Anti-solvent addition

Cocrystals are often prepared by a traditional solution crystalhsation approach such as solvent evaporation, coohng, or anti-solvent addition. There are a number of reasons for the popularity of the solution-based approach. Solution crystallisation can yield large, well-formed single crystals, from which one may easily evaluate crystal habit and surface features. Analysis of the diffraction pattern of a single crystal is typically the best means of obtaining an absolute crystal structure determination. Further, solution crystalhsation is an established and effective purification step. 

Supersaturation Molecular mobility Nucleation temperature Nucleation rate Growth rate Dissolution rate Meta-stable zone width Evaporation rate Heating/cooling rate Anti-solvent addition rate... 

Figure 6. Expansion paths for anti-solvent addition.

Nonoyama, N., K. Hanaki, and Y. Yabukt (2006). Constant supersaturation control of anti-solvent-addition batch crystaUization. Org. Process R D 10, 727-732. 

Heating/cooling rate Anti-solvent addition rate... 

In the late 1940s, a method was developed (Cohn et al. 1946) for the fractionation of proteins from blood plasma by means of ethanol (an anti-solvent) addition to aqueous solutions at specified conditions of temperature, pH, and ionic strength. Briefly, a series of five successive batch ethanol precipitations were used to prepare fractions of fibrinogens, globulins, and albumin. The conditions used in each step are in Table 11.1 along with the major protein(s) precipitated at each step. More recently, a method employing a series of MSMPR precipitators has been reported (Chang 1988). 

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. 

In GAS or SAS, a batch of solution is expanded by mixing it with a supercritical fluid in a high-pressure vessel (Figure 24.6). Due to the dissolution of the compressed gas, the expanded solvent exhibits a decrease of the solvent power. The mixture becomes supersaturated and the solute precipitates in the form of microparticles. As shown in Figure 24.6, the precipitator is partially filled with the liquid solution of solid substance. The supercritical anti-solvent is then pumped up to desired pressure and introduced into the vessel, preferably from the bottom in order to achieve a better mixing of the solvent and anti-solvent. After a specified residence time, the expanded solution is drained under isobaric conditions in order to clean the precipitated particles. In this mode of operation, the rate of supercritical anti-solvent addition can be an important parameter in controlling the morphology and the size of solid particles. 

The most influential parameter is the rate of supersaturating the system, i.e. the rate of cooling, evaporation of solvent or addition of anti-solvent addition. An equally influential parameter is the concentration of additives or impurities in the mother phase (Chapter 6). Another influence is the thermal history of the phase, namely, how long and to which degree has the phase been heated above saturation. 

Most of the ethylene dichloride produced is utilized for the manufacture of vinyl chloride, which may be obtained from it by pyrolysis or the action of caustic soda. Large quantities are also used in anti-knock additives for gasoline. As a solvent It has been displaced by trichloroethylene and tetrachloroelhyJene. U.S. production 1978 4-75 megatonnes. 

The regioselectivity of addition of Itydrogen bromide to alkenes can be complicated if a free-radical chain addition occurs in competition with the ionic addition. The free-radical reaction is readily initiated by peroxidic impurities or by light and leads to the anti-Markownikoff addition product. The mechanism of this reaction will be considered more fully in Chapter 12. Conditions that minimize the competing radical addition include use of high-purity alkene and solvent, exclusion of light, and addition of free-radical inhibitors. ... 

Manufacture of rhodium precatalysts for asymmetric hydrogenation. Established literature methods used to make the Rh-DuPhos complexes consisted of converting (1,5-cyclooctadiene) acetylacetonato Rh(l) into the sparingly soluble bis(l,5-cyclooctadiene) Rh(l) tetrafluoroborate complex which then reacts with the diphosphine ligand to provide the precatalyst complex in solution. Addition of an anti-solvent results in precipitation of the desired product. Although this method worked well with a variety of diphosphines, yields were modest and more importantly the product form was variable. The different physical forms performed equally as well in hydrogenation reactions but had different shelf-life and air stability. 

The addition of hydrogen halide to alkene is another classical electrophilic addition of alkene. Although normally such reactions are carried out under anhydrous conditions, occasionally aqueous conditions have been used.25 However, some difference in regioselectivity (Markovnikov and anti-Markovnikov addition) was observed. The addition product formed in an organic solvent with dry HBr gives exclusively the 1-Br derivative whereas with aq. HBr, 2-Br derivative is formed. The difference in the products formed by the two methods is believed to be due primarily to the difference in the solvents and not to the presence of any peroxide in the olefin.26... 

Other preparative snags also occur in the addition of HHal to alkenes. Thus in solution in H20, or in other hydroxylic solvents, acid-catalysed hydration (p. 187) or solvation may constitute a competing reaction while in less polar solvents radical formation may be encouraged, resulting in anti-Markownikov addition to give 1-bromopropane (MeCH2CH2Br), via the preferentially formed radical intermediate, MeCHCH2Br. This is discussed in detail below (p. 316). 

Uses Solvent for lacquers, varnishes, dopes, nitrocellulose, natural and synthetic resins in cleaning solutions, varnish removers, dye baths mutual solvent for formation of soluble oils lacquer thinners emulsion stabilizer anti-icing additive for aviation fuels. 

Uses. Fuel and lubricant additive solvent in cosmetics solvent in petroleum refining coupling agent in hydraulic brake fluid and printing inks gasoline anti-icer additive... 

Uses. Solvent jet fuel anti-icing additive in the semiconductor industry in manufacture of printed circuit boards... 

Substituted cyclopropane systems also undergo nucleophilic addition of suitable solvents (MeOH). For example, the photoinduced ET reaction of 1,2-dimethyl-3-phenylcyclopropane (112, R = Me) with p-dicyanobenzene formed a ring-opened ether by anti-Markovnikov addition. The reaction occurs with essentially complete inversion of configuration at carbon, suggesting a nucleophilic cleavage of a one-electron cyclopropane bond, generating 113. The retention of chirality confirms that the stereochemistry of the parent molecule is unperturbed in the radical cation 112 " ". 

Lactose may be obtained in two crystalline forms a-lactose and P-lactose (in addition to amorphous forms). The alpha form is obtained when water is incorporated into the lattice structure during crystallization (usually by supersaturation below 93.5°C) (5). Alternatively, the beta form does not contain water and exists as a non-hygroscopic and anhydrous form. Amorphous lactose is formed when either the crystallization is rapid or sufficient transient energy is introduced into the crystalline forms (74), i.e., spray drying (75), micronization and milling (76), freeze-drying, and anti-solvent crystallization (77). 

Acid-catalyzed photohydration of styrenes19 and additions to cyclohexenes20 leading exclusively to the Markovnikov products are also possible. Sensitized photoaddition, in contrast, results in products from anti-Markovnikov addition. The process is a photoinduced electron transfer21 taking place usually in polar solvents.22,23 Enantiodifferentiating addition in nonpolar solvents has been reported.24 The addition of MeOH could be carried out in a stereoselective manner to achieve solvent-dependent product distribution 25... 

The difference in particle size and particle size distribution is regulated via the mode and the rate of addition of the anti-solvent. 

Benzene is an important feedstock and component of gasoline. It is widely used as anti-knock additive and solvent. However, benzene must be removed from the flue gases that are emitted frorr petrochemical plants, petroleum tanks, coke ovens, distillation towers and the installations in which benzene is used as a solvent, due to its carcinogenicity. 

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