Crystal clear: production of co-crystals

Pharmaceutical drug discovery is a magical world, full of preclinical hope and promise, but what are the steps to take when the drug misbehaves by demonstrating low solubility, poor physical and material properties, and even refuses to form a salt?

One option could be to leave the drug and hope that it changes its behaviour and allows a salt to form; however, as this is improbable, one alternative would be to reject the stubborn drug candidate. Unfortunately, though, because a viable dosage form still needs to be produced and with approximately $120 million spent on preclinical testing, this is not a viable option. The only way, then, is to go forward to the possibility of developing a co-crystal.

By forming a co-crystal, the solubility of the drug candidate (and other neutral molecules) can be improved. It involves combining the drug with another pharmaceutically accepted material, such as a sugar or vitamin, as acidic and basic counter co-formers. A co-crystal is a new crystalline structure produced from the two forming materials, which is a solid at room temperature. (See Figure 1).

Solution, attrition or melt?

The next challenge to be addressed is which method to use to produce the co-crystal. The crystallisation of the co-crystal can be done through solution, attrition or melt routes. Solution growth as a methodology has limited success due to the volume of solvent required for large-scale production. Also, the solvent used affects the crystallisation outcome due to the ternary nature of the phase diagram for the co-crystal, the components and the solvent. The mechano-chemical formation of co-crystals using milling techniques (for example, grinding and liquid-assisted grinding) has been explored and has shown promising results. But it is a batch operation that cannot readily be scaled up, requires high-energy consumption and as such, the potential for exploitation of pharmaceutical co-crystals on an industrial scale is limited. Both methods have yielded a low purity of co-crystal, with typical conversion rates of 20-60%.

This leaves melt crystallisation for co-crystal formation, which is widely accepted as an attractive proposition, particularly with the increasing awareness within the pharmaceutical sector of continuous processing and the benefits that this brings.

Innovative approach to co-crystallisation

A new method of producing co-crystals has been developed by an inter-disciplinary team consisting of pharmaceutical scientists and process engineers working at the Centre for Pharmaceutical Engineering Science at the University of Bradford, in the UK. The team proposes a continuous approach producing co-crystals, utilising hot melt extrusion technology, which is solvent-free and can be readily scaled.

Known as solvent-free co-crystallisation (SFCC), this novel method has been proven in initial experiments to yield a high purity of co-crystals in model systems and lends itself well to quality control by in-line monitoring. The technology enables a single-step process for generation and agglomerates of co-crystals. The process provides the opportunity to form co-crystals unachievable by conventional techniques and thus generate new drug formulations (see Figure 2).

Twin screw extrusion has been used in the pharmaceutical industry since the mid-1990s for a variety of applications including the manufacture of solid dispersions, controlled-release-rate products and transdermal films. Interest from commercial companies, such as Amgen, indicates the business potential of the co-crystal technology, and the possibility that exists to enhance process understanding and optimisation for a range of pharmaceutical formulations.

Mapping the crystallisation process

The research being carried out at the University of 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.

A key issue is the ability to map the crystallisation process in real time and to link this to a fundamental understanding of the melt-driven co-crystallisation process. 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 will significantly improve the potential for the 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.

Impact of SFCC technology

A major concern for the pharmaceutical industry is the reduction in the numbers of new molecules coming through from research to market, while the patents for the majority of common drugs are running out. Moreover, the expenses involved in bringing new molecules to market are extremely high and, in some cases, prohibitive. This has led to the development of a repositioning and reformulation strategy, which has been implemented through the platform technologies of specialist pharma companies.

The Bradford team's goal is to support the pharmaceutical industry through the development of innovative and scalable new technology. The principal beneficiaries will be in the manufacturing sector, particularly the pharmaceutical, nutraceutical, fine chemicals and agrochemical industries, although clearly the potential to impact the wider community in terms of healthcare benefits are paramount.

Other recipients will include the public and private sectors, particularly areas associated with healthcare and therapeutics. But in the short term, those organisations involved in the R&D of drug-delivery systems will be the primary beneficiaries, together with associated industries such as nutraceutical, agrochemical 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 drug sectors, of emerging aspects of process monitoring and control. The research will have medium-term benefits for the UK and international pharmaceutical industries and associated sectors, and wider long-term benefits for the public through the possibility of novel therapeutic treatments.

In conclusion:

• The pharmaceutical research and manufacturing sectors will gain from the availability of a new method of forming 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 that result from the new manufacturing route.
• In the longer term (five to ten 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.

In the future, no matter how stubborn or difficult behaviour a drug candidate exhibits, there will always be a means to transform it into a viable dosage form.