Carbon dioxide, as antisolvent

Fusaro, F. Mazzotti, M. Gas antisolvent recrystallization of paracetamol from acetone using compressed carbon dioxide as antisolvent. Cryst. Growth Des. 2004, 0 (0), 1-9. 

Mukhopadhyay M. Purification of phytochemicals by selective crystallization using carbon dioxide as antisolvent. Proceedings of the 10th International Symposium on Supercritical Fluid Chromatography, Extraction and Processing, Myrtle Beach, SC, August 2001. 

Mukhopadhyay M. Partial molar volume reduction of solvent for solute crystallization using carbon dioxide as antisolvent. J Supercrit Fluids 2003 25(3) 213-223. 

Mukhopadhyay M, Singh S. Refining of crude lecithin using dense carbon dioxide as antisolvent. Accepted for publication in J Supercrit Fluids 2003. 

Muller M, Meier U, Kessler A, Mazzotti M. Experimental study of the effect of process parameters in the recrystallization of an organic compound using compressed carbon dioxide as antisolvent. Ind Eng Chem Res 2000 39(7) 2260-2268. 

Muhrer G, Mazzotti M. Precipitation of lysoz5une nanoparticles from dimethyl sulfoxide using carbon dioxide as antisolvent. Biotechnol Prog2003 19 549-556. 

Bakhbakhi, Y, Alfadul, S., and Ajbar, A. Precipitation of ibuprofen sodium using compressed carbon dioxide as antisolvent. European Journal of Pharmaceutical Sciences 48 (2013) 30-39. 

Figure 12.10 Domains of occurrence of the polymorphs I, I + III, III, III + IV, and IV of a certain organic compound during the precipitation using supercritical carbon dioxide as antisolvent. Graph adopted from P York.

The supercritical fluid mefhod is a relafively new method, which can minimize the use of organic solvents and harsh manufacturing conditions taking advantage of two distinctive properties of supercritical fluids (i.e., high compressibility and liquid-like density). This method can be broadly divided into two parts rapid expansion of supercritical solutions (RESS), which utilizes the supercritical fluid (e.g., carbon dioxide) as a solvent for the polymer, " and supercritical antisolvent crystallization (SAS), using the fluid as an antisolvent that causes polymer precipitation. Recent reviews of the supercritical technology for particle production are available in the literature. ... 

Dense gas IM samples were precipitated from dimethylsulfoxide solutions using carbon dioxide as an antisolvent, while spray dried products were generated from insulin suspensions in mannitol aqueous solutions. Dense gas and spray dried IMC samples were produced from aqueous solutions in the DG antisolvent process carbon dioxide modified with ethanol was used as an antisolvent. The particle size of DG processed formulations was substantially larger than the corresponding spray dried material for both IM and IMC samples 21.8 vs. 5.71pm and 11.9 vs. 7.24pm, respectively, as measured by laser diffraction of the dry powders. The aerosol performance of DG processed IMC formulations, however, was superior to the spray dried counterpart, as measured by impactor studies. In fact, the RF of the DG processed IMC was 47.6%, while spray dried IMC had an RF of 30.0%. The aerosol performance of IM samples followed an opposite trend with the DG product exhibiting an RF of 26.6% and the spray dried of 30.6%. ... 

Snavely W, Subramaniam B, Rajewski RA, and Defelippis MR. Micronization of Insulin from Halogenated Alcohol Solution using Supercritical Carbon Dioxide as an Antisolvent./P/tarro Sci 2002 91 2026—2039. 

Table 3 lists different drugs precipitated by the SAS, ASES, and PCA processes. Almost all authors used carbon dioxide as the compressed antisolvent. 

Snavely WK, Subramaniam B, Rajewski RA, Defelippis MR. Micronization of insulin from halogenated alcohol solution using supercritical carbon dioxide as an antisolvent. J Pharm Sci 2002 91 2026-2039. 

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). 

Dense gas antisolvent techniques are amenable to the precipitation of proteins because of the low solubility of these compounds in DGs such as carbon dioxide. Lysozyme, trypsin, myoglobin, and insulin are examples of peptides that have been precipitated from organic solutions using CO2 as an antisolvent. Both batch and semicontinuous DG antisolvent techniques have been used to precipitate proteins from organic solvents such as methanol, ethanol, and dimethyl sulfoxide. ... 

Results related to drug micronization by GAS are summarized in Table 2, which also includes some data dealing with biocompatible polymers often used as carriers in sustained delivery devices (91-95). Unless otherwise noted, the antisolvent used in these studies is carbon dioxide. The GAS technique was successfully carried out to achieve the fractionation of various mixtures (96,97). 

