Purification by crystallization

The purification effect can be limited or decreased by a finite solubility of the impurity in the target crystal and also by kinetic effects such as fast growth conditions whereby the rejection becomes incomplete. Most detrimental to the purification is the incomplete removal of the mother phase from the isolated crop. 

Crystallization Basic Concepts and Industrial Applications, First Edition. Edited by Wolfgang Beckmann. 

While microimpurities in particular have an impact on phenomena at the crystal-liquid interface, large impurity contents may influence the solubility and driving force of crystallization (degree of supersaturation), the physical and chemical properties of the solution and of the crystalline product (particle size and particle size distribution, purity), and the phenomena at the crystal-liquid interface. 

The efficiency of the rejection of impurities can be decreased by kinetic effects of the growing interface, that is, when the desorption of impurity molecules from the interface is not fast enough so that the impurity molecules become kinetically incorporated. In addition, any depletion of impurities must be accompanied by a transport of this impurity molecule from the interface into the bulk of the mother phase this transport can also become a limiting factor for the purification. 

In addition, impurities can be incorporated into the crop via mother liquor entrapped between crystals and mother liquor adhering to the crystal surface 

In the past the TNT, washed free from acids, was further purified by crystallization. For this purpose 95% alcohol was mostly used. Since alcohol is not a very good solvent for TNT, in several countries it was customary to add a certain quantity of benzene (e.g. 5%) as in Germany before Wodd War II. In other countries toluene was added. Since benzene and toluene vapours are more toxic than that of alcohol, in some U.S.S.R. factories alcohol alone was used for the crystallization. 

Various other solvents for the crystallization of TNT have been suggested carbon tetrachloride (U.S.A., World War I), benzene, o nitrotoluene (Stettbacher [23]). More modem method consists in crystallizing TNT from nitric acid (see below under continuous method of crystallization). 

With the outbreak of World War I the shortage of alcohol compelled German factories to give up the crystallization method and to confine purification either to thorough washing with hot water or to crystallization by dissolving the TNT in concentrated sulphuric acid followed by precipitation with water (Vender s method [24]). The precipitation could be controlled by adding sufficient water to allow lower nitrated and unsymmetrical derivatives of TNT to remain in solution. 

After the war the method of purification by crystallization was not resumed, as purification by means of sodium sulphite was introduced. 

Although the purification of TNT by sodium sulphite was widely used after World War I a number of factories continued with the crystallization method using among other solvents toluene, which directly after crystallization was used for nitration. 

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Crystallization and Purification Solvent. Dimethylacetamide is useful ia the purification by crystallization of aromatic dicarboxyHc acids such as terephthahc acid [100-21-0] and/vcarboxyphenylacetic acid [501-89-3]. These acids are not soluble ia the more common solvents. DMAC and dibasic acids form crystalline complexes containing two moles of the solvent for each mole of acid (16). Microcrystalline hydrocortisone acetate [50-03-3] having low settling rate is prepared by crystallization from an aqueous DMAC solution (17). 

Raw Materials. Eor the first decade of PET manufacture, only DMT could be made sufficiently pure to produce high molecular weight PET. DMT is made by the catalytic air oxidation of -xylene to cmde TA, esterification with methanol, and purification by crystallization and distillation. After about 1965, processes to purify cmde TA by hydrogenation and crystallization became commercial (52) (see Phthalic ACID AND OTHER... 

Gumylphenol. -Cumylphenol (PGP) or 4-(1-methyl-l-phenylethyl)phenol is produced by the alkylation of phenol with a-methylstyrene under acid catalysis. a-Methylstyrene is a by-product from the production of phenol via the cumene oxidation process. The principal by-products from the production of 4-cumylphenol result from the dimerization and intramolecular alkylation of a-methylstyrene to yield substituted indanes. 4-Cumylphenol [599-64-4] is purified by either fractional distillation or crystallization from a suitable solvent. Purification by crystallization results in the easy separation of the substituted indanes from the product and yields a soHd material which is packaged in plastic or paper bags (20 kg net weight). Purification of 4-cumylphenol by fractional distillation yields a product which is almost totally free of any dicumylphenol. The molten product resulting from purification by distillation can be flaked to yield a soHd form however, the soHd form of 4-cumylphenol sinters severely over time. PGP is best stored and transported as a molten material. 

Hydroquinone may also be used in place of 4-chloroplienol. In this case an aluminum chloride—sodium chloride melt is usually employed. However, the yield is not satisfactory (43). It has also been reported that the reaction of hydroquinone with substantially stoichiometric phthaUc acid dichloride in the presence of anhydrous aluminum chloride in moderately polar solvents, such as nitrobenzene at around 100°C gives quinizarin (44). The reported yield is 65% after purification by crystallization from toluene. 

