Exploring the cutting-edge science that's transforming medicine, materials, and manufacturing at the microscopic level
Imagine a substance that can seep through solid materials like a gas while simultaneously dissolving compounds like a liquid. This isn't a futuristic concept from science fiction—it's the remarkable reality of supercritical fluids, a unique state of matter that's quietly revolutionizing how we create microscopic particles for medicine, technology, and environmental solutions. These hybrid substances exist in a special realm where the conventional distinctions between liquids and gases blur, giving them extraordinary capabilities that scientists are harnessing to build intricate microscopic structures with unprecedented precision.
At the heart of this innovation lies a powerful application: particle formation. From life-saving medications with enhanced effectiveness to advanced materials with tailored properties, the ability to create precisely controlled microscopic particles represents one of the most significant applications of supercritical fluid technology 4 .
Traditional methods of particle creation often struggle with controlling size, shape, and purity, frequently requiring harsh chemicals or high temperatures that can damage delicate compounds. Supercritical fluids offer a cleaner, more precise alternative that's rapidly transforming manufacturing processes across industries.
Recent groundbreaking research has further unveiled that these fluids are far more complex than previously thought. A 2025 study published in Communications Physics has shaken conventional understanding by demonstrating that supercritical fluids can form long-lived liquid-like clusters even when not in equilibrium, challenging their long-standing description as purely homogeneous media 3 . This discovery not only deepens our fundamental understanding of these peculiar substances but also opens new possibilities for optimizing industrial processes that rely on their unique properties.
To understand supercritical fluids, we must first grasp the concept of the critical point—a specific temperature and pressure threshold unique to each substance where its liquid and gas phases become indistinguishable. When a substance is heated and pressurized beyond this critical point, it enters a supercritical state that defies conventional classification 6 .
This hybrid nature gives supercritical fluids their remarkable practical value. They can diffuse through solids like gases, reaching deep into porous materials, while simultaneously dissolving compounds like liquids, making them exceptionally effective processing media.
The journey to creating a supercritical fluid begins with understanding phase behavior. For every pure substance, there exists a precise combination of temperature and pressure—its critical point—where the substance can coexist as both a liquid and a gas simultaneously. Beyond this threshold, these two distinct phases merge into one homogeneous supercritical phase that exhibits properties of both states 6 .
Phase Diagram Visualization
[Interactive phase diagram showing transition from liquid/gas to supercritical fluid]
This transition isn't merely theoretical; it brings practical advantages that make supercritical fluids invaluable across industries. Their tunable density and solvation power mean that slight adjustments to temperature or pressure can dramatically alter their dissolving capability, providing exquisite control over processing conditions. Additionally, supercritical CO₂ is non-toxic, non-flammable, and environmentally benign, unlike many industrial solvents it replaces 8 .
The exceptional properties of supercritical fluids have been harnessed to develop several sophisticated particle formation techniques. These methods fall into two primary categories identified by researchers: processes for substances that are soluble in supercritical fluids (primarily the RESS method), and processes for sparingly soluble materials (mainly the SAS approach) . Together, these techniques enable the processing of an enormous range of materials into solid phases with carefully tailored properties and morphologies.
| Technique | Acronym | Mechanism | Key Applications |
|---|---|---|---|
| Rapid Expansion of Supercritical Solutions | RESS | Dissolves material in SCF then rapidly expands through nozzle to trigger precipitation | Pure drug micronization, polymer microfibers |
| Supercritical Anti-Solvent | SAS | Uses SCF as anti-solvent to reduce solute solubility in liquid solvent | Drug-polymer composites, protein microparticles |
| Precipitation from Gas Saturated Solution | PGSS | Saturated solution rapidly expands; solvent vaporizes leaving precipitated solute | Eutectic formulations, heat-sensitive compounds |
The RESS (Rapid Expansion of Supercritical Solutions) method capitalizes on the extreme sensitivity of a supercritical fluid's solvent power to small changes in pressure.
The resulting large supersaturation, coupled with the rapid attainment of uniform conditions, typically leads to small particles with a narrow size distribution .
The SAS (Supercritical Anti-Solvent) process takes a different approach, particularly valuable for substances that don't dissolve readily in supercritical fluids.
An additional advantage of this method is that the original liquid solvent becomes miscible with the supercritical fluid and can be carried away .
A third technique, PGSS (Precipitation from Gas Saturated Solution), involves dissolving the supercritical fluid as a solute in a liquid solution.
This method is particularly effective for processing polymers and heat-sensitive compounds 4 .
