A Novel Continuous Method for Co-crystal Formation

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.

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.