SAS Processing

Fig. 8.3-1. Scheme of operating plants commonly used for SAS processes... 

Zanette [4], The organic solvent considered was tetrahydrofuran (THF), the polymer was Eudragit , and the drug was a compound supplied by a pharmaceutical company. However, the procedure discussed here can be applied easily to any SAS process of this type. 

Prestone HONEYWELL INTERNATIONAL INC Price Street House and Home INTERFACE INC Prime Polymer Co., Ltd. MITSUI CHEMICALS INC Primex Plastics Corporation ICC INDUSTRIES Primor BUNGE ALIMENTOS SA Process Systems Enterprise SAMSUNG PETROCHEMICALS CO LTD ProEco HE 801 COGNIS DEUTSCHLAND GMBH CO KG... 

The possibility to obtain a full solvent-free product, controlling in the same time the dimension of particles, is probably the most important feature when pharmaceutical substances are used. In the SAS process the SCF is used as the antisolvent. An organic solvent has to be involved in addition to the SCF and the solid solute. Basically, the process is performed by first dissolving the solid of interest in the organic liquid then, the SCF, which has low solvent capacity with respect to the solid but is completely miscible with the liquid, is added to the solution to get the precipitation of the solid. This method has been proposed by Gallagher and coworkers [8] to crystallize difficult-to-handle high explosives. Recently, other applications have been set forth to produce crystals of pharmaceuticals [9,10]. 

In all cases, the SAS process ensured the total recovery of the polymer initially charged in the precipitator. The residual DMSO content was usually lower than 1.5%, and this value can be further decreased by increasing the length of the purification step. 

A supercritical C02-based technique was applied to produce a biocompatible polymer in form of microspheres. With the SAS process carried out in a batch mode, micronic particles of polymer were obtained with a narrow particle size distribution. Co-precipitation of pharmaceuticals for the production of controlled drug delivery systems has been proposed as a preliminary result, since further analyses are under development. The experimental apparatus is easy-to-use and the purification of the precipitated solid from the solvent can be achieved by suitably increasing the time for solvent removing. 

A new, versatile apparatus for the determination of reliable SLV and LLE phase-equilibrium data has been designed and tested. In a first project this equipment will be used for the separation of polymers by molecular weight with the SAS process. We will test the concept of using pressure, temperature and gas content to fine-tune the selectivity of that process. 

Three tasks were pursued in the research and development phase of the Gulf Canada SA process SA binder characteristics, processing technology, and design technology. This chapter summarizes and reports the progress which has been made towards commercial application of the acquired technology. 

Premixing. The development and engineering of the SA processing technology is based on extensive laboratory and field experience with SA binder and SA mixes. The key aspects and requirements for the incorporation of sulfur in paving mixes for industrial-scale mix production are uniformity of dispersion, SA ratio, and coating of the aggregate by the binder. 

Mass transfer is also favored by the high diffusivity that characterizes supercritical fluids. The difference in density between the liquid and the antisolvent also plays a role in determining the direction of mass transfer. However, the SAS process does not seem to be substantially limited by mass transfer resistances. ... 

Thermodynamic constraints to the SAS process can be summarized in the required miscibility between the liquid solvent and the supercritical antisolvent and the insolubility of the solute in the antisolvent and in the solvent-antisolvent mixture. Data are available for various binary mixtures liquid-supercritical fluid and can be described as type I using the classification of van-Konynenburg and Scott. If jet break-up is obtained and mass transfer is very fast, high-pressure VLEs of the ternary system liquid-I-solute-I-supercritical fluid can control the precipitation process. 

Besides these thermodynamic criteria, the most common approach used in the literature is based on the operation at pressures above the binary (liquid - SC-CO2) mixture critical point, completely neglecting the influence of solute on VLEs of the system. But, the solubility behavior of a binary supercritical COj-containing system is frequently changed by the addition of a low volatile third component as the solute to be precipitated. In particular, the so-called cosolvency effect can occur when a mixture of two components solvent+solute is better soluble in a supercritical solvent than each of the pure components alone. In contrast to this behavior, a ternary system can show poorer solubility compared with the binary systems antisolvent+solvent and antisol-vent+solute a system with these characteristics is called a non-cosolvency (antisolvent) system. hi particular, in the case of the SAS process, they hypothesize that the solute does not induce cosolvency effects, because the scope of this process lies in the use of COj as an antisolvent for the solute, inducing its precipitation. 

Therefore, the approach followed in this chapter considers pseudo-binary diagrams, i.e., equilibria involving the third component are, however, neglected, but modifications due to the presence of the solute are considered on the binary system. We will observe in the analysis of the experimental results that this approach can provide interesting information regarding the evolution of the SAS process, and the morphology and dimension of the precipitated particles. A rationalization of the experimental results is also proposed. 

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). 

One variant of the GAS or SAS process (SCF as antisoivent) is solution enhanced dispersion by supercritical fluids (SEDS). Coaxial nozzles are used to introduce drug solution and carbon dioxide at the desired temperature and pressure. In this case, the SCF carries out both droplet breakup and antisoivent functions. SEDS has been tested for a number of pharmaceutical compounds. As noted above, this is a continuing effort. 

Lim et al. extended the PCA concept, suggesting spraying the liquid solution continuously in a continuum of SF by means of a capillary this new method was termed the SAS process (21,22). In this semicontinuous operating mode, the SCF and the primary solvent are continuously removed, while the solid remains in the autoclave. 

The SEDS process appeared not long after the other antisolvent processes just described, and it was first developed and patented by Bradford Particle Design (15). The general principle is the same as that for SAS process supercritical CO2 and the organic solution are introduced cocurrently in the reactor, and... 

Based on the use of supercritical carbon dioxide, liposomes of soy lecithin were prepared by means of two micronization techniques the RESS and SAS processes (36). Since phospholipids are only poorly soluble in supercritical CO2, ethanol was used as a cosolvent. While the RESS process failed to separate the phospholipids from the solvent, resulting in a gel deposit, the SAS process was successful in producing microparticles (14—40 pm) under semicontinuous mode, when CO2 and the liquid solution were allowed to flow cocurrently. IR spectra of the particles seemed to indicate that they were free of residual solvent. Thus, by employing supercritical fluids, this study demonstrated that the anisolvent process is capable of obtaining liposomes whereas the RESS process failed. 

Similar studies have also been performed by the research group of Charbit in Marseilles (61,62) in which fine PPL particles were formed by decompression using the SAS process. The focus of this research was to develop drug delivery systems, but it would equally applicable to the functional food area. Typically, a 2 wt% solution of soy-derived lecithin is... 

In an SAS process, scCOa is used to reduce the solvation power of conventional solvents so that the solutes precipitate. Particularly, the diffusivity of sc CO2 is about two orders of magnitude larger than those of liquids and mass transfer from sc CO2 to liquid phase is so fast that it facilitates the production of very small particles of the solute contained in the liquid phase. Previously, using this precipitation method, we have successfully produced vanadium phosphate catalysts. 

Figure 1. Schematic of the apparatus for the precipitation using SAS process...

In the GAS (SAS) process, the OS-HC solution is first loaded into the autoclave, and then the pressure is increased by feeding the SCF up to the value required for precipitation. At this point, three phases are present in the vessel the solid product, the liquid mixed-solvent and a vapor phase, essentially SCF. GAS (SAS) batch is a completely batch operation, very simple to carry out. However, as the system undergoes all pressure conditions, between the initial and final, the product obtained depends also on the pressure profile during pressurization. 

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