Bedding down with fluidisation

Pharmaceutical companies may be able to use a more environmentally friendly drug processing method if researchers in the West Midlands can successfully develop a new technique for handling nanoparticles.

Teams at Birmingham and Warwick universities are hoping to solve the problem of capturing and preserving the properties of nanoparticles produced during supercritical fluid (SCF) precipitation processes by combining it with fluidised bed technology.

'If you produce a drug substance in the nanoparticle form, it is impossible to get such a material to flow; it agglomerates very easily and is very difficult to handle and deal with. We have got what we think is a novel way of turning that into a form that can be handled, using fluidised bed technology,' said Warwick's Prof Jonathan Seville.

Fluidised beds are widely used in many industries as reactors, dryers, agglomerators and coaters. They are used in the pharmaceutical industry for coating liquids on to tablets and capsules, rather than for handling powdered active drug substances collected from SCF processes. Fluidisation in the process occurs when a fluid, usually a gas, flows upwards through a bed of solid particles and causes them to be suspended, which makes them easier to handle.

The SCF process involves dissolving a drug in a supercritical fluid, a fluid above its thermodynamic critical point that possesses properties of gas and liquid. By adjusting the pressure, nanoparticles from the drug can be precipitated from the SCF.

'We would normally use supercritical carbon dioxide, which means high pressures, typically hundred of bars, but not necessarily high temperatures,' said Seville. 'The supercritical fluid process on the whole operates not much above ambient temperature, unlike a lot of conventional processes.'

Supercritical CO₂ is a good solvent for certain kinds of drug substances. While it may be possible to dissolve some substances directly in the supercritical CO2, insoluble drug substances would have to be dissolved in another solvent, such as ethanol, and the supercritical CO₂ then used as an antisolvent, resulting in a crystallisation process.

According to Seville, SCF processes have a number of advantages over conventional crystallisation processes.

'When you precipitate out the drug, it is a shock process, so where most crystallisation processes are quite slow, this is a very fast precipitation — it happens in fractions of a millisecond. The result is you get very small and uniform particles,' he said.

Moreover, Seville said it is sometimes possible to get a different polymorphic form (substances with the same chemical composition but different crystal structures) of the drug, which could result in some drugs having more active properties.

'This sort of process has advantages in producing potentially a better product, but it also has very strong environmental advantages because most drug processing involves large quantities of organic solvents, most of which are environmentally damaging and can sometimes have toxicity problems of their own,' he added.

It is not unusual to have 100kg of waste material for every kilogram of active ingredient produced. With the SCF technique, however, the waste-cleaning element is avoided because it is only CO₂ being used, which can be recompressed or recycled.

Conventional crystallisation can be laborious in comparison, because it involves dissolving the drug in a solvent at temperature, then cooling it to produce crystals. The result is a varied distribution of crystal size and sometimes imperfect crystals, which can break up in subsequent processing. They also require washing to remove the solvent, which is a process that may be repeated several times to get the desired product.

'The washing stage is quite a difficult one, whereas we have no problem with that because if you reduce the pressure, the CO₂ will simply turn into a gas and come off,' said Seville.

While it is possible to achieve the nanoparticulate drug substances in the conventional method, Seville said it was more problematic because the bigger particles have to be milled in air jet mills, which fires them at each other at very high velocity.

The main problems include the particles not being uniform in size, and the high-speed impact can change the form of the drug and make it less effective in the body.

As well as defining a technique for handling the nanoparticles from SCF particle production, the project will cover the characterisation of the products from the fluidised beds and their conversion into tablets or other forms of dosage.

It will not just be the pharmaceutical industry that would benefit from the project's achievements, however, as the researchers said the new technology would also help manufacturers of food, toners, coatings, chemicals and catalysts.