(37a) A Novel Hypergravity Platform to Tune the Particle Size Distribution of Small Molecules with Increasing g-Levels

Microgravity can have a meaningful impact on pharmaceutical research and development. Decades of research on the International Space Station (ISS) have shown that a reduced gravity environment can enable improved control over particle size, shape, and crystal quality¹, which can unlock new therapeutic formulations. Commercialization of reusable rockets has increased access to low-Earth orbit and provides opportunities to conduct pharmaceutical R&D in space at relatively low cost. Microgravity suppresses convection and sedimentation, and the resulting diffusion-driven transport changes the crystallization kinetics. In contrast, an increased gravity environment achieved through centrifugal forces changes nucleation and growth rates by changing local concentration gradients. In this work², a large diameter centrifuge was used to generate high centrifugal forces. A Technobis Crystal16 reactor³ was strapped on to an arm of the centrifuge to carry out seeded cooling crystallizations of L-histidine at variable effective g-forces. It was shown that changing g-levels has a nonlinear effect on the particle size distribution of the product crystals. With increasing g-levels, the mode of the PSD initially increases, however further increases in g-level result in a reversal of the trend, and the mode of the PSD is reduced. State-of-the-art process analytical technology (PAT) including in-situ microscopy, and in-situ Raman spectroscopy were used to track the state of the system during the crystallization process. A hypothesis was constructed which depicted a spatial variation of supersaturation with increasing g-levels, which could explain the shift in the mode of the PSD with increasing g-levels. This hypothesis was validated with carefully designed dissolution experiments. The role of crystal breakage as a possible mechanism which can explain the shifts of the PSD was refuted based on experiments carried out at different g-levels. Our novel hypergravity platform can play a crucial role in generating gravity-sensitivity data for molecules to help down-select promising molecules and process conditions for microgravity flight studies.

References

1. Snell, E. H., & Helliwell, J. R., Microgravity as an environment for macromolecular crystallization–an outlook in the era of space stations and commercial space flight. Crystallography Reviews, 2021, 27(1), 3-46.
2. Pal K., Radocea A., Gravity as a knob for tuning particle size distributions of small molecules, Crystal Growth and Design, 2024, 24(6), 2301-2666.
3. https://www.crystallizationsystems.com/products/crystal16/