The condensed reaction mixture is evaporated in film evaporator 16 under vacuum. The crude l-(2,6-dimethyl)-phenoxy-2-aminopropane hydrochloride is precipitated in tank 17 using HCl dissolved in organic solvent //, separated in centrifuge 18, and dried in tray drier 19. The final purification by crystallization from solvent III occurs in crystallizer M. Pure l-(2,6-dimethyI)-phenoxy-2-amino-propane hydrochloride is separated in centrifuge 21 and dried in tray drier 22. The plant is equipped with typical solvent recovery and storage facilities not shown in the figures. 

In the current era many medicinal chemists are unaware of the very important role of compound soUd state properties on aqueous solubility and therefore to oral absorption. In many organizations compound purification by crystallization has disappeared being replaced by automated reverse-phase HPLC purification. If medicinal chemists isolate a compound as a white powder from evaporation of... 

If, instead of purification by crystallization, the crude anti/syn product mixture is chromatographed directly using the 3-component eluant, it is possible to increase the yield of each pure isomer to approximately 30%. 

Crystals Obtained by Acid Addition. Figure 4 shows the effect of initial solution composition on the impurity content of crystals obtained by acid addition. Clearly, this corresponds to the definition of an ideal system as presented above. These data show the order followed in impurity incorporation in the L-Ile crystals is L-Val > L-Leu > L-a-ABA, although there is only one data point on a-amino butyric acid. Also, the value of purification factors for all impurities is less than one. This means that purification by crystallization was indeed occurring. 

Since the recovery of neutral Lrlle may be performed after crystallization, redissolution and recrystallization, the concentrations of impurities in the solution were reduced by an order of magnitude in an additional series of experiments. Figure 8 shows the results. Once again L-VaJ is relatively unimportant and Puu appears constant, but note that the data do not go through the origin. Moreover, close examination shows that Puu > 1 which means that purification by crystallization has not occurred. Figure 9 shows that the purification factor for L-Leu is not constant and, therefore, the system is nonideal. 

A comparison of the steps crystallization and sweating shows, that the purification effect by sweating can be as high as the purification by crystallization (see also ( )). The loss of mass by sweating (7%-10%) is even less than the loss of mass by crystallization (20%-30%) (2) as to be found in industrial applications. 

Further purification by crystallizing from boiling anhydrous alcohol yields a product melting at 120.5-1210. 

R.A. Findlay and J.A. Weedman, Separation and purification by crystallization, in Advances in Petroleum Chemistry and Refining, Wiley-Interscience, New York, 1958, Vol. 1, pp. 118-209. 

The advantages of this industry scale synthesis are the use of non-halogenated solvents, formation of inert inorganic salts as waste products, recycling of valuable side products, ambient temperatures, relinquishment of protecting groups and purification by crystallization or filtration. 

The exudation process is a modified purification by crystallization. At present it is applied to purify grade m TNT and to recover impurities present in TNT for use as TNT oil in the preparation of explosive compositions. The process may be carried out in two ways. 

The recovered picric acid usually contains large quantities of mineral matter (determined as ash - 0.2%, compared with the permissible limit of 0.03%, as well as H2S04 (0.1% instead of 0.02%). Such a product cannot be used for military purposes without further purification by crystallization from water. 

During the oxidation to form hydroperoxides, the natural cis,cis unsaturation of linoleate is converted to cis, trans and trans, trans isomers. Privett and co-workers (10) concluded that at least 90% of linoleate hydroperoxide preparations are conjugated. When the oxidation is conducted at 0°C the hydroperoxides are predominately cis, trans isomers, but room temperature oxidation produces a large amount of trans, trans unsaturation (11, 12). Ethyl or methyl linoleate hydroperoxides are relatively low melting and as a result purification by crystallization is difficult. Bailey and Barlow (13) prepared high melting p-phenylphenacyl linoleate, oxidized the ester in benzene solution, and isolated virtually pure hydroperoxide by crystallization. Infrared spectra of the 99% purity p-phenylphenacyl linoleate hydroperoxide correspond to a trans, trans conjugated isomer. 

G.D. Botsaris and K. Toyokura, Separation and Purification by Crystallization, American Chemical Society, 1997. 

Then, after purification by crystallization, the mixed acetal is cleaved under acetic conditions to provide the hemiacetal 16. 

The CF3-dihydroartemisinin 12 is chemically stable and is easily prepared on large scale, in one reaction step with purification by crystallization [56], It is therefore considered to be a good candidate for future development. 

Controlling the crystallization pressure is essential for both purification by crystallization and for efficient operations on scale. By adjusting solution conditions to decrease the solubility of the product within the metastable zone, the desired molecules can be pressured to come out of solution and crystallize (Figure 11.3) [18]. Gradual cooling without seeding leads to one nucleation event and the... 

An example of this approach is shown in Figure 12.7. During the preparation of the fosinopril sodium intermediate 3 about 2% of the regioisomeric impurity 6 was formed [41]. Compounds 3 and 6 are too similar to be readily separated based on their chemical properties, and it was hoped that through purification of the subsequently derived intermediates, no regioisomer-derived impurities would be carried along to the final product. Since 3 is a low-melting solid and was isolated as a solid residue, no purification by crystallization was readily available. 

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