A technology that could help pharmaceutical companies significantly reduce the costs of developing drug compounds by monitoring crystals as they form has been created by a UK university.
Researchers at Leeds University and Durham-based industry partner Bede X-Ray Metrology have developed a technique that uses powder X-ray diffraction to analyse crystal forms of a drug while it is being processed in a reactor (online) rather than removing a sample from the reactor to test (offline).
‘We have refined the technology to the extent that we have a system you can wheel into a pilot plant and hook it up. Basically you can pump your slurry around the instrument and while you are doing crystallisation of some kind, which might take several hours, you can actually monitor what’s going on,’ said Dr Robert Hammond at Leeds.
The temperature-controlled cell is connected to a reactor, or crystalliser, using coaxial pipes, which are insulated with a heating jacket to ensure the sample travels through the cell and back into the reactor under constant temperature conditions, as a change in heat levels would affect the crystallisation process. When the sample flows into the device, an X-ray generator illuminates the sample and a measurement of diffraction is taken from the flowing slurry.
‘Some of the X-rays are diffracted by the crystals and the angle at which the X-rays are diffracted depends on the internal arrangement of the molecules in the crystal,’ said Hammond.
‘Each individual polymorph of a pharmaceutical material will have a set of characteristic diffraction peaks, which means the X-ray diffraction pattern is a “finger print” for a particular polymorph.’
The diffraction patterns are monitored using a curved, position-sensitive detector — a gas-filled detector that can detect X-ray diffraction events at all diffraction angles simultaneously.
Hammond said: ‘A diffracted X-ray enters the detector and causes gas molecules to be ionised, which in turn causes a current to flow due to a high voltage potential that is applied.
‘The difference in the time at which the current is detected at either end of the detector indicates the position, and therefore the angle, at which the diffracted X-ray originally entered the detector.’
X-ray diffraction is normally used in offline analyses on a small scale, such as in a laboratory setting, by separating out the solid from the slurry and looking at its composition in a diffractometer. This allows researchers to experiment with different types of recrystallising solvents before scaling them up for mass production.
‘If you are doing polymorph screening, you can then try lots of different solvents and combinations, and you could very rapidly evaluate the different polymorphs you are getting from different recrystallisation solvents,’ said Hammond.
However, he said doing this process online would provide significant benefits for drug companies carrying out stage one clinical trials, that is, the point at which they are testing the scalability of the process.
Normally researchers try to avoid isolating samples from a crystallisation process until the end, but this means that the point at which problems occur cannot be easily or accurately ascertained.
‘If you get unexpected change in the form just because you are doing it at a different scale size the thing about having this thing online is you can see something is happening within a few minutes because you can see the diffraction patterns,’ said Hammond.
‘They can then do something to change the material — they might reheat or rework it, rather than ending up with a batch of material in the wrong form.’
In line with regulation, companies are not allowed to rework materials once they have been produced so are obliged to destroy problem batches, for example, by incineration.
The results of this are high levels of wasted materials, cost and delays in getting the product to market, which is important because companies only have a limited time to recoup their investment before generic drugs can infiltrate the market.
A UK university has developed technology that could help pharmaceutical companies significantly reduce the costs of developing drug compounds