Are metastable polymorphs stable solid solutions?

Polymorphism is the ability of a compound to crystallise in more than one crystal structure. Since most drug compounds are crystalline, discovery and control of polymorphism is a key aspect of drug development and manufacturing.

It is well known in this context that metastable polymorphs are usually discovered first and that stable polymorphs may make an appearance eventually (with time and money). Often, this appearance is linked to an increase in the purity of the active pharmaceutical ingredient (API). Whilst this is general knowledge shared by crystallisation scientists, we currently have a very limited understanding of the fundamental reasons behind it.

In the current project we seek to utilise the above observation to our advantage. We have some experimental and computational evidence that impurities are in fact changing the thermodynamic stability of solid forms through insertion in their crystal lattices (formation of solid solutions). We seek to first test and confirm our hypothesis to then exploit this concept in order to access elusive polymorphs experimentally, be able to produce them reliably and exploit their structure and properties. Developing a deeper understanding of the impact of impurities in the formation of solid solutions and thus in the realisation of solid forms will have a significant impact in the development of pharmaceuticals, a multi-billion pounds business of great importance to the UK economy.

The main aim of this project is to stabilise polymorphs through the formation of solid solutions with small amount of additives. Not only will this project allow for the realisation of new crystal forms but also for the utilisation of old crystal forms because of the extra thermodynamic stability that the additive will bring on them.

Through an understanding of crystal and molecular structure and the interactions of foreign molecules in a drug lattice, we seek to make new improved drug crystal materials. This research will have several areas of impact:
1. It will generate new fundamental knowledge in the formation of solid solutions and the impact of impurities on polymorph stabilities.
2. Through the developed strategy, new predicted crystal polymorphs will be realisable (some offering improved bioavailability).
3. Such knowledge will be disseminated through talks and posters at conferences as well as publications.
4. Software will be developed and delivered other academics and industrial partners. Such software will assist the design of new solid solutions and the selection of impurities that will selectively stabilise a metastable polymorph.
5. Knowledge will be transferred to industry through different strategies.
6. Staff will be developed. This include the PI, a PDRA and a PhD student which has been funded through an iCASE award.
7. The long term impact of this strategy would be to accelerate drug R&D thus potentially reducing drug development times and costs.