Crystallization is a physical process by which solid matter is formed from the reorganization of the constituent atoms or molecules into a highly ordered structure known as a crystal. Crystals may form by precipitating from a solution, by freezing, or by deposition directly from a gas. In microgravity, the absence of buoyancy-driven convection affects each of these physical processes.
Large Molecule Crystallization (e.g., protein crystal growth) is used for drug discovery by structural definition or target site identification, or improvements in producing, processing, and/or purifying active pharmaceutical ingredients (APIs) from large and/or complex molecules.
- Some macromolecules, including many biologics like proteins or some monoclonal antibodies, have been difficult to crystallize on Earth in sufficient quantity and/or quality. This is because insufficient homogeneity or non-uniform size distributions result in a disordered crystalline structure as the crystal size increases. A lack of homogeneity in crystalline structures formed in 1g not only limits our ability to characterize the physical structure of some macromolecules for research applications but also limits the safety and efficacy of therapeutics for clinical application, including those which may have already been granted FDA approval. Microgravity crystallization has been successful in producing large, uniform crystals from previously difficult-to-crystallize macromolecules. Space-based crystallization has resulted in significant advancements in our knowledge of the macromolecular structure of investigational new drugs (INDs) and the discovery of potential binding sites on drug targets inside the body with high specificity and fewer side effects.
- Merck & Co. is leveraging the ISS National Lab to improve the manufacturing process for the production and purification of monoclonal antibodies for cancer therapeutics using crystallization processes in microgravity. A previous ISS National Lab-sponsored experiment focused on pembrolizumab (Keytruda®), Merck’s cancer immunotherapy drug, developed crystalline suspensions of the monoclonal antibody in high yield with homogeneous particle sizes that benefit drug purification steps and drug delivery to patients on Earth.
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- In a project funded in part by the National Cancer Institute, researchers from Frederick National Laboratory for Cancer Research sought to leverage microgravity to improve crystallization of a protein linked to several of the deadliest cancers, including pancreatic, lung, and colon cancers. Results showed that microgravity can significantly improve the quality of certain protein crystals, providing data that enables structure determination not possible using Earth-grown crystals.
KRAS protein crystallization samples in a 96-well tray.
Media Credit: Image courtesy of Frederick National Laboratory for Cancer Research
Small Molecule Crystallization is used for drug development and improvements in producing, processing, and/or purifying active pharmaceutical ingredients (APIs) from small molecules.
Microgravity has been shown to improve crystalline uniformity and generate novel crystal morphologies, sometimes yielding crystalline products with improved performance characteristics when compared with crystals grown on Earth from the same constituent atoms or molecules. It is possible that new crystalline polymorphs can be produced in microgravity and returned to Earth as seed crystals for terrestrial manufacturing—negating the need for transportation to and from LEO for scaling manufacturing to meet demand.
