiating the effervescence prematurely. Upon dissolution of the co-crystal and the basic component effervescence occurs. 
IP Reference US20170128359 
Protection Patent application published
Year Protection Granted 2014
Licensed Yes
Impact Patent has been licensed to Octopoda Innovations Limited, Skipton
Description The present invention relates to effervescent compositions which are resistant to water vapour in the atmosphere and to methods of preparing such compositions. In particular, the invention relates to an effervescent composition comprisinga co-crystal. The co- crystal comprises an acidic component and a basic component is separate. The co-crystal comprising the acidic component is resistant to water uptake avoiding initiating the effervescence prematurely. Upon dissolution of the co-crystal and the basic component effervescence occurs. 
IP Reference WO2016001681 
Protection Patent application published
Year Protection Granted 2016
Licensed Yes
Impact The technology will be licensed to Health Innovation, Skipton, UK and application has been submitted to Innovate UK for co-development of this technology
Title United States Patent 10420718 B2 
Description The present invention relates to effervescent compositions which are resistant to water vapor in the atmosphere and to methods of preparing such compositions. In particular, the invention relates to an effervescent composition comprising a co-crystal. The co-crystal comprises an acidic component and a basic component is separate. The co-crystal comprising the acidic component is resistant to water uptake avoiding initiating the effervescence prematurely. Upon dissolution of the co-crystal and the basic component effervescence occurs. 
IP Reference United States Patent 10420718 B2 
Protection Patent granted
Year Protection Granted 2019
Licensed Yes
Impact Centre for Pharmaceutical Engineering Science(CPES) at University of Bradford developed a crystal engineering based technology EfferShield (US10420718) to address manufacturing, packaging issues and also providing low sodium effervescent products. The patent is licensed to Octopoda Innovations which is currently working with the CPES team on EfferShield scale up and commercialisation