Crystallization from solution product purity

Product purity and consistency, which are paramount norms in bulk drug manufacturing, are today observed through the impurity profiles to an unprecedented extent. This puts a great deal of pressure on the mastery of purification methods, mostly on those based on crystallization from solution. 

The first industrial crystallizers and crystallization processes came up about 150 years ago. The crystallization process became entirely independent of locations (e.g., solar ponds) or stationary energies and all product purities became educible. The further development led to different crystallizers adjusted to the respective crystallization processes and concentrated on the product quality aspect demanded by the market. Applying vacuum technology opened the possibility to choose operation apart from the atmospheric pressure and herewith the opportunity to precisely design the crystallization processes to the respective phase systems and the material properties. Today, these vacuum crystallization processes have become the common standard in the industrial continuous single mass crystallization from solutions. 

However, pMBCl 42 has a thermal stability issue and is expensive (Aldrich price 25 g for 69.90 the largest bottle). On the other hand, pMBOH 43 is stable and economically viable (Aldrich price 500 g for 84.90 the largest bottle). It was found that mono-N-alkylation of 36 proceeded well by slow addition (over 3 h) of 43 to a solution of 36 in acetonitrile in the presence of a catalytic amount of acid (p-TsOH) at 70 °C, as shown in Scheme 1.16. Slow addition of alcohol 43 minimized the self-condensation of 43 to form symmetrical ether 44, which was an equally effective alkylating agent. The product 41 was then directly crystallized from the reaction mixture by addition of water and was isolated in 90% yield and in >99% purity. A toluene solution of 41 can be used for the next reaction without isolation but the yield and optical purity of the asymmetric addition product were more robust if isolated 41 was used. In general, the more complex the reaction, the purer the starting materials the better. 

Batch crystallization. Crystallization is extremely common in the production of fine and specialty chemicals. Many chemical products are in the form of solid crystals. Also, crystallization has the advantage that it can produce a product with a high purity and can be more effective than distillation from the separation of heat-sensitive materials. Crystallization has already been discussed in Chapter 10 and has two main steps. Firstly the solute to be crystallized is dissolved in a suitable solvent, unless it is already dissolved, for example, solute dissolved in a solvent from a previous a reaction step. Secondly, the solid is then deposited in the form of crystals from the solution by cooling, evaporation and so on. 

The distilling flask, collection flask, and column are continuously evacuated with a high-vacuum system. When the bulk of the pentane and residual hexane have distilled away, the temperature of a silicone oil bath surrounding the distillation flask is raised from room temperature to 125° over about a one-hour period. When the distillation rate diminishes appreciably, the temperature is slowly raised to 150° and maintained there until no more liquid is obtained. The distillation flask is cooled to room temperature before air is admitted to the system. The distilled product weighs 86.5 g. (89% yield checkers report 89 %t) and melts at 32 to 32.5°. In this state of purity, (bromomethyl)-carborane is suitable for most uses, but it may be further purified by crystallization from pentane or methanol. For example, crystals obtained by chilling a solution of 86.5 g. of the car-... 

However, the formation of these products does not appear to play a critical role in the decision as to whether the 425 nm and 480 nm maxima are due to different states of the same molecule or to different compounds. It was reported that special care was taken to ensure the purity of luminol and of 3-aminophthalate 109>. In commercially available 3-amino-phthalic acid a yellowish impurity exhibiting brilliant green fluorescence was detected 109> this substance also formed in neutral solutions of pure 3-amino phthalic acid and crystallized from these solutions in yellow crystals. The structure of this substance was determined to be 53 its absorption spectrum has a maximum at 388 nm the fluorescence maximum is at 475 nm, with a fluorescence quantum yield of about 0.75 in DMF i 9). 

Most of the impurities from a crystalline mass can often be removed by dissolving the crystals in a small amount of fresh hot solvent and cooling the solution to produce a fresh crop of purer crystals. The solubility of the impurities in the solvent must, however, be greater than that of the main product. Re-crystallisation may have to be repeated many times before crystals of the desired purity are obtained. A simple recrystallisation scheme is ... 

Ciystallization from solution is an important separation and purification process in a wide variety of industries. These range from basic materials such as sucrose, sodium chloride and fertilizer chemicals to pharmaceuticals, catalysts and specialty chemicals. The major purpose of crystallization processes is the production of a pure product. In practice however, a number of additional product specifications are often made. They may include such properties as the ciystd size distribution (or average size), bulk density, filterability, slurry viscosity, and dry solids flow properties. These properties depend on the crystal size distribution and crystal shape. The goal of crystallization research therefore, is to develop theories and techniques to allow control of purity, size distribution and shape of crystals. 

