Cheaper pharmaceuticals

The manufacture of pharmaceuticals could be made cheaper with a new system that monitors the crystallisation of chemical compounds used for drugs.

The process analytical technology (PAT) tool includes a probe, which collects images of the crystallisation process inside a pharmaceutical reactor, and software to determine the size and shape of the drug compound crystals. The information gathered can give indications on the purity and quality of the product.

‘The feeling is that if we go to a culture of full process understanding we will get cheaper products,’ said Prof Kevin Roberts of Leeds University’s Institutes of Process Research and Development and Particle Science and Engineering.

His research team worked with industrial scientists at Perdix Technologies in the Netherlands to develop and commercialise the probe, which they combined with Morphologi, commercially available image analysis software developed by the UK’s Malvern Technologies.

Roberts said until now there has been little effort made to monitor and control the crystal formation in pharmaceutical manufacturing.

He said Leeds has developed a technique that uses powder X-ray diffraction to analyse crystal forms of a drug while it is being processed (The Engineer, 16 June).

‘In general we don’t actually control the formation of crystals in the manufacturing process and that means that product properties of crystals can be quite variable,’ he said.

‘So after crystallising the active pharmaceutical ingredient of a drug compound you might get a range of sizes and shapes of crystals.’

Roberts said this means before the product can be formulated into a tablet, the particles must be processed so they attain the same size and physical properties.

‘Now we want to make the crystals in such a way they formulate directly,’ he said.

The new In-Situ Particle Viewer (ISPV) probe would film inside the reactor so operators can see exactly what is happening to the crystals as they are forming. If a crystal were forming in an irregular manner, the operator would be able to adjust the conditions inside the reactor to correct it.

One parameter they could change, Roberts said, would be the rate at which the crystal is cooled.

Roberts said that when the probe is combined with the image analysis software it is capable of revealing information that pharmaceutical manufacturers never had before.

Roberts said the part that makes analysis of crystals so challenging is that it is difficult to attain measurements of products that are not spherical.

‘The image analysis software automates the process and it can tell you lots of things about the crystal, such as the shape distribution and the distribution of perimeters of particles,’ he said. ‘If the crystal was breaking up under the fluid mechanics’ shear stress inside the vessel you could see it from the shape distribution.’

This kind of monitoring and control, he said, will help the pharmaceutical manufacturing process become faster and more efficient, which will cut waste, save money and shorten the time it takes drugs to get to market.

Roberts said increased control over pharmaceutical manufacturing processes would be a ‘paradigm shift almost identical to the semiconductor industry’.

He said: ‘Essentially we’re working towards developing high-quality Six Sigma manufacturing processes for the pharmaceutical sector, very much mirroring the approaches already adopted by high-tech sectors such as microelectronics.’

Leeds worked with a number of global pharmaceutical companies on the project, including GSK, Pfizer and AstraZeneca. The ability to monitor the crystallisation process will make an obvious difference in their industry, Roberts said, since nearly 80 per cent of all drug compounds are made that way.

However, the technique could also have lesser known applications outside the pharmaceutical industry.

‘Crystallisation is also used in making chocolate, sugar, salt, all agrichemicals and speciality materials and dyes pigments,’ he said. ‘It’s a very common technique.’

Roberts added that the global agribusiness Syngenta and the UK-based nuclear technology specialists Nexia Solutions were involved in the project and are interested in using the system for their manufacturing processes.

‘Crystallisation is very important for manufacturing of nuclear fuel as well,’ he said.

Siobhan Wagner