Supercritical fluid anti-solvent process

Supercritical fluid anti-solvent processes have been recently proposed as alternatives to liquid anti-solvent processes commonly employed in the industry. The key advantage of the supercritical processes over liquid ones is the possibility to completely remove the anti-solvent by pressure reduction. This step of the process is problematic in case of liquid anti-solvents since it requires complex post-processing treatments for the complete elimination of liquid residues. Furthermore, the supercritical anti-solvent is characterized by diffusivity that can be up to two orders of magnitude higher than those of liquids. Therefore, its very fast diffusion into the liquid solvent produces the supersaturation of the solute and the precipitation in micronized particles with diameters that are not possible to obtain using liquid anti-solvents or other methods. 

Krukonls, V. J., Coffey, M. P., Gallagher, P. M. Exploratory Development on a New Process to Produce Improved RDX Crvstsls L Supercritical Fluid Anti-Solvent Recrystallization. Phasex Corp. Final Rept. to U.S. Army Ballistics Research Laboratory, 1988, Contr. DAAA15-86-C-007. 

The most important limitation of RESS is the low solubility of compounds in supercritical fluids and the use of co-solvent to improve solubility is usually costly and not economically feasible. As an alternative a supercritical fluid anti-solvent (SAS) process was introduced where a supercritical fluid is used to cause substrate precipitation or recrystallization from a polar liquid solvent (Subramaniam et ah, 1999). Zhong et ah (2008) successfully used SAS to produce alcohol soluble zein micro- and nanoparticles. A number of other technologies based on manipulating supercritical fluids have been successfully used to produce nanoparticles (Della Porta and Reverchon, 2008 Matsuyama et ah, 2003 Meziani and Sun, 2003 Shariah and Peters, 2003 Subramaniam et ah, 1999). 

Wang, W., Liu, G., Wu, J., and Jiang, Y. Co-precipitation of 10-hydroxycamptothecin and poly (1-lactic acid) by supercritical C02 anti-solvent process using dichloromethane/ethanol co-solvent. The Journal of Supercritical Fluids 74 (2013) 137-144. 

This process is also called supercritical fluid anti-solvent (SAS). Here, supercritical fluid is added to a solution of shell material and the active ingredients and maintained at high pressure. This leads to a volume expansion of the solution that causes supersaturation such that precipitation of the solute occurs. Thus, the solute must be soluble in the Hquid solvent, but should not dissolve in the mixture of solvent and supercritical fluid. On the other hand, the liquid solvent must be miscible with the supercritical fluid. This process is unsuitable for the encapsulation of water-soluble ingredients as water has low solubility in supercritical fluids. It is also possible to produce submicron particles using this method. 

Gas anti-solvent processes (GASR, gas anti-solvent recrystallization GASP, gas antisolvent precipitation SAS, supercritical anti-solvent fractionation PCA, precipitation with a compressed fluid anti-solvent SEDS, solution-enhanced dispersion of solids) differ in the way the contact between solution and anti-solvent is achieved. This may be by spraying the solution in a supercritical gas, spraying the gas into the liquid solution. 

Wang, Y., et al. (2004), Polymer coating/encapsulation of nanoparticles using a supercritical anti-solvent process, /. Supercrit. Fluids, 28, 85-99. 

Magnan C, Badens E, Commenges N, Charbit G. Soy lecithin micronization by precipitation with a compressed fluid anti-solvent—influence of process parameters. J Supercrit Fluids 2000 19 69-77. 

At high pressures a considerable amount of a gas can be dissolved in a liquid solution. Once dissolved in the liquid phase it may act as an anti solvent. In literature this type of drowning out is often referred to as the Gas Anti-Solvent (GAS) process, it is also known as the Supercritical Anti-Solvent (SAS) process or as Precipitation with a Compressed fluid Anti solvent (PCA). 

Supercritical anti-solvent micronization can be performed using different processing methods and equipment [17]. Different acronyms were used by the various authors to indicate the micronization process. It has been referred to as GAS (gas anti-solvent), PCA (precipitation by compressed anti-solvent), ASES (aerosol solvent extraction system), SEDS (solution enhanced dispersion by supercritical fluids), and SAS (supercritical anti-solvent) process [8,17]. Since the resulting solid material can be signiflcantly influenced by the adopted process arrangement, a short description of the various methods is presented below. 

Both the nucleation of supercritical anti-solvent bubbles in a polymer+organic solvent-rich phase in the supercritical anti-solvent process (SAS) (or, equivalently, precipitation with a compressed antisolvent PCA) (e.g., [76]) and the nucleation of bubbles of a dissolved supercritical fluid from a saturated and nozzle-expanded solution containing a solute to be precipitated, in the formation of particles from gas-saturated solutions (PGSS) [77] are bubble nucleation problems, to which the above ideas apply. In the latter case, the nucleation of bubbles occurs simultaneously with that of solid particles within the bulk supersaturated solution. 