Under an atmosphere of nitrogen, a solution of n-butyl lithium in hexane (321 ml, 15%) was added to a solution of diisopropylamine (48.6 g, 0.48 mole) in tetrahydrofuran (1000 ml) at -30°C and the mixture was stirred for one hour. The reaction mixture was then cooled to -72°C and methyl 3,3-dimethyl acrylate (55 g, 0.48 mole) was added to it. Stirring was continued at -65° to -75°C for 30 min. To the resulting mixture, a solution of p-ionylidene acetaldehyde (100 g, 0.458 mole, 9-trans content 80%) was added and the reaction mixture was stirred at -65° to -75°C for 1 h. The reaction mixture was then warmed to 40°C and stirred at this temperature for 3 h. Solvent was removed under vacuum and the reaction mixture was diluted with water (700 ml) and methanol (300 ml). Activated charcoal (4 g) was then added and the mixture was refluxed for 30 min. The heterogeneous mixture was filtered through hyflo and the hyflo bed was washed with methanol (300 ml) and water (150 ml). The aqueous methanolic layer was then extracted with hexanes (2 x 500 ml) and acidified with 10% sulfuric acid to pH 2.80.5. The desired product was then extracted with dichloromethane (2 x 500 ml). The combined dichloromethane layer was washed with water (2 x 300 ml) and concentrated in vacuo to afford the desired isotretinoin. Crystallization from methanol (200 ml) afforded isotretinoin (44 g) in greater than 99% HPLC purity. 

To a solution of 2,3-butanedione dioxime (23.2 g, 0.2 mole) in 500 mL of boiling 95% ethanol in a 2-L Erlenmeyer flask is added a solution of cobalt(II) nitrate hexahydrate (29.0 g, 0.10 mole) in 500 mL of hot 95% ethanol. The red-brown solution is boiled on a hot plate for 5 minutes and then a solution of sodium bromide (15.8 g, 0.15 mole) in water (20 mL) is added. The brown solution is allowed to cool to 35°. Dimethyl sulfide (11 mL, 0.15 mole) is added, and the resulting solution is stirred vigorously for 8 hours with the flask open to the atmosphere. During the stirring a brown solid precipitates from solution. The solid is collected by suction filtration on a Buchner funnel and washed successively with 200-mL portions of water, ethanol, and diethyl ether. The fine, dark-brown crystals are air dried and dissolved in dichloromethane and the system is filtered. The filtrate is evaporated to give typically 20 g of product (yield is about 50%). Its purity, as it is isolated in the above procedure, is adequate for subsequent procedures of synthesis. The product can be purified further by recrystallization from dichloromethane-hexane. Anal Calcd. for Ci0H2oN404SBrCo C, 27.85 H, 4.68 N, 12.99 Br, 18.53. Found C, 27.61 H, 4.59 N, 13.03 Br, 18.64. 

Cool the reaction mixture in an ice bath. If crystallization does not occur, withdraw a drop of solution on a stirring rod and rub it against the inside surface of the flask to induce crystallization. Collect the product by suction filtration and wash it free of yellow mother liquor with a 1 1 mixture of 95% ethanol and water. The product should be colorless and of sufficient purity (mp 134-135°C) to use in subsequent reactions usual yield is 10-12 g. If desired, the moist product can be recrystallized from 95% ethanol (8 mL per g). 

Concentration.—The oldest, simplest and, combined with cooling, most used method of producing crystalline solids from solutions is by concentration of the solution. The oldest application is without doubt found in the evaporation of sea water for the production of sodium chloride (common salt). Prehistoric man must have learned this process from the accumulation of salts left by the evaporation of shallow pools of sea water above tide level filled during storms and concentrated to the point of crystallization by combined sun and wind. Except in so far as the best method for securing crystals of highest purity has been... 

Crystallization from the melt, often considered in recent decades for avoidance of solvents, can be effective in manufacturing very high purity product even when solvents are not an issue. The need to pay attention to mass and heat transfer principles, and to provide suitable agitation to meet system requirements, bears many similarities to more conventional CrystalUzation from solution. 

The next step is done in a hood owing to evolution of nitric oxide. A 500-ml. beaker is charged with 65 ml. of 71% ( conc d. ) nitric acid, and the pulverized crude 2,4-dinitrosoresorcinol is added in small amounts with stirring in 60-70 minutes, keeping the temperature at 4-8°. The ice bath is removed to allow the mixture to warm to room temperature for 30 minutes. Then the mixture is heated slowly to 75° for 45 minutes to complete the reaction. The mixture is cooled to room temperature and the product is filtered off with Whatman No. 4 paper, then washed with five 40-ml. portions of water. Dilute sodium carbonate solution (25 ml.) is added and let stand 1 hour before collecting and drying the product, 2,4,6-trinitroresorcinol. Yield 28.7 g. (84%), m.p. 168-170°. Purity and stability may be improved by crystallization from dil. sodium carbonate solution. 

In solution crystallization product purity is controlled to a great extent by the efficiency of solid-liquid separation. Impurities dissolved in the ciystallizer liquid are normally removed by spinning liquor from the crystals and then washing the resulting cake. The residual impurity level is a function of factors listed in the following equation ... 

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