Precipitation and crystallization techniques

The potential of supercritical fluids (SCFs) as media suitable to develop new processes for the production of crystals as well as amorphous powders has been outlined and studied since the mid-1980s. 

The precipitation or crystallization of a compound by a SCF can be performed according to different techniques, four of which will be considered here. They are  

All of the techniques considered in this chapter are new. CSS was developed, among others, by Tavana and Randolph [1] in the late 1980s. The development of PGSS, due to Weidner et al. [2], is dated 1994. RESS was first proposed by Krukonis in 1984 [3] to comminute thermally labile organics and pharmaceu- 

CSS is the least used and more classic one, so it will be discussed only briefly. Owing to lack of freely available information, PGSS can be addressed only as far as its physical background is concerned, and with reference to a qualitative apparatus scheme. Therefore, RESS and GASP are the main topics in this chapter as far as details about apparatus and procedure are concerned. 

It is noteworthy that, although many SCFs have been investigated as precipitation media in all of the techniques defined above, CO2 is the one most often considered and used, because of its particularly favorable properties. 

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Rubidium acid salts are usually prepared from rubidium carbonate or hydroxide and the appropriate acid in aqueous solution, followed by precipitation of the crystals or evaporation to dryness. Rubidium sulfate is also prepared by the addition of a hot solution of barium hydroxide to a boiling solution of rubidium alum until all the aluminum is precipitated. The pH of the solution is 7.6 when the reaction is complete. Aluminum hydroxide and barium sulfate are removed by filtration, and rubidium sulfate is obtained by concentration and crystallization from the filtrate. Rubidium aluminum sulfate dodecahydrate [7488-54-2] (alum), RbA SO 12H20, is formed by sulfuric acid leaching of lepidolite ore. Rubidium alum is more soluble than cesium alum and less soluble than the other alkali alums. Fractional crystallization of Rb alum removes K, Na, and Li values, but concentrates the cesium value. Rubidium hydroxide, RbOH, is prepared by the reaction of rubidium sulfate and barium hydroxide in solution. The insoluble barium sulfate is removed by filtration. The solution of rubidium hydroxide can be evaporated partially in pure nickel or silver containers. Rubidium hydroxide is usually supplied as a 50% aqueous solution. Rubidium carbonate, Rb2C03, is readily formed by bubbling carbon dioxide through a solution of rubidium hydroxide, followed by evaporation to dryness in a fluorocarbon container. Other rubidium compounds can be formed in the laboratory by means of anion-exchange techniques. Table 4 lists some properties of common rubidium compounds. 

The long story of the methods for the separation of the individual rare earths may broadly be divided into two main parts a) classical methods b) modern methods. Old-fashioned classical techniques like fractional crystallization, fractional precipitation and fractional thermal decomposition were not only used by the early workers in the past, but still remain as very important methods for economical production of rare earths on commercial scales. Modem methods like solvent (liquid-liquid) extraction, ion exchange or chromatographic (paper, thin layer and gas) techniques have both advantages and limitations. 

The main difficulty with the classical fractionation process is that, as the fractionation progresses, the number of fractions increases, and their size becomes smaller. With fractional precipitation processes, the number of operations practicable is much smaller than the fractional crystallization, because of the trouble in redisolving the precipitates and following another reprecipitation. In fractional crystallization schemes sometimes the liquor and crystal fractions can be combined with the help of modem analytical techniques by determining their compositions, thus achieving multiplication of stages. 

Industry employs several techniques for solving these problems [116]. The most common are selective product crystallization, where the catalyst and the excess substrates and reagents are left in the liquid phase, and catalyst precipitation and filtration, where the catalyst is precipitated as a salt from the organic reaction mixture. Other techniques include flash distillation of the product under high vacuum, and liquid/liquid extraction of the catalyst from the reaction mixture. 

Final product isolation in a form suitable for further processing into the final dose form of the pharmaceutical, e.g., as a tablet or an injectable solution. Secondary production of this type is sometimes done in a separate facility, with the raw material referred to as the bulk product or, more recently, the active pharmaceutical ingredient. Examples of unit operations at this stage of processing include lyophilization, precipitation, or crystallization followed by solid isolation using filtration and drying techniques. In some cases, the final product must be produced in a sterile form, which introduces additional complications when selecting suitable process equipment. 

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