Crystallization metastable zone

The shape of the equilibrium line, or solubility curve, is important in determining the mode of crystallization to be employed in order to crystallize a particular substance. If the curve is steep, i.e. the substance exhibits a strong temperature dependence of solubility (e.g. many salts and organic substances), then a cooling crystallization might be suitable. But if the metastable zone is wide (e.g. sucrose solutions), addition of seed crystal might be necessary. This can be desirable, particularly if a uniformly sized product is required. If on the other hand, the equilibrium line is relatively flat (e.g. for aqueous common salt... 

As mentioned above, crystallization is possible when the concentration of the solute is larger than the equilibrium saturation, i.e. when the solution is supersaturated with the solute. The state of supersaturation can be easily achieved if the solution is cooled very slowly without agitation. Above a certain supersaturation (this state is also called supersolubility) spontaneous formation of crystals often, but not always, occurs. Spontaneous nucleation is less probable in the state between equilibrium saturation and supersolubility, although the presence of fine solid impurities, rough surfaces, or ultrashort radiation can cause this phenomenon to occur. The three regions (1) unsaturation (stable zone), where crystallization is impossible and only dissolution occurs, (2) metastable zone, extending between equilibrium saturation and supersolubility, and (3) labile zone, are shown in Fig. 5.3-20. 

In general, excessive production of nuclei is detrimental since crystals produced under these conditions are fine, difficult to filter, and may contain a large fraction of impurities. Therefore, the solution should be kept in the metastable zone and be prevented to enter the labile zone. This can be achieved by seeding crystals into the solution to obtain a sufficient number of nuclei in the solution when penetrating the metastable zone. The mass of seeds mseed of size L.md that is required to produce crystals of size L, r with the desired yield Y, r is given by ... 

Crystallization remains the primary means of controlling the polymorphic or solva-tomorphic state of a compound, and various groups have examined the influences of processing parameters on the identity and quality of the isolated form. Seeding was used to reduce the size of the metastable zone of eflucimibe, and thereby control the identity of the desired polymorphic identity of the product through a reduction in concomitant crystallization [16], Process improvements have been developed that were found to improve the filterability and enhance the bulk density of ranitidine Form-1 [17], while the variation of process parameters used in an oscillatory baffled crystallizer enabled better selection to be made between the metastable a- and /i-forms of (z.)-glutamic acid [18]. 

Supersaturation is the driving force for crystallization and is a prerequisite before a solid phase will appear in a saturated solution. Figure 1. shows the situation for a cooling crystallization. At point 1 the system is under saturated and the concentration of dissolved solute is below the solubility curve defined by Eq 3. As the system cools it becomes saturated at point 2 but remains as a metastable liquid phase until the metastable zone is crossed at point 3, where... 

Figure 1 Supersaturation and Metastable Zone Width in a Cooling Crystallization...

The rate of primary nucleation and width of the associated metastable zone are difficult to measure with precision in the laboratory, because of their dependence on environmental factors. Dust particles contaminating a solution, and imperfections on the surface of the crystallizer and agitator are often... 

At point 1, the only form that is supersaturated is Form I, and because supersaturation is a pre-requisite to crystallization it is the only form that could precipitate as a solid phase. If the metastable zone is crossed for Form I before the solubility curve is reached for Form II then Form I will crystallize first and continue to grow unhindered. Unfortunately the width of the metastable zone cannot be predicted theoretically at the present time and is sensitive to physