Polymorphism can be a major challenge in drug development. Late discovery of a more stable and less soluble polymorph at late development stages can severely impact patients and manufacturing costs.
Unfortunately, there is no reliable way of predicting the polymorphic landscape of active pharmaceutical ingredients (API) as of now. Although there has been numerous research done on computational prediction of the number of polymorphs, their solid structure, and characteristics, we are nowhere close to relying on these predictions. So, for now, empirical experimentation is the best tool for discovery and understanding API polymorphism.
When designing polymorph screening experiments, different parameters need to be considered. Combinations of different solvents/solvent mixtures with different crystallisation techniques and varying API concentrations can result in the formation of different polymorphs. Since predictions are not possible yet, the larger the number of trials, the higher the chance of discovering novel solid forms. That is why high-throughput screening (HTS) can be beneficial when exploring the polymorphic landscape of APIs.
The Eurofins CDMO Alphora team of solid state experts utilises high-throughput screening to maximise the chance of discovering new solid forms. Our HTS platform enables us to execute hundreds of crystallisation trials in parallel using a minimum amount of material. We explore several solvents/solvent mixtures and crystallisation techniques concurrently. High-throughput characterisation of the final solids makes it possible to identify novel crystalline forms that will then be prepared at a larger scale for complete physicochemical characterisation. A similar approach is also applied to the discovery of new salts and co-crystals, which are usually screened to improve the physicochemical properties of the API, such as solubility and stability.
This workflow allows us to explore common solvents with different techniques for crystallisation and gives us a good picture of the polymorphic landscape complexity. Depending on the results, more screenings may be designed, or the best solid form may be selected based on the physicochemical characteristics, solubility and stability. Performing these solid form screenings early on during development and selecting a suitable solid form is essential to the success of drug development and to avoid unpredicted challenges related to polymorphism at later stages. For more information, visit: www.eurofins.com/CDMO