Kikic, I., Bertucco, A. and Lora, M. (1997) Thermodynamic Description of Systems Involved in Supercritical Anti-Solvent Processes, The 4 International Symposium on Supercritical Fluids, Sendai, Japan, pp. 39-42. 

Besides the supercritical fluid extraction (SFE) for preparation of medicines and materials processing, supercritical fluid technology involves processes such as supercritical anti-solvent (SAS), rapid expansion supercritical solutions (RESS), rapid expansion of a supercritical solution into a liquid solvent (RESOLV), supercritical assisted atomization (SAA), impregnation and solution enhanced dispersion by supercritical CO2 (SEDS) that involves the supercritical fluid in drug processing to drug delivery systems. 

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. 

U. Foerter-Barth, U. Teipel, and H. Krause, Formation of particles by applying the gas anti-solvent (GAS) process, in Nottingham, 1999 Supercritical fluids Chemistry and Materials, Institut National Polytechnique de Lorraine, pp. 175-180. 

The application of supercritical fluids as anti-solvents is an alternative recrystallization technique for processing solids that are insoluble in SCF. This method exploits the ability of gases to dissolve in organic liquids and to lower the solvent power of the liquid for the compounds in solution, thus causing the solids to precipitate. 

The mixed-crystal system formed by indomethacin and saccharin (l,2-benzisothiazol-3(2H)-one-l,1-dioxide) has been used to evaluate the feasibility of using supercritical fluids as media for the design and preparation of new cocrystals [44]. In this work, the relative merits of supercritical fluid processes (i.e., cocrystallization with a supercritical solvent, supercritical fluid as anti-solvent, and the atomization and anti-solvent technique) were evaluated, as well as the influence of processing parameters on product formation and particle properties of the yields. It was reported that while the anti-solvent and atomization procedures yielded pure cocrystal products, only partial to no cocrystal formation took place when using the crystallization process. 

Supercritical fluids have been shown to be excellent recrystallization agents for a variety of materials, and their use in recrystallizing an explosive, nitroguanidine (NQ), is presented. A new process, GAS (gas anti-solvent) Recrystallization, is described. 

Gallagher PM, Coffey MP, Krukonis VJ, Klasutis N. Gas anti-solvent recrystallization new process to recrystallize compounds insoluble in supercritical fluids. In Johnston KP, Penniger JML, eds. Supercritical Fluid Science and Technology. Washington, DC American Chemical Society, 1989 334-354. Dixon D, Johnston KP, Bodmeier R. Polymeric materials formed by precipitation with a compressed fluid antisolvent. AIChE J 1993 39 127-136. Chattopadhyay P, Gupta RB. Production of griseofulvin nanoparticles using supercritical CO2 antisolvent with enhanced mass transfer. Int J Pharm 2001 228 19-31. 

Low reactivity in general Reversible reactivity with weak nucleophiles (e.g. amines) Potential for product processing applications supercritical anti solvents, SAS rapid expansion of supercritical solution, RESS super fluid chromotography, SEC Reacts with strong nucleophiles... 

Gallagher P.M., Coffey M.P., Krukonis V.J., KlasutisN., Gas Anti-Solvent recrystallization new process to recryst lize compounds insoluble in supercritical fluids. Supercritical fluid science and technology, Johnston K.P., Penninger J.M.L., 1989, (406), 334-354,. 

Lesoin, L., Crampon, C., Boutin, O., and Badens, E. Preparation of liposomes using the supercritical anti-solvent (SAS) process and comparison with a conventional method. The Journal of Supercritical Fluids 57 (2011) 162-174. 

The routes to particle synthesis via supercritical fluids basically follow two paths. Rapid Expansion of Supercritical Solution (RESS) and Supercritical Anti-Solvent (SAS). The basic processing steps are outlined in Figure 21.18 and Figure 21.19, respectively. RESS involves homogenization of the particles raw material in the supercritical fluid followed by rapid expansion of the solution through an expansion device such as a nozzle. Depending on the nozzle design, time-temperature and time-pressure profiles, and whether one uses... 

One of the requirements for the development of new polymer processes based on SCCO2 is knowledge about the phase behavior of the mixture involved, which enables one to tune the process variables properly to achieve maximum process efficiency. Important parameters in the phase behavior of the system are the solvent quality, the molecular weight, chain branching, and chemical architecture of the polymer, as well as the effect of end groups, and addition of a co-solvent or an anti-solvent. The literature available on the phase behavior of polymers in supercritical fluids has been reviewed extensively by Kirby and McHugh [38]. 

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