For decades, supercritical fluids were regarded as fundamentally homogeneous single-phase systems, distinct from subcritical fluids that exhibit clear liquid and vapor phases. This conventional view described them as structureless fluids with negligible surface tension and no phase transitions 3 . However, a revolutionary 2025 study published in Communications Physics has dramatically challenged this understanding by providing direct experimental evidence of long-lived liquid-like clusters existing in non-equilibrium supercritical fluids.
This discovery carries profound implications because supercritical fluids in industrial applications frequently operate under dynamic, non-equilibrium conditions rather than strict thermodynamic equilibrium. Understanding this newly revealed complexity offers crucial information for improving processes ranging from semiconductor cleaning to plant thermal-hydraulic engineering 3 .
The research team employed an ingenious combination of techniques to detect and characterize the elusive clusters:
The researchers created non-equilibrium conditions using a compressor system consisting of rotating motors and pistons with check valves. When the motor completed one cycle, the pistons compressed the gas and ejected it through a check valve opening at 300 bar 3 .
The team constructed a high-pressure chamber with five sapphire windows for optical diagnosis, capable of withstanding pressures up to 300 bar without leaking 3 .
For direct evidence of nanometer-scale particles, the researchers conducted small-angle neutron scattering (SANS) experiments at the 40-m SANS beamline at the HANARO experimental reactor 3 .
To observe the temporal evolution of clusters, SANS data was collected every minute, with corrections applied for detector sensitivity and electrical noise 3 .
The experiments yielded fascinating insights that challenge conventional understanding:
| Measurement Type | Observation | Interpretation |
|---|---|---|
| Opacity | Significant increase in opacity with pressure; 100 bar SCF too opaque to see through chamber | Indicated presence of dense particles scattering light |
| Visual Observation | Fogginess observed at 100 bar pressure, gradually diminishing over time; transparency restored after one hour | Demonstrated temporary non-equilibrium phase coexistence |
| Neutron Scattering | Detection of nanometer-scale features in krypton SCF | Provided direct evidence of liquid-like clusters |
| Temporal Evolution | Clusters dissolved slowly over extended timescales | Revealed long-lived nature of non-equilibrium structures |
Cluster Formation and Dissolution Over Time
The opacity measurements showed a remarkable dependence on the fluid species. Krypton exhibited a significant increase in opacity, while helium remained unchanged from its initial level at 1 bar. The researchers attributed this variation to differences in thermophysical properties, with cluster formation resulting from localized cooling caused by adiabatic expansion at the compressor outlet 3 .
Most significantly, the SANS experiments provided the first direct evidence of nanometer-scale particles in supercritical fluids under non-equilibrium conditions. These clusters form through adiabatic expansion and cooling, persisting as liquid-like fluid packages before eventually evaporating into the gas-like background. Their extended lifetime—surviving for approximately an hour—strongly influences the physical properties and behavior of the supercritical fluid in industrial applications 3 .
The pharmaceutical industry has embraced supercritical fluid technology as a green and efficient pathway for drug development. By controlling drug particle size and morphology, researchers can significantly enhance the solubility and permeability of hydrophobic drugs, thereby improving their bioavailability 4 .
Two innovative technologies—SHIFT (super-stable homogeneous intermix formulating technology) and SPFT (super-table pure-nanomedicine formulation technology)—exemplify this progress. SHIFT has been successfully applied to create homogeneous dispersions of diagnostic probes like indocyanine green in iodinated oil, providing more stable photophysical properties and longer visualization times for guiding surgical tumor resection 4 .
Beyond pharmaceuticals, supercritical fluid technology enables the production of sophisticated materials with tailored properties. The RESS process can create molecularly oriented polymer microfibers for high-performance applications, while the SAS technique allows the formation of composite drug-polymer microparticles for controlled drug release and biologically active protein microparticles for controlled delivery of peptides and enzymes .
As research continues to reveal the complex behavior of supercritical fluids under both equilibrium and non-equilibrium conditions, scientists are developing increasingly sophisticated approaches to harness their unique properties. The discovery of long-lived clusters in non-equilibrium supercritical fluids suggests potential for deliberately engineering these microstructures to optimize industrial processes 3 .
This might lead to enhanced efficiency in extraction processes, more precise control over particle formation, and new applications in fields ranging from planetary science to advanced manufacturing.
The ongoing development of supercritical fluid technology represents a compelling convergence of fundamental science and practical application. As our understanding deepens and equipment becomes more advanced, these remarkable fluids will undoubtedly continue to provide innovative solutions to complex challenges across medicine, materials science, and environmental technology—proving that some of the most powerful factories are indeed invisible to the naked eye.