HSE and RAS Scientists Describe the 'Double Collective Slowing' of Drug Molecule Responses

The model linked molecular shape, medium density and diffusion

Drug molecules can rapidly change their spatial shape, yet their overall measurable response may decay slowly — because of their surroundings. Using ibuprofen in supercritical carbon dioxide as an example, researchers from HSE University and the Institute of Solutions Chemistry of the Russian Academy of Sciences described this effect; the HSE press service told Gazeta.Ru about the work. The study is published in The Journal of Chemical Physics.

What happens near the critical point

Supercritical CO₂ exists at temperatures and pressures above the critical values; such a solvent is used, in particular, to produce fine particles of pharmaceutical substances: when the pressure is lowered, the dissolved compound precipitates into a solid phase. Even before particles form, the medium affects the ratio of conformations — the different shapes of flexible molecules. Near the critical point, the solvent density fluctuates strongly: regions of higher and lower density grow larger, and their rearrangement slows down.

Double collective slowing

The authors built a model linking three processes: changes in molecular shape, density fluctuations, and diffusion — the redistribution of solution components. The calculations revealed two slow collective processes: one associated with density fluctuations, the other with the need to transport matter over ever greater distances. The molecules themselves continue to change shape rapidly, but their coupling with the slowly rearranging solvent makes both processes visible in the measured signal. The authors called this mechanism double collective slowing.

Author's comment and practical significance

“The slow memory of the solvent is passed on to the molecules, although the rate of the transitions between shapes themselves remains practically unchanged,” explained Yuri Budkov, a leading research fellow at HSE MIEM. In the model example, the response could decay according to a power law, considerably more slowly than the usual exponential. According to the authors, the model helps explain why measurements of molecular transformations may reflect not only the rate of the transformations themselves but also the prolonged rearrangement of the surrounding medium. For technologies producing drug microparticles in supercritical CO₂, this means that the measured kinetics may contain a contribution from the medium that cannot be reduced to the properties of the molecules themselves — this interpretation follows from the model described in the paper.