High-Throughput Screening for Discovery of Novel Solid Forms
Author: Bahareh Khalili, PhD, Manager, Solid State Research & Development, Eurofins CDMO Alphora Inc.
Polymorphism can be a major challenge in drug development. Ritonavir, the anti-HIV medication, is a famous story dealing with this challenge. Late discovery of a more stable and less soluble polymorph while the drug was released to the market, severely impacted patients, and manufacturing, costing Abbott hundreds of millions of dollars.
Unfortunately, there is no reliable way of predicting polymorphic landscape of active pharmaceutical ingredients (API) as of now. Although there has been numerous research done on computational prediction of 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. Combination of different solvents/solvent mixtures with different crystallization techniques and varying API concentration 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 discovery of novel solid forms. That is why high-throughput screening (HTS) can be beneficial when exploring polymorphic landscape of APIs.
At Eurofins CDMO Alphora, our team of solid state experts utilize high-throughput screening to maximize the chance of discovering new solid forms. Our HTS platform enables us to execute hundreds of crystallization trials in parallel using minimum amount of material. We explore several solvents/solvent mixtures and crystallization techniques concurrently. High-throughput characterization of the final solids makes it possible to identify novel crystalline forms that will be then prepared in larger scale for complete physicochemical characterization. Similar approach is also applied to discovery of new salts and co-crystals which are usually screened to improve physicochemical properties of the API such as solubility and stability.
A routine high-throughput screening in our solid state lab is summarized bellow:
- ~290 trials in one screening
- 3 crystallization techniques and ~40 solvent systems
- <1 g of material required
- In 2 weeks
- HTS-PXRD characterization
Selected solid forms preparation and characterization:
- PXRD
- DSC/TGA
- DVS
- HPLC/NMR
- PLM/SEM
Solubility, stability, dissolution, and permeability assessment of the selected solid forms:
- Accelerated stability
- PION Micro Flux
This workflow allows exploring common solvents with different techniques for crystallization 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.
