Researchers from the Universities of Cambridge and Copenhagen have developed a new method of predicting the physical stability of potential drug candidates, which could help in the development of more effective medications. The results were published in two papers, Physical Chemistry Chemical Physics and The Journal of Physical Chemistry B.

Solids have a molecular structure of either crystal (ordered) or glass (disordered). Though chemically these forms are exactly the same, they have different properties. Most importantly, solids with a glass structure are more soluble in water, making them especially useful for medical applications as medicines need to be water-soluble in order to dissolve into the bloodstream and effectively reach their target.

Many molecules in the glass form have been discovered to provide cures, but their structural instability has meant they are not being used for medicines. However, the newly developed method will allow previously discarded drug molecules to be re-considered for use in a stable glass form.

“Most of the medicines in use today are in the crystal form, which means that they need extra energy to dissolve in the body before they enter the bloodstream,” said study co-author Professor Axel Zeitler.

“Molecules in the glass form are more readily absorbed by the body because they can dissolve more easily, and many glasses that can cure disease have been discovered in the past 20 years, but they’re not being made into medicines because they’re not stable enough.”

The study investigated how to predict when and how a solid will crystallise. Using optical and mechanical measuring techniques, researchers found that the movement of molecules within a solid is ultimately responsible for crystallisation, a hypothesis that was first proposed in 1969 but which has remained unproven until now.

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Glass solids undergo spontaneous crystallisation after a certain period of time, causing them to lose their disordered structure and all of the properties that makes them effective. As such, scientists have long been concerned with how they can predict when crystallisation will occur.

“This is a very old problem, and for pharmaceutical companies, it’s often too big of a risk,” said Zeitler.

“If they develop a drug based on the glass form of a molecule and it crystallises, they will not only have lost a potentially effective medicine, but they would have to do a massive recall.”

Solving the question of how to predict crystallisation would mean a more widespread and practical application of glass solids.

Previous studies had examined the glass transition temperature when trying to monitor the crystallisation process. This is the temperature above which molecules can move more freely within a solid and be measured more easily.

However, Zeitler and his colleagues used dynamic mechanical analysis and terahertz spectroscopy to demonstrate that molecular movements at a lower temperature are responsible for crystallisation. Compared to the large molecular motions that occur above the glass transition temperature, the movements above the lower temperature threshold are much smaller and subtler. Though harder to measure, the localised movement is a crucial part of crystallisation.

“If we use our technique to screen molecules that were previously discarded, and we find that the temperature associated with the onset of the localised motion is sufficiently high, we would have high confidence that the material will not crystallise following manufacture,” said Zeitler. “We could use the calibration curve that we describe in the second paper to predict the length of time it will take the material to crystallise.”

The technology has been licensed to Cambridge spin-out company TeraView, which will commercialise its use in the pharmaceutical industry to make medicines that can be released more easily into the body.