The work concerns the developability of BCS Class II drugs – lead molecules that exhibit low solubility but good permeability, explained Axel Zeitler, Professor of Microstructure Engineering at the University of Cambridge.
“If solubility from any known crystalline phases is too low, making the drug into an amorphous formulation is a great opportunity to keep the drug candidate in development,” he told us.
However, it is currently nearly impossible for a pharmaceutical company to quickly test if such an amorphous form would have sufficient physical stability.
“The only way to find out reliably is to make a drug amorphous and store it for up to two years and check afterward whether or not the drug is still amorphous,” explained Zeitler, noting that the process is wasteful, expensive, and time-consuming.
While researchers have tried to develop assays to test for the stability of amorphous drugs, Zeitler said all the methods were linked to the glass transition temperature.
“In our work, we show that it is not the glass transition temperature that matters but the temperature of a lower transition process, which we have shown represents the true onset of molecular mobility,” he explained.
The researchers, from the Universities of Cambridge and Copenhagen, used optical and mechanical measuring techniques and found that localized movement of molecules within a solid is responsible for crystallization.
Zeitler said the development will enable companies to screen drug molecules to find out which ones will “happily stay amorphous for a really long time and which ones will rapidly crystallize.”
“If the drug stays amorphous happily it is very easy to make it into a better soluble drug product and the company can be confident that the drug remains amorphous over the shelf life of the product,” he added.
This allows companies to reduce risk by identifying potential problem molecules early in the development process. The advance could also potentially give new life to previously discarded molecules.
Zeitler said there has been “quite some interest” from pharmaceutical companies, and while he was unable to tell us any company names, he said it is fair to state that “a good number of large pharmaceutical companies are actively interested in this technology.”
The technology has been licensed to a Cambridge spin-out company TeraView, which is developing the method for use in the pharmaceutical industry.
Author: Michael T. Ruggiero et al
Title: The significance of the amorphous potential energy landscape for dictating glassy dynamics and driving solid-state crystallisation
Source: Physical Chemistry Chemical Physics, 19, 30039-30047 (2017)
Author: Eric Ofosu Kissi et al
Title: The glass transition temperature of the β-relaxation as the single predictive parameter for recrystallization of neat amorphous drugs
Source: The Journal of Physical Chemistry B (2018)