Crystallization with Supercritical Fluids

Supercritical fluids (SCFs) are gases and liquids above their critical point. In this state, they are single-phase fluids with some advantageous properties of both liquids and gases. These properties enable them to be used in a unique manner to engineer, or design particles with proper process manipulation. 

A comprehensive review of particle design using SCF is provided by Gupta (2006), York et al. (2004), and Jung and Perrut (2001). York (1999) and Subramaniam et al. (1997) give excellent reviews on use of this technology with pharmaceutical compounds. 

SCF processing on a large scale had its earliest success with extraction processes. The dccaffci nation of coffee and tea is carried out in tonnage quantities, and methylene chloride residues thus arc eliminated. Extraction of essential oils and flavors has been commercially successful. Because SCF often have only limited solvation properties for some desired materials, SCF processes abound in which nonsupercritical solvents are added at critical points. 

Because of its low toxicity and relatively low temperature and pressure critical point, carbon dioxide is the dominant SCF used in the pharmaceutical industry. At its best, an SCF process can produce, in a single step, a pure, dry crystalline solid with high productivity. Much research and development is being carried out in this field. 

The common types of SCF processing and their common acronyms, are  

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Micronization with supercritical fluids - Crystallization - Rapid expansion - Gas anti-solvent Recrystallization - Precipitation with compressed anti-solvent - Solution-enhanced dispersion - Particles from gas-saturated solutions 80 - 300 fine particles and powders from various products and of designed properties... 

The rapid expansion of supercritical solutions (RESS) was explored by several authors as a novel route to the formation of microparticles. Ohgaki [1] produces fine stigmasterin particles by the rapid expansion of a supercritical C02 solution. Amorphus fine particle and whisker-like crystals (0,05 - 3 pm) were obtained with different preexpansion pressures. Johnston [2] obtained submicron particles from different polymers. Loth [3] described the mirconisation of phenacetin with supercritical fluids. 

Edwards, A.D. Shekunov, B.Y. Kordikowski, A. Forbes, R.T. York, P. Crystallization of pure anhydrous polymorphs of carbamazepine by solution enhanced dispersion with supercritical fluids (SEDS ). J. Pharm. Sci. 2001, 90 (8), 1115-1124. 

Other separation processes are liquid-solid extraction with supercritical fluids, crystallization, and separation by membranes. 

The relative importance of the nucleation and growth phases in the formation of crystals from supercritical fluids has received attention. Mohamed et al. [96] recently studied the size distribution of naphthlene crystals from a supercritical mixture. The supercritical solution was first completed by contact of carbon dioxide with solid naphthalene at a high pressure in an extraction cell, then expanded through a nozzle in a crystalliser. Apparently both the pre-... 

Supercriticalfluid solvents are those formed by operating a system above the critical conditions of the solvent. SolubiHties of many solutes ia such fluids often is much greater than those found for the same solutes but with the fluid at sub atmospheric conditions. Recently, there has been considerable iaterest ia usiag supercritical fluids as solvents ia the production of certain crystalline materials because of the special properties of the product crystals. Rapid expansion of a supercritical system rapidly reduces the solubiHty of a solute throughout the entire mixture. The resulting high supersaturation produces fine crystals of relatively uniform size. Moreover, the solvent poses no purification problems because it simply becomes a gas as the system conditions are reduced below critical. 

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... 

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. 

With cryogenic trapping, the extraction mixture is cooled down until the supercritical fluid expands and the analytes deposit. The trapping temperature to be used depends on whether the analytes are to be isolated from the fluid or this is to be liquefied and the collection vessel sealed in order to avoid losses of analytes through partial crystallization or the formation of aerosols during cooling. When the temperature of the cryogenic trap is very low, the restrictor must be heated in order to avoid the formation of two phases. As with collection on a solid sorbent, an additional preparative step is required. 

Nagano et al. [22] measured the CO2 uptake in Cgg in a study of the effects of supercritical fluid treatment, the aim of which was to remove solvent molecules from Cgg. Carbon dioxide was found to interact strongly with Cgg, and to have a remarkable effect on the orientational phase transition of Cgg crystals at 250 K. The kinetic features of the process suggested that CO2 absorbs inside the C g... 

The pressure-temperature phase diagrams also serve to highlight the fact that the polymorphic transition temperature varies with pressure, which is an important consideration in the supercritical fluid processing of materials in which crystallization occurs invariably at elevated pressures. Qualitative prediction of various phase changes (liquid/vapor, solid/vapor, solid/liquid, solid/liquid/vapor) at equilibrium under supercritical fluid conditions can be made by reference to the well-known Le Chatelier s principle. Accordingly, an increase in pressure will result in a decrease in the volume of the system. For most materials (with water being the most notable exception), the specific volume of the liquid and gas phase is less than that of the solid phase, so that... 

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