Gas antisolvent recrystallization

Compounds not soluble in a supercritical fluid can be recrystallized in a process termed gas antisolvent (GAS) recrystailization. The process was first applied to the recrystailization of an explosive, RDX (cyclotrimethylenetrinitramine) into 

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. 

Carbon dioxide and other gases dissolve in many, many liquid solvents, Francis (1954) studied the solubility behavior of many classes of liquids, such as hydrocarbons, ketones, and alcohols, with carbon dioxide. He found that at about 25°C and 800 psi, many of the liquids are miscible with COj. In a prelude to the studies of GAS recrystallization, the absorption of CO2 into several liquids was studied using a sight glass (Jerguson gauge). The work of Francis was extended to higher temperatures than 25°C because of yield, particle size, and economic considerations. 

Absorption of CO into a liquid occurs with an expansion of the liquid. An example of the expansion behavior of cyclohexanone is given in figure 12.9, which shows three expansion curves at three temperature levels cyclohexanone is one of the solvents used in the industrial manufacture of RDX. As expected, higher pressure is required at higher temperature to reach equivalent 

The initial recrystallization tests were also carried out in the sight glass this was to provide a facility for visual determination of recrystallization behavior. Recrystallization of materials is very complex irrespective of the process, be it with liquid antisolvents or with gas antisolvents. For example, the particle size and particle size distribution (PSD) that results during recrystallization is a function of the solute, the solvent, the concentration of solute in 

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Gas Antisolvent Recrystallizations. A limitation to the RESS process can be the low solubility 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 C02 can be rapidly added to a solution of a crystalline solid dissolved in an organic solvent (114). Carbon dioxide and most oiganic solvents exhibit full miscibility, whereas in this case the solid solutes had limited solubility in C02. Thus, C02 acts as an antisolvent to precipitate solid 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 /zm) of a difficult-to-comminute explosive (114) recrystallization of p-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). 

Precipitation of the particles occurs by two methods involving atomization of a feed 1) rapid expansion of supercritical solutions containing dissolved drug, and 2) gas antisolvent recrystallization, the supercritical fluid acting as an antisolvent for dissolved drug contained in droplets of another miscible or partially... 

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. 

Gas Antisolvent Recrystallization New Process To Recrystallize Compounds Insoluble in Supercritical Fluids... 

Gas antisolvent processes can be performed in a semicontinuous mode. In this case the solution and the antisolvent are continuously introduced in the system until the desired amount of the product is formed. The introduction of the solution is then stopped and the DG flux extracts the residual solvent from the system. The system is then depressurized to enable collection of the product. The solution is generally introduced through an atomization nozzle that favors the prompt expansion of the solution and the formation of small particles. Different process configurations have been utilized, i.e., co- and countercurrent introduction of the solution and antisolvent fluxes and various nozzles have been designed. The process is referred to by different acronyms such as ASES (aerosol solvent extraction system), SAS (supercritical antisolvent), SEDS (solution enhanced dispersion by supercritical fluids), PCA (precipitation with a compressed fluid antisolvent), GASR (gas antisolvent recrystallization), GASP (gas antisolvent precipitation). 

Gallagher PM, Colfey MP, Krukonis VJ, Klasutis N. Gas antisolvent recrystallization new process to recrystallize compounds insoluble in supercritical fluids. In Penniger JML, ed. Supercritical Fluid Science and Technology. ACS Symposium Series 406. Washington, DC American Chemical Society, 1989 334-354. 

Krukonis VJ, Gallagher PM, Colfey MP. US patent 5 360 478, 1991. Gallagher PM, Krukonis VJ, Colfey MP. US patent 5 389 263. 1992. Gallagher PM, Colfey MP, Krukonis VJ, Hillstrom WW. Gas antisolvent recrystallization of RDX Formation of ultrafine particle of a difficult-to-comminute explosive. J Supercrit Fluids 1995 5 130-142. 

Bothun GD, White KL, Knutson BL. GAS antisolvent recrystallization of semicrystalline and amorphous poly(lactic acid) using compressed CO2. Polymer 2002 43 4445-4452. 

Corrigan OI, Crean AM. Comparative physicochemical properties of hydro-cortisone-PVP composites prepared using supercritical carbon dioxide by the GAS antisolvent recrystallization process, by coprecipitation and spray drying. Int J Pharm 2002 245 75-82. 

As described in Chapter 3, several SCF techniques are available for the preparation of drug delivery systems. These include rapid expansion of supercritical solutions (RESS), gas antisolvent recrystallization (GAS), supercritical antisolvent recrystallization (SAS), supercritical antisolvent with enhanced mass transfer (SAS-EM), solution-enhanced dispersion by supercritical fluids (SEDS), supercritical fluid nucleation (SFN), precipitation with compressed antisolvent (PCA), and aerosolized supercritical extraction of solvents (ASES). While RESS and SFN involve the expansion of a supercritical fluid solution of a drug to form drug particles, GAS, SAS, SAS-EM, SEDS, PCA, and ASES use a supercritical fluid as an antisolvent to precipitate particles of a drug dissolved in an organic solvent (5). General RESS and GAS processes are further elaborated in Sections 1.1.1 and 1.1.2. 

With high solubilities of SCFs in organic solvent, a volume expansion occurs when the two fluids make contact, leading to a reduction in solvent density and parallel fall in solvent capacity. Such reductions cause increased levels of supersaturation, solute nucleation, and particle formation. This process, generally termed gas antisolvent recrystallization, thus crystallizes solutes that are insoluble in SCFs from liquid solutions, with the SCF, typically SCF CO2, acting as an antisolvent for the solute. The GAS process was initially developed for crystallizing explosive materialsP. ... 

Some examples of commercial active component production and production of substances with defined and uniform particle sizes (organic and inorganic materials) realized on pilot plant by using the RESS are given in Table 24.8. Other processes were also tested for synthesis of the particles with uniform size distribution as well as production of particles with specific structure (gas antisolvent recrystallization, GASR precipitation with a compressed antisolvent, PCA solution enhanced dispersion of solids, SEDS particles from gas-saturated solutions, PGSS) as shown in Table 24.9. All these processes are of special interest in pharmaceutical industry and in the production of different polymers. 

Gallagher, P.M., Coffey, M.P., Knikonis, V.J. and Klasutis, N. (1989) Gas Antisolvent Recrystallization New Process to Recrystallize Compounds Insoluble in Supercritical Fluids, in Supercritical Science and Technology, ACS Symposium Series 406, Johnston, K.P., Penninger, J.M.L., Eds., American Chemical Society Washington D.C., pp. 334-354. 

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. 

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