Single solvent crystallization

The ideal situation is a single solvent crystallization (Table 1.9). The compound of interest is not soluble in a solvent at low temperatures but very soluble at higher temperatures. In cases such as these, the material should be dissolved in a minunum amount of hot solvent and the solution allowed to cool slowly with stirring. 

The preferred choice for an API crystallization process is a cooling crystallization from a single solvent. This is because temperature and cooling rate are relatively easy to control and to scale up consistently. The decision criteria is based on the solubility profile with temperature and the available yield and productivity. 

In this example a productivity of 100 kg/m3, yield of >85% and Maximum solids fraction at isolation of 0.3 are specified. The solvents that match these constraints are 1,4-dioxane, Ethanol, Isobutanol, Pentanol, Propanol, Isopropyl alcohol, 1,1,1-Trichloroethane and Water. On the basis of these results the first choice of a cooling crystallization from a single solvent appears feasible and an antisolvent addition should not be required. From this list the alcohols and water are certainly the best choices from a health, safety and environmental... 

All freeze separation processes depend on the formation of pure solvent crystals from solution, as described for eutectic systems in Section 15.2.1. which allows single-stage operation. Solid-solution systems, requiring multistage-operation, are not usually economic. Several types of freeze crystallisation processes may be designated according to the kind of refrigeration system used as follows . 

In ternary systems of relevance to solvent extraction these may be two (partly) immiscible solvents and one (solid) solute, or two (solid) solutes and a single solvent. The latter system may constitute a partial system of quaternary or higher mixtures that involve two liquid phases, which are solvent extraction systems. In principle, however, a system of two solid solutes and a liquid solvent could split into two liquid phases, one rich in the one solute, the second in the other. In general, when one solute crystallizes out from a ternary (two solutes... 

Where no single solvent is found suitable, a mixture of two mixable solvents, one of which the product is soluble and the other insoluble, may be used. The substance is dissolved in a small quantity of the solvent that has the strongest dissolving power, then the solvent that does not dissolve the product, is added until complete crystallization occurs. This process can be carried... 

Let us analyze the following specific reaction [H. Schmalzried, et. al. (1990) T. Frick (1993)]. A single crystal of NiO is used as a solvent for the solid reactants CaO and Ti02, both being moderately soluble in NiO. They isothermally diffuse into NiO from opposite sides (Fig. 9-12 a). Solutes for this type of reaction do not form stable compounds with the solvent crystal, but must form at least one stable compound with each other. 

A solid solution is a solid mixture of one or more compounds within a solvent of another solid crystalline compound. For the mixture to be considered a solid solution the crystal structure of the solvent must remain essentially unchanged upon the addition of the solute (s) and the whole mixture must remain as a single homogeneous phase. We can distinguish two types of inclusion within the solvent crystal substitutional in which the solute molecule replaces a solvent molecule in the lattice, or interstitial in which the solute molecule fits into a space in between solvent particles. The properties of the solvent material are affected by the formation of solid solutions because the process results in distortions in the crystal lattice and disrupts the overall homogeneity of the host material. 

Fig. 4.8 Arrangement for surveying a variety of potential solvents for crystallization. A single small crystal is placed on a microscope cover slip. (It may be helpful to mark the location of the crystal by circling it with a felt tipped pen.) The cover slip is then inverted on a short ( 4-6 mm) piece of Tygon tubing mounted on a microscope slide. A few drops of a trial solvent are placed on the side around the periphery of the tubing. They will seep into the space inside the tubing and evaporate, filling it with vapours that may or may not dissolve the crystal. Recrystallization of the sample may be followed on the microscope, and the same sample may be reused many times without loss of material, a Cover slip with crystal in a marked circle, b Microscope slide with a slice of tubing and the coverslip with the crystal (whose size has been exaggerated for clarity).

If crystals do not form on cooling, you rfiay have formed a supersaturated-solution and you should -- scratch with a Pyrex glass rod, as described for -single solvent selection (Box 13.1). 

Fig. 13 Solubility of CBZ NCT cocrystal (1 1) and single component crystal of CBZ(III) at 25°C as a function of total NCT concentration in ethanol, 2-propanol, and ethyl acetate. The solid lines represent the predicted solubility, according to Eq. (28) with values for Ksp and Kn in Table 5. Filled symbols are experimental cocrystal solubility values in ( ) ethanol, (a) 2-propanol, and ( ) ethyl acetate. The dashed lines represent the predicted solubility of CBZ(III) based on Kn values calculated from the cocrystal solubility analysis. Table 5. Open symbols are experimental CBZ(III) polymorph solubility values in pure solvent. (Reproduced from Ref. l)...

Single-component solvent evaporation methods depend on the removal of solvent in order to obtain the saturated solution required for crystallization to occur. If single-solvent solutions do not yield diffraction-quality crystals, mixtures of solvents may be tried. Multi-component solvent evaporation methods depend on the difference in the... 

Multiple uses. It is desirable to use as the extraction solvent a material that can serve a number of purposes in the manufacturing plant. This avoids the cost of storing and handling multiple solvents. It may be possible to use a single solvent for a number of different extraction processes practiced in the same facility, either in different equipment operated at the same time or by using the same equipment in a series of product campaigns. In other cases, the solvent used for extraction may be one of the raw materials for a reaction carried out in the same facility, or a solvent used in another operation such as a crystallization. 

Crystallization by cooling is normally carried out in a single solvent—one of the advantages of this method of generating supersaturation. In many cases, however, the substrate may be in a solvent mixture to start out, or a second solvent may be added to reduce the ultimate solubility to increase the yield. 

A typical reaction yield of this approach was approximately 73% based upon the charge of 7-chloro. The charge ratio of Iso/7-chloro was 1.5 to 1. Excess Iso was charged to increase the reaction selectivity. However, unreacted Iso was lost in the mother liquor. The final yield after the crystallization was approximate 67%. The isolated cake contained the desired product Mono with approximately 4-5 wt% Bis-adduct. A single solvent (toluene) was used in the process. 

In this single-solvent polymorph screening approach, the solvent is added to the API and heated to an appropriate temperature until the solid is completely dissolved. The resulting solution is quickly cooled to a specific crystallization temperature chosen to create the desired degree of supersaturation. Rapid cooling... 

A good first pass approach in cases where a compound will not crystallize from a single solvent is to find a solvent in which the compound of interest is relatively soluble and a solvent miscible in the first in which the compound is not soluble (Table 1.10). Dissolve the compound in a minimum amount of the first solvent near the lower of the two boiling points, and then slowly add a second solvent, in which the compound is not soluble, until the solution becomes cloudy. If the antisolvent has a much lower boiling point than the solvent, allow the solution to cool slowly with stirring and add seeds periodically until the solids persist. 

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