Anti-solvent processes, particle

One goal of RESS/CSS, the anti-solvent processes such GAS, and the PGSS process, is to obtain submicron- or micron-sized particles. Technological features of the various high-pressure micronization processes are summarised and compared in Table 9.8-4 [58]. 

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. 

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. 

Hanna M, York P (1998) Method and apparatus for the formation of particles, Google Patents Jung J, Clavier JY, Perrut M (2003) Gram to kilogram scale up of supercritical anti-solvent process. 

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. 

Gas anti-solvent experiments for different products using supercritical carbon dioxide (CO2) Process Substance Solvent Pressure Temperature Particle Ref. 

In Tables 9.9-3 to 9.9-5 a summary of the recrystallization process of pharmaceuticals and bio-polymers, and co-precipitation by supercritical anti-solvent is presented. In Figures 9.9-1 and 9.9-2 examples of very long needle crystal and nano-particles are reported. 

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. 

In an anti-solvent recrystallization process, then, particle size and particle size distribution is determined by the interaction between the nucleation rate and the growth rate of crystals, on one hand, and by the rate of creation of supersaturation, on the other hand all three are influenced by the manner of addition of the anti-solvent. Figure 5 is a qualitative picture of simultaneous events that occur when an anti-solvent is added to a solution of a solute that is to be recrystallized. The three zones shown in Figure 5, designated I, II, and III, denote three areas of supersaturation. Zone I is for a supersaturation less than 1, i.e., for actual solute concentrations less than saturation. No growth of particles will occur in this zone (and in fact if there are any particles that are "somehow" present, they will dissolve). In Zone II, the supersaturation is less than the critical value discussed earlier, but "some" nucleation can occur particles that are present in this... 

The second method is quite harsh but similar to RESS process as they both involve use of SFCO as a solvent rather than an anti-solvent. This process involves dissolving the SF in molten solute and the resulting supercritical solution fed via an orifice into a chamber to allow rapid expansion under ambient conditions [17], The dissolved gas decreases the viscosity of the molten compound and so the gas saturated liquid phase is expanded to generate particles from materials that are not necessarily soluble in SF. The presence of the CO allows the material to melt at temperature significantly lower than the normal melting or glass transition temperature. 

Precipitation from saturated solutions using SF as antisolvent, takes advantage of the limited solvation power of SFCO for proteins. This method utilizes a similar concept to the use of anti-solvent in solvent based crystallization processes. The high solubility of SFCO in organic solvents leads to volume expansion when the fluids make contact. This leads to reduction in solvent density and subsequent fall in salvation capacity. This leads to super-saturation, solute nucleation and particle formation. 

Won D-H, Kim M-S, Lee S, ParkJ-S, and Hwang S-J. Improved Physicochemical Characteristics of Felodipine Solid Dispersion Particles hy Supercritical Anti-Solvent Precipitation Process. IntiJPharm 2005 301 199-208. 

The anti-solvent type supercritical precipitation processes described earlier, e.g., GAS, are highly dependent on the solubility (or miscibility) between CO2 and solvent. In the case of CAN-BD, the particle size appears to be affected more by the CO2 to water ratio, and much less by the solubility of CO2 in the water. We plan to do further work in the future to substantiate the correlation shown in Figure 7 by vaiying other pertinent process parameters. 

The aim of this work is to study the semi-batch precipitation of the polymer poly (2,6-dimethyl-1,4-phenylene ether) from a solution in toluene, using high-pressure CO2 as an anti-solvent. The influence of the process conditions on the degree of crystallinity, and the particle size and size distribution has been determined. 

As the anti-solvent is added the polymer solution splits into a polymer-rich phase and a solvent-rich phase. In the highly concentrated polymer-rich phase the PPE solidifies and the residual solvent is taken up by the solvent-rich phase. The size of these solid PPE particles is approximately 1pm and independent of the varied process conditions. 

Whereas the size of the primary particles is independent of the varied process conditions, their extent of agglomeration can be influenced by the rate of anti-solvent addition and the process temperature. By quickly adding the anti-solvent, at a high pressure build-up rate, the extent of agglomeration is reduced because the process time becomes shorter and less time is available for agglomeration. 

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... 

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. 

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