Title: A Novel Continuous Method for Co-crystal Formation
Funder: Engineering and Physical Sciences Research Council

Abstract: 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.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE