Precipitations using supercritical fluids

Several techniques have been proposed using supercritical fluids for precipitations. The main advantage is the lower viscosity of supercritical fluids compared to classical fluids, which facilitates mixing and thus higher supersaturations can be achieved. Due to its ready availability, negligible toxicity, and convenient critical point of 32 °C and 100 bar, carbon dioxide is used in most cases as a supercritical fluid. 

The supercritical or near-critical carbon dioxide is used as a solvent, as the solubility of most organic compounds is substantia] near the critical point and decreases readily with decreasing pressure. On the other hand, near-critical carbon dioxide can also be used as antisolvent, as the critical fluid can dissolve to substantial amounts in organic solvents. At the same time, the solubility of organic compounds in the organic solvent is substantially decreased. 

Organic solvents are known to dissolve considerable amounts of carbon dioxide when pressurized to near- or supercritical conditions. Concurrently, the solubility of 

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Martin, T.M. Bandi, N. Shulz, R. Roberts, C.B. Kompella, U.B. Preparation of budesonide and budesonide-PLA microparticles using supercritical fluid precipitation technology. AAPS Pharm. Sci. Tech. 2002, 3 (3), El 8. 

Debenedetti and coworkers (88,89) provided one of the first examples of microencapsulation of a drug in the polymeric matrix. Richard and coworkers (90) provided a recent example of the microencapsulation process when they produced microparticles with the encapsulated model protein that showed sustained release. Foster and coworkers (87) also reported precipitation of copper-indomethacin by PVP with a 96-fold enhancement in the dissolution rate of indomethacin. These examples clearly demonstrated the advantages of using supercritical fluid processing for the preparation of polymer-drug formulations with potentially improved therapeutic properties. 

Kompella UB, Koushik K. Preparation of drug delivery systems using supercritical fluid technology. Crit Rev Ther Drug Carrier Syst 2001 18 173-199. Petersen RC, Matson DW, Smith RD. Precipitation of polymeric materials from supercritical fluid solution the formation of thin films, powders, and fibers. Polym Prepr (Am Chem Soc, Div Pol Chem) 1986 27 261-262. 

Extraction of nicotine from tobacco using supercritical fluid is carried out in a manner quite similar to the decaffeination of roasted coffee described in U.S. 3,843,824. Tobacco is first contacted with dry supercritical CO2 which extracts the aroma constituents. The C02-aroma stream is expanded to subcritical conditions via expansion across a valve the aromas precipitate from soludon. The CO2 vapor is recompressed, is adjusted in temperature to supercritical conditions via heat exchangers, and is recycled to the extractor via a compressor. The aromas extracdon step condnues until the aroma constituents are removed from the tobacco. 

Montes, A., Gordillo, M.D., Pereyra, C., de la Rosa-Fox, N., and Martmez de la Ossa, E.J. Silica microparticles precipitation by two processes using supercritical fluids. The Journal of Supercritical Fluids 75 (2013) 88-93. 

Compressed gases (such as carbon dioxide) can also be used effectively as solvents for extraction of coal. Toluene, dodecane, p-cresol, etc. can be applied under supercritical conditions. Some advantages of using supercritical fluid as solvents are (1) an extract with low molecular weight (approximately 500) and higher hydrogen content can be obtained, (2) solvent recovery is easy, and (3) the reduction in the operating pressure or temperature precipitates the extract. 

When using supercritical fluids in place of liquids (non-solvent),an advanced, and greener, manufacturing approach to induce precipitation of the polymer can be achieved. This approach is commonly named the supercritical assisted phase inversion method (SAPIM) (Cardea et al, 2010). 

Gas AntisolventRecrystallizations. A limitation to the RESS process can be the low solubihty in the supercritical fluid. This is especially evident in polymer—supercritical fluid systems. In a novel process, sometimes termed gas antisolvent (GAS), a compressed fluid such as CO2 can be rapidly added to a solution of a crystalline soHd dissolved in an organic solvent (114). Carbon dioxide and most organic solvents exhibit full miscibility, whereas in this case the soHd solutes had limited solubihty in CO2. Thus, CO2 acts as an antisolvent to precipitate soHd crystals. Using C02 s adjustable solvent strength, the particle size and size distribution of final crystals may be finely controlled. Examples of GAS studies include the formation of monodisperse particles (<1 fiva) of a difficult-to-comminute explosive (114) recrystallization of -carotene and acetaminophen (86) salt nucleation and growth in supercritical water (115) and a study of the molecular thermodynamics of the GAS crystallization process (21). 

The usual means of identifying and quantifying the level of these additives in polymer samples is performed by dissolution of the polymer in a solvent, followed by precipitation of the material. The additives in turn remain in the Supernatant liquid. The different solubilites of the additives, high reactivity, low stability, low concentrations and possible co-precipitation with the polymer may pose problems and lead to inconclusive results. Another sample pretreatment method is the use of Soxhlet extraction and reconcentration before analysis, although this method is very time consuming, and is still limited by solubility dependence. Other approaches include the use of supercritical fluids to extract the additives from the polymer and Subsequent analysis of the extracts by microcolumn LC (2). 

Applications The majority of SFE applications involves the extraction of dry solid matrices. Supercritical fluid extraction has demonstrated great utility for the extraction of organic analytes from a wide variety of solid matrices. The combination of fast extractions and easy solvent evaporation has resulted in numerous applications for SFE. Important areas of analytical SFE are environmental analysis (41 %), food analysis (38 %) and polymer characterisation (11%) [292], Determination of additives in polymers is considered attractive by SFE because (i) the SCF can more quickly permeate throughout the polymer matrix compared to conventional solvents, resulting in a rapid extraction (ii) the polymer matrix is (generally) not soluble in SCFs, so that polymer dissolution and subsequent precipitation are not necessary and (iii) organic solvents are not required, or are used only in very small quantities, reducing preparation time and disposal costs [359]. 

For the analysis of organic additives in polymeric materials, in most cases, prior extraction will be necessary. Depending on the nature of the additive, many different approaches are employed. These include soxhlet extraction with organic solvent or aqueous media, total sample dissolution followed by selective precipitation of the polymer leaving the additive in solution, assisted extraction using pressurised systems, ultrasonic agitation and the use of supercritical fluids. In trace analysis, solid phase extraction (SPME) from solution or solvent partition may be required to increase the analyte concentration. 

The same types of catalyst have been employed in 1-octene hydroformylation, but with the substrates and products being transported to and from the reaction zone dissolved in a supercritical fluid (carbon dioxide) [9], The activity of the catalyst is increased compared with liquid phase operation, probably because of the better mass transport properties of scC02 than of the liquid. This type of approach may well reduce heavies formation because of the low concentration of aldehyde in the system, but the heavies that do form are likely to be insoluble in scC02, so may precipitate on and foul the catalyst. The main problem with this process, however, is likely to be the use of high pressure, which is common to all processes where supercritical fluids are used (see Section 9.8). 

PCA [Precipitation with a compressed anti-solvent] A process for making a solid with unusual morphology by spraying a solution of it into a supercritical fluid. The process resembles spray drying into a supercritical fluid. Used for making microspheres, microporous fibers, and hollow microporous fibers. 

In the RESS method, the solute of interest is solubilized in a supercritical fluid, which is then rapidly expanded through a nozzle. As the fluid expands, it loses its solvent capabilities and the solute precipitates out. While this technique has the advantage of not using any organic solvent, it is restricted by the generally poor solubility of most polymers in supercritical fluids. Indeed, polymers generally have to be below 10,000 MW in order to be eligible for this method of particle production [126]. 

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