SuperFluids™ Crystallization - CRY

Crystallization of natural therapeutics for improved purity and polymorphism

SuperFluids™ CRY Process

In Aphios' SuperFluids™ CRY process, a supercritical or near-critical fluid is slowly added to a conventional organic liquid solvent containing the solute to be crystallized.

If the supercritical or near-critical fluid is used as the anti-solvent, its dissolution into the solvent is typically accompanied by a change in polarity of the solvent mixture, and consequently, a reduction of the fluid's solvation power relative to a particular substance. Density may also decrease, resulting in further reduction in solvation capacity. As a result, the mixture becomes supersaturated, which causes nucleation at the molecular level and the formation of well-ordered and highly pure crystals. In certain cases, the mixture density may actually be greater than that of the neat solvent. In this case, crystallization is caused primarily by the polarity change of the mixture.

Crystals can be recovered by simply decompressing the mixture or displacing the SuperFluids™ mother liquor under isobaric and isothermal conditions. Simple decompression will result in the co-precipitation/crystallization of impurities from the SuperFluids™ mother liquor.

The preferred technique for harvesting crystals is the displacement of SuperFluids™ mother liquor under isobaric and isothermal conditions. This can be done with neat anti-solvent which would gradually change the molar composition of the SuperFluids™ mother liquor and reduce the co-precipitation/crystallization of impurities.

Crystals are preferably harvested by the displacement of SuperFluids™ mother liquor with an equivalent polarity SuperFluids™ stream under isobaric and isothermal conditions. This technique should result in well-ordered crystals of the largest size and highest purity.

The SuperFluids™ CRY process can also be reversed in that the SuperFluids™ can become the solvent of the natural therapeutic with the co-solvent as an anti-solvent. Such a reversal will result in the crystallizing out of closely related impurities and an improvement in the purity of the natural therapeutic. The latter can then be recovered by slow decompression and reduction in the density and solvation capacity of the SuperFluids™.

Differences Between CRY and Other Supercritical Fluid Crystallization Processes

Aphios' SuperFluids™ CRY process differs from the GAS and CAFS processes. In the latter, organic compounds are first dissolved in an organic solvent and then rapidly injected into the supercritical fluid phase resulting in precipitation/crystallization as a result of dramatic changes in solubility.

Alternatively, the organic solvent is solubilized into a supercritical fluid phase and then rapidly expanded. These processes do not depend on the development of a super-saturation state which results in nucleation at the molecular level.

Harvesting of crystals by the GAS and CAFS techniques is also done by the simple decompression technique which could result in highly impure crystals if the feedstock has impurities that are closely related to the compound of interest.

Advantages and Benefits of the CRY Crystallization Process

  • Improved product purity as a result of the formation of high-quality crystals
  • Environmental advantages due to a reduction in the use of organic solvents, as the anti-solvents are typically inorganic compounds. The generation of problematic mixed organic solvent phases is avoided.
  • Improved product quality with less residual solvent contamination, as the anti-solvent compound has high volatility and is thus readily removed from the product material
  • Improved handling and formulation properties by virtue of compact crystal morphology
  • Improved processes and products in the area of drug delivery, e.g., more uniform and extended release of therapeutic from microsphere carriers
  • Improved process economics


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