Supercritical antisolvent crystallization

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. ... 

Supercritical fluids can be used to induce phase separation. Addition of a light SCF to a polymer solvent solution was found to decrease the lower critical solution temperature for phase separation, in some cases by mote than 100°C (1,94). The potential to fractionate polyethylene (95) or accomplish a fractional crystallization (21), both induced by the addition of a supercritical antisolvent, has been proposed. In the latter technique, existence of a pressure eutectic ridge was described, similar to a temperature eutectic trough in a temperature-cooled crystallization. 

Depolymerization, e.g., polyethylene terephthalate and cellulose hydrolysis Hydrothermal oxidation of organic wastes in water Crystallization, particle formation, and coatings Antisolvent crystallization, rapid expansion from supercritical fluid solution (RESS)... 

Supercritical fluid crystallization (SFC) is a technique for precipitating or crystallizing solutes dissolved in liquid solvents by injecting or mixing the solvent system with a compressed or supercritical fluid antisolvent. SFC is unique in that it uses a compressed gas to trigger the crystallization. Two benefits often associated with SFC include single-step processing of particulate pharmaceuticals with controlled... 

Shekunov BY, Baldyga J, York P. Particle formation by mixing with supercritical antisolvent at high Reynolds numbers. Chem Eng Sci 2001 56 2421-2433. Sohnel O, Garside J. Precipitation. Oxford Butterworth-Heinemann, 1992. Mullin JW. Crystallization. Oxford Butterworth-Heinemann, 1993. 

Wubbolts FE, Bruinsma OSL, De Graauw J, Van Rosmalen GM. Continuous gas antisolvent crystallization of hydroquinone from acetone using carbon dioxide. Proceedings of the 4th International Symposium on Supercritical Fluids, Sendai, Japan, 1997 63-66. 

Amaro-Gonzalez D, Mabe G, Zabaloy M, Brignole E. Gas antisolvent crystallization of organic salts from aqueous solutions. J Supercrit Fluids 2000 17 249-258. 

Weber A, Tschemjaew J, Berger T, Bork M. A production plant for gas antisolvent crystallization. In Perrut M, Subra P, eds. Proceedings of the 5th Meeting on Supercritical Fluids, 1998 281-285. 

Supercritical antisolvent and related processes (GAS/SAS/ASES/SEDS). Precipitation using SCFs as non-solvents or antisolvents utilizes a similar concept to the use of antisolvents in solvent-based crystallization processes. 

Weber Brun, G., Martin, A., Cassel, E., Figueiro Vargas, R.M., and Cocero, M.J. Crystallization of caffeine by supercritical antisolvent (SAS) process Analysis of process parameters and control of polymorphism. Crystal Growth and Design 12 (2012) 1943-1951. 

In this chq)ter, a survey of the use of supercritical fluids for producing these systems is presented Three tecniques are considered the rapid expansion of supercritical solutions (RESS), the antisolvent crystallization (GAS, SAS, PCA) together with supercritical solution impregnation (SSI). 

A popular method is antisolvent crystallization in which very high supersaturation is achieved by the addition of a second solvent, that is, an antisolvent, which decreases the solubility of the solutes. Supersaturation levels can be controlled by varying the amount of antisolvent added. For example, nucleation and growth rates of L-histidine polymorphs are influenced by the composition of the solvent (mixture of water and ethanol). Various other factors such as antisolvent addition rate and initial concentrations of the solution also control crystallization behavior. Supercritical CO2 can also be used as an antisolvent. ... 

Figure 12.9 Crystals of an active compound crystallized by an antisolvent crystallization using supercritical carbon dioxide. In the case shown, an inverse drowning-out mixing scheme was used, leading to small particles.

A new approach in the 1990s was to use supercritical fluid technology to produce uniform particles to replace crystallization. Even though super critical fluids were discovered over 100 years ago, and the commercial plant was built over 20 years ago in the United States, it is only now that the technology is used for a number of pharmaceutical applications (2-5), so as to produce aspirin, caffeine, ibuprofen, acetaminophen, etc. One of the major areas on which the research and development of supercritical fluids is focused is particle design. There are different concepts such as rapid expansion of supercritical solution, gas antisolvent recrystallization, and supercritical antisolvent to generate particles, microspheres, microcapsules, liposomes, or other dispersed materials. 

Abstract Supercritical antisolvent technology can precipitate polyvinylpyrrolidone (PVP) particles and crystallize paracetamol (PCM) crystals first separately and then together in the form of a solid dispersion. Supercritical carbon dioxide (SCCO2) is used as an antisolvent. For PVP particle generation, ethanol, acetone, and mixtures of ethanol and acetone are used as solvents. The initial concentration of PVP in the solution was varied between 0.5 and 5 wt%, the operation pressure between 10 and 30 MPa, and the composition of ethanol/acetone solvent mixtures between 100 and 0 wt% of ethanol at a constant temperature of 313 K. An increase in the content of the poor solvent acetone in the initial solution leads to a significant decrease in mean particle size. Fully amorphous PVP powder always precipitates for all the parameters investigated. 

Martin, A., Scholle, K., Mattea, F., Meterc, D., Cocero, M. J. (2009). Production of polymorphs of ibuprofen sodium by supercritical antisolvent (SAS) precipitation. Crystal Growth Design, 9, 2504—2511. 

Rossmann, M., Braeuer, A., Dowy, S., Gallinger, T. G., Leipertz, A., Schluecker, E. (2012). Solute solubility as criterion for the appearance of amorphous particle precipitation or crystallization in the supercritical antisolvent (SAS) process. Journal of Supercritical Fluids, 66, 350-358. 

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). 

Examples of solvent-mediated transformation monitoring include the conversion of anhydrous citric acid to the monohydrate form in water [235,236], CBZ with water [237] and ethanol-water mixtures [238,239], and cocrystallization studies of CBZ, caffeine, and theophylline with water [240]. Raman spectroscopy was used to monitor the crystallization rate and solute and solvent concentrations as griseofulvin was removed from an acetone solution using supercritical CO2 as an antisolvent [241]. Progesterone s crystallization profile was monitored as antisolvent was added [242]. 

Most drugs and proteins are not soluble in commonly used supercritical fluids, and therefore are processed instead by the SC antisolvent technique,the most popularized being the SEDS, process which is illustrated in Fig. 9. SEDS-produced crystals can have extremely smooth surfaces, as shown by scanning electron microscopy and atomic force microscopy, and the surface may be more hydrophobic and less wettable than crystals grown under more polar conditions.A scanning electron micrograph of acetominophen crystals produced by the SEDS process is shown in Fig. 10. 

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. 

Cocero MJ, Ferrero S, Vicente S. Gas crystallization of fi-carotene from ethyl acetate solutions using CO2 as antisolvent. Proceedings of the 5th International S5unposium on Supercritical Fluids, Atlanta, April 13-18, 2000. 

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