Some compounds, particularly pharmaceuticals, are difficult to micronize by conventional grinding or jet milling. For example, materials that have low (< 60°C) melting point or that are waxy cannot be ground or milled to fine size (< 1 or 2 m) because they will smear or form amorphous (and size unstable) particles. Two supercritical fluid processes have been developed in response to these difficulties:
In one, supercritical fluids are employed to dissolve a compound, then by pressure decrease cause precipitation.
In the other process, the gas acts as an antisolvent, causing recrystallization because of solubility decrease.
The pressure dependent solubility of materials in SCFs forms the basis of the particle formation process termed RESS (Rapid Expansion of Supercritical Solutions); RESS is employed with SCF soluble compounds. If a compound is not soluble in a gas (and many very polar compounds are not), the gas can be used as an antisolvent, causing recrystallization when the gas and an organic solvent solution are admixed.
The process termed GAS (Gas Anti Solvent) Recrystallization exploits the miscibility of carbon dioxide with virtually all laboratory and industrial solvents. With a gas antisolvent the rapidity and intimacy of mixing far exceeds what liquid antisolvents can achieve. SCF recrystallization processes have been applied to scores of pharmaceuticals, polymers, cosmetics, biomolecules, dyes, and even explosives.
The advantages of both processes reside in the (literally) millisecond time scale for pressure reduction or admixing of solution and gas, which creates a high supersaturation ratio resulting in the formation of ultrafine particles of narrow size range. The ability to produce micron or submicron particles opens up a spectrum of opportunities for the creation of new or improved products.
For example, creation of a new pharmaceutical product that could be delivered via inhalation, instead of parenterally, would certainly justify the application of supercritical fluids, especially if traditional jet milling could not achieve the desired product characteristics.
The jet milled steroid shown in the top photograph below contains 8% particles larger than 3 microns, and it cannot be used in a specific ophthalmalogical ointment. Current particle processes are inadequate for producing the required particle size and size distribution to meet the stringent specification: no particles greater than 3 microns.
8% Particles larger than 3 microns by traditional methods
100% Particles less than 3 microns by SCF
Supercritical fluids produce ultra fine, narrow range (none greater than 3 microns), solvent free material as shown above.
The application of supercritical fluids in the pharmaceutical industry is further discussed within this site. See our published article on supercritical fluids in the pharma industry.
Supercritical fluids provide processing capabilities not available with other purification and recrystallization methods. Phasex has developed processes for purifying heat labile compounds, recrystallizing pharmaceuticals, and extracting active components from botanical substrates. Our selective extraction and recrystallization using supercritical fluids has benefited the pharmaceuticals industry with increased yield and solvent-free products.