In the processing of formoterol fumarate by means of the SEDS technique (31), totally amorphous material was obtained when dry carbon dioxide was used as the antisolvent, while the use of water-saturated carbon dioxide afforded a mixture of amorphous formoterol fumarate and crystalline dihydrate form. 

The process acronym, GAS, describes how. supercritical fluids are employed in the process the gas is used as an antisolvent to precipitate a solute from a liquid solution. The process is generally applicable to the recrystallization of materials if two conditions are satisfied (1) if the compound is insoluble (or only slightly soluble) in the gas, and (2) if the gas is (very) soluble in the liquid. If a liquid solution containing the compound to be recrystallized is contacted with a gas, e.g., carbon dioxide, the gas will dissolve into the solution and, when sufficient gas is absorbed by the solution, the gas will act as an antisolvent and the material will recrystallize. 

Many volatile low-molecular-weight organics are completely miscible with carbon dioxide at relatively modest temperatures and pressures. However, nonvolatile compounds or those with higher molecular weights, especially polymers, are often insoluble. Insoluble liquid compounds may be dispersed into CO2 with the aid of appropriate surfactants to form a kinetically stable o/c emulsion [10,11]. Stable emulsions are important in separation processes, heterogeneous reactions and materials formation processes, such as precipitation with a compressed fluid antisolvent [40]. These emulsions are the precursors to solid latex particles in dispersion polymerization. Stabilization of o/c emulsions has been studied in-situ to understand surfactant design for polymerization [10,11]. 

Supercritical anti-solvent and related processes (GAS/SAS/ASES/SEDS) In these processes, the SCE is used as an antisolvent that causes precipitation of the substrate(s) dissolved initially in a liquid solvent. This general concept consists of decreasing the solvent power of a polar liquid solvent in which the substrate is dissolved, by saturating it with carbon dioxide in supercritical conditions, causing the substrate precipitation or recrystallization. Depending on the desired solid morphology, various methods of implementation are available ... 

ASES (aerosol solvent extraction system) This is the first modification of the gas antisolvent process and involves spraying the solution through an atomization nozzle as fine droplets into compressed carbon dioxide (Figure 8.4). The dissolution of the SCF into the liquid droplets is accompanied by a large volume expansion and, consequently. 

A recent proposal concerns mixed organic-aqueous tunable solvents (OATS) such as dimethyl ether-water, the solubility of which for substrates can be influenced by a third component such as carbon dioxide. CO2 acts as a antisolvent and as a switch to cause a phase separation and to decant the phases from each other (preferably under pressure). This behavior makes the operation of bi- or multiphase homogeneous catalytic processes easier and more economic the preferential dissolution at modest pressure of carbon dioxide causes phase separation which results in large distribution coefEcients of target molecules in biphasic organic-aqueous systems. This extraordinary behavior lead to a sophisticated flow scheme (Figure 6) [7]. 

Different precipitation processes based on supercritical carbon dioxide have been proposed in which CO2 performs different functions as solvent, in the rapid expansion of supercritical solutions (RESS) process, as antisolvent, in the supercritical antisolvent (SAS) process, or as solute, in the particles from gas saturated solutions (PGSS) process. 

In this chapter, the possibihty of using late transition metal catalysts to synthesize polyolefins in supercritical carbon dioxide was demonstrated [43]. The multicomponent phase behavior of polyolefin systems at supercritical conditions was studied experimentally by measuring cloud-point curves as well as by modeling polymer systems at supercritical conditions. The cloud-point measurements show that CO2 acts as a strong antisolvent for the ethylene-PEP system, which implies that the polymerization concerned will involve a precipitation reaction. The model calculations prove that SAFT is able to describe the ethylene-PEP-CO2 system accurately. Solubility measurements of the Brookhart catalyst reveal that the maximum catalyst solubility is rather low (in the order of 1x10 mol L ). However, a number of strategies are given to enhance this value. 

On this basic concept different practical ways of performing the recrystallization process can be used. In the first method, to the solution is simply added the dense carbon dioxide. The volume of the solution increases several-fold in the presence of the antisolvent due to the decrease in density. This causes a concurrent decrease in solvent power the solutitm becomes supersaturated, and the solute precipitates, often as crystalline microparticles. This essentially batch process is normally termed gas antisolvent (GAS) [32]. 

In the second method the solution is sprayed through a nozzle into compressed carbon dioxide the process is termed as precipitation with compressed antisolvent (PCA) [33] and liquid or supercritical antisolvents can be employed. In the case of continuous flow of the solution and of the antisolvent the process is termed also as aerosol solvent extraction system (ASES) [34], in the case of countercurrent flow and supercritical antisolvent precipitation (SAS) in the case of co-current flow [35]. 

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