Small scale crystallization

When small samples (less than 200mg) are to be crystallized it is particularly important to remove traces of insoluble material and to avoid contamination by dust, filter paper, etc. Thus it is essential to use carefully cleaned glassware and purified solvents, and to filter the hot solution. The paratus shown in Fig. 11.1 is convenient for small scale (5-200mg) crystallizations. Place the sample in the bulb and wash it with a few drops cf solvent. The procedure is as follows  

Heat the bulb in an oil bath or a water bath so that the solvent refluxes up to the level of the sintered disc. Add more solvent, in small portions, until the compound has dissolved. 

Remove the apparatus from the bath, wipe the bulb to remove oil or water, and quickly filter the hot solution into a clean receiver by pressurizing the vessel using hand bellows or an inert gas line. Filtering under pressure in this way avoids the problem of unwanted crystallization, and reduces transfer losses. The hot solution can be filtered into a small conical flask, but on a scale of lOOmg or less, a Craig tube (Fig. 11.2) gives better recovery because it allows the crystals to be recovered without another filtration. 

Filter the hot solution into a suitably sized Craig tube and cover the tube with aluminium foil while crystalhzation occurs (Fig 11.2a). 

When crystallization is complete fit the matching glass rod (a close fit is essential) into the Craig tube and secure it tightly with a rubber band (Fig. 11,2b). Place the inverted assembly in a centrifuge tube and centrifuge for a few minutes (remember to use a counter-balancing tube and solvent). 

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The multicellular structure of laminar convection in small-scale crystal growth systems complicates the interpretation of the boundary layer analysis,... 

The scale of operation often has an overriding importance on the selection of the equipment because of the means used for heat transfer. For very small-scale crystallization work it is common to use radiation. The capacity of such equipment varies from a few liters up to several hundreds of liters per day (of solution cooled). For operation on scales up to several thousand liters per day, it is possible to use tanks with water-cooled coils and an agitator. For large-scale applications where the quantity of solution is thousands of liters per day, it is almost universal practice to use vacuum evaporation to remove the solvent this is true whether the solution is cooled by adiabatic evaporation or in equipment where crystallization occurs because of isothermal evaporation. 

The oxime is freely soluble in water and in most organic liquids. Recrystallise the crude dry product from a minimum of 60-80 petrol or (less suitably) cyclohexane for this purpose first determine approximately, by means of a small-scale test-tube experiment, the minimum proportion of the hot solvent required to dissolve the oxime from about 0-5 g. of the crude material. Then place the bulk of the crude product in a small (100 ml.) round-bottomed or conical flask fitted with a reflux water-condenser, add the required amount of the solvent and boil the mixture on a water-bath. Then turn out the gas, and quickly filter the hot mixture through a fluted filter-paper into a conical flask the sodium chloride remains on the filter, whilst the filtrate on cooling in ice-water deposits the acetoxime as colourless crystals. These, when filtered anddried (either by pressing between drying-paper or by placing in an atmospheric desiccator) have m.p. 60 . Acetoxime sublimes rather readily when exposed to the air, and rapidly when warmed or when placed in a vacuum. Hence the necessity for an atmospheric desiccator for drying purposes. 

Scraped-Surface Crystallizer For relatively small-scale apph-cations a number of ciystallizer designs employing direct neat exchange between the shiny and a jacket or double wall containing a cooling medium have been developed. The heat-transfer surface is scraped or agitated in such a way that the deposits cannot build up. 

Figure 16-17. Left transmission electron micrograph of small single crystals of Ooct-OPV5 scale bar 5 pnt. The arrows indicate the 6-axis direction. Right electron diffraction pattern of the same single crystals. The arrow indicates the 613 relteclion spot (crysial dimensions 5x40 pm2 Philips STiiM CM 12 operated at 120 kV. lnslilul Charles Sudron, Strasbourg).

FIGURE 20.6 Phase images of ethylene-propylene-diene terpol3mier (EPDM) samples at different scales. Images of the unvulcanized sample are shown in (a, d) and images of samples, which were cross-linked with different amount of sulfur curative—1 phr—in (b, e) and 2 phr—in (c, f). White arrows in (f) most likely indicate locations with small sulfur crystals. 

It should therefore not be surprising that for relatively small-scale operations involving solids handling within the fine and intermediate chemicals industry, batch operation is preferred. Similarly, continuous processes that involve precipitation or crystallization, a common unit operation in fine chemicals, are rare. Small-scale examples are known, for instance, a continuous crystallization process was used by Bristol-Myres Squibb in order to improve dissolution rates and bioavailability of the product [12]. The above does indicate that not all process or parts thereof are suited for conversion from B2C, given the current technology. 

Early on in the drug development program, only small amoimts of material are available for crystallization studies. Parallel crystallization technique in test tubes allows for the identification of many solvent systems using small amoimts of material. On a small scale, it is not easy to control the rate of cooling or the rate of evaporation to achieve supersaturation. However, the antisolvent addition strategy to achieve supersaturation in combination with seeding, allows rapid identification of several crystallization systems using a minimum amount of compound. 

Using piecewise constant control profiles and orthogonal collocation on finite elements, this approach was further developed by Renfro (Renfro, 1986 Renfro et al, 1987) to deal with much larger problems. More recent simultaneous applications that involve SQP, orthogonal collocation, and piecewise constant control profiles have been presented by Patwardhan et al (1988) for online control, and by Eaton and Rawlings (1988) for optimization of batch crystallizers. These studies have shown that simultaneous approaches can be applied successfully to small-scale applications with complex constraints. 

NOTTS Use cod, but not very cold water in the condenser. Due to the high freezing point oi l 1CN the use of odd water may cause it to crystallize in the condenser. This process is an improvement over the old method using ferrocyanide in that it results in a product of greater purity. Commercial HCN is currently produced by reacting ammonia and methane gases in an arc furnace. While extremely cheap and effective, it is not very suitable fir small scale production. 

Methylene difluorocyclopropanes are relatively rare and their rearrangement chemistry has been reviewed recently [14]. In addition, electron deficient alkenes such as sesquiterpenoid methylene lactones may be competent substrates. Two crystal structures of compounds prepared in this way were reported recently [15,16]. Other relatively recent methods use dibromodifluoromethane, a relatively inexpensive and liquid precursor. Dolbier and co-workers described a simple zinc-mediated protocol [17], while Balcerzak and Jonczyk described a useful reproducible phase transfer catalysed procedure (Eq. 6) using bromo-form and dibromodifluoromethane [18]. The only problem here appears to be in separating cyclopropane products from alkene starting material (the authors recommend titration with bromine which is not particularly amenable for small scale use). Schlosser and co-workers have also described a mild ylide-based approach using dibromodifluoromethane [19] which reacts particularly well with highly nucleophilic alkenes such as enol ethers [20], and remarkably, with alkynes [21] to afford labile difluorocyclopropenes (Eq. 7). 

Before 1925, there were a few compounded oils made for special purposes, such as lubrication of marine engines and steam cylinders, but additives were not used in automotive crankcase oils. In the 1930 s, chemical compounds made by condensation of chlorinated paraffin wax with naphthalene were found to lower the pour points of oils. Pour depressants (9) apparently are adsorbed on small wax crystals which separate from oils when they are chilled. The protective adsorbed layer of additive prevents the normal interlacing of larger wax crystals which forms a gel. In 1934 polymerized unsaturated hydrocarbons first came into large scale commercial use to lower the temperature coefficient of viscosity of oils. Other compounds for increasing the viscosity index of oils have since become common. 

The alkali sulphates can also be made by neutralizing, say, a soln. of 5 grms. of sulphuric acid in 30 c.c. of water with the alkali hydroxide or carbonate, and evaporating the soln. until crystals begin to form. The process is not economical except on a small scale. It is used mainly for lithium, rubidium, and caesium sulphates. H. Erdmann 20 treated a hot soln. of crude rubidium iron alum with milk of lime made from purified lime, and filtered the liquid from the excess of lime, calcium sulphate, and ferric hydroxide, by suction. The small amount of lime in soln. is precipitated by adding rubidium carbonate. The filtrate is neutralized with sulphuric acid, and evaporated to the point of crystallization. 

A very convenient process for the production of this salt on the small scale is thet recommended by Walch-NEe. A pound of pure crystallized carbonate of soda is dried as perfectly as possible, and then intimately mixed with five ounces of pure sulphur the mixture is gradually heated in a glass or porcelain basin to the melting point of the sulphur, and kept at that tempera-tore for some time, stirring constantly in order to bring every part in contact with the air. The sulphide of sodium formed at first absorbs oxygen from the air, aud is converted with feeble Incandescence into hyposulphite of soda, The mass, when cold, is dissolved in water boiled with sulphur for some time, and the filtrate is evaporated, when very fine and pure crystals separate. If the heat employed be too strong, part of VOL. it. 

For inorganic substances, chemical reactions may be carried out on a small scale on microscope slides, the crystallization of reaction products being watched. Tests for particular ions or atom groups have been devised, the criterion of identity being, not solubility or colour, as in macroscopic qualitative chemical analysis, but crystallographic properties. For information on such methods, see Handbook of Chemical Microscopy, by Chamot and Mason (1958). 

Figure 1. Schematic diagrams of several commonly used systems for melt crystal growth of electronic materials (a) vertical Bridgman, (b) Czochralski, and (c) small-scale floating-zone systems.

Transitions from steady-state to time-dependent surface-tension-driven motions are well known also and are important in meniscus-defined crystal growth systems. For example, the experiments of Preisser et al. (51) indicate the development of an azimuthal traveling wave on the axisymmetric base flow in a small-scale floating zone. 

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