Supercritical fluids make custom powders

The aura of mystery surrounding Bradford Particle Design (BPD) was dispelled at the opening ceremony of its new manufacturing facilities by the Secretary of State for Trade and Industry, Stephen Byers. A commercial spin-off from the University of Bradford, BPD was established in 1994 by academics from the university and is set to change the way pharmaceutical drugs are manufactured. 'It all seems to have happened like magic,' said Sir Christopher Benson, non-executive chairman. BPD aims to exploit a technology known as SEDS (Solution Enhanced Dispersion by Supercritical fluids) for the controlled formation of particles. The SEDS process was initially developed in the University of Bradford's School of Pharmacy by Professor Peter York and Mazen Hanna, now respectively BPD's deputy chairman/chief scientist and principal scientist, and early work was funded by Glaxo Wellcome. The 13 000ft2 manufacturing facilities at Listerhills Science Park, Bradford, reflects the company's high standard of efficiency and commitment to industry.

As Byers unveiled the company plaque he said: 'The new plant is not only a world leader in new technology for the production of pharmaceuticals, it is a shining example of creative collaboration between university and industry and a signpost to the future for supporting the science base in the United Kingdom.' Historically, the drive of the pharmaceutical industry has been towards drug chemical purity rather than physical characteristics. Problems encountered in drug processing are often caused by powder formation, which is involved for 80 per cent of drugs produced. York explained: 'We have found a way of controlling the formation of particles to produce the desired size, consistency and processing behaviour in a straight forward single-stage process which has been successfully transferred to industrial scale proportions.' The wider picture The company now employs 29 people, 22 of whom are scientists. The team is truly multidisciplinary, inclusing pharmacists, physical chemists, chemical engineers, crystallographers, physicists, biochemists, analytical chemists and general engineers. In addition, the company retains strong links with the School of Pharmacy and carries out a great deal of collaborative research. The company is particularly proud of this relationship, which has so far led to the publication of more than 30 joint publications.

All of this has been achieved in just six years. One reason for BPD's rapid growth is its policy of collaboration with a growing number of multinational pharmaceutical companies. The company has worked with Glaxo Wellcome, AstraZeneca and Bristol-Myers Squibb in the UK, Europe, the USA and Japan. Further funding of £500 000, in the form of UK government research and development grants, has been awarded to the project by the Department of Trade and Industry.

BPD's strategy is to provide clients with a comprehensive and fully supported service for supplying materials prepared to 'current good manufacturing practice' specification. Through the SEDS process, early development and formulation studies can be made, through clinical trial supplies, to manufacturing scale. This capability allows BPD to carry out projects for clients from quantities on a laboratory scale to hundreds of kilograms in clinical trials. A manufacturing venture is currently being positioned to provide full-scale manufacturing capacity by mid 2002.

The technology itself replaces a multiple-step procedure - solvent crystallisation, filtration, drying and milling - with a single process, making it an example of the growing trend towards process intensification. The process forms dry fine powders in a single vessel, and is particularly useful for generating very fine particles. This is notoriously difficult with current process technologies - they cannot be generated directly because of problems with filtration. Instead, larger particles are grown in crystallisers, which are then milled to the required size. However, this procedure is fraught with problems. Health and safety concerns are particularly pressing, as milling is inherently 'messy' and tiny particles of highly bio-active substances present a considerable risk.

The spray's the thing The SEDS system works by spraying both a solution of a drug in an organic solvent and supercritical carbon dioxide into a particle-formation vessel through a single, specially designed nozzle. The CO2 disperses and mixes the solution while simultaneously extracting the organic solvent. This rapidly forms the dry, solvent-free particles needed for pharmaceutical formulation, which collect in the base of the particle generation vessel.

The 'engineering' of the particles' physical properties results from tight control of the operating conditions within the vessel. 'BPD has shown that a range of directed property changes - including particle size and shape, crystalline phase, polymorphic purity, improved chemical purity profile and reduced residual solvent - can be achieved for a wide variety of chemicals,' the company says. This wide variety includes inorganic chemicals, polymers, organic molecules and biologicals materials, such as peptides and proteins, which are becoming increasingly important to the pharmaceutical industry.

The advantages of the process aren't confined to process technology. For respiratory drugs, it allows the formation of 1-5micron particles - the optimum size for deep penetration into the lungs. Currently, particles of this size can only be made by high-energy milling which, apart form the safety problems detailed above, risks damaging the crystalline structure of the particles, making them less effective. Moreover, it creates highly-charged material which sticks together is are difficult to process. SEDS particles, however, are formed at the size needed, so are highly crystalline, stable and uncharged.

SEDS can help pharmaceutical manufacturers avoid the problem of poor solubility, which is increasingly common with current drugs. If the active ingredients cannot dissolve in the bloodstream, they can't be absorbed by the body and therefore don't work. SEDS offers two ways around this: particles can be made with diameters of less than a micron and huge surface areas, which maximises the dissolution rates; or the active ingredient can be co-formulated with a polymer, which makes the active ingredient amorphous and therefore more likely to dissolve. Current technology achieves this by co-precipitation or spray drying, but BPD claims that SEDS gives finer micron or non-sized particles and reduces the polymer loading of the particles.

Another area where SEDS could challenge the status quo is in the fast-developing world of protein and peptide drugs. Again, the current technologies for particle formulation are spray and freeze drying, but evidence suggests that these can both damage the active ingredients. Particles made using the SEDS technique are stable, flowable and require no additives.

A matter of taste The system can also be used as part of the formulation process. SEDS allows the separation of components from a mixture, by encouraging the selective formation of particles of one substance over another. It can also be used to generate particles containing both active ingredients and excipients, or of coated microparticles with modified drug release properties or masked taste. The current manufacturing facility is a small-scale unit, configured in accordance with current good manufacturing practice to produce clinical research materials. Scaled-up 40-fold from York and Hanna's original laboratory rig, the plant will be used to convince the pharmaceutical majors that the SEDS system will add value to their products while saving them time and money. 'This facility will speed the clinical evaluation of new particulate products,' comments Malcolm Skingle, manager of global external scientific affairs at Glaxo Wellcome. 'The technology will benefit many aspects of pharmaceuticals processing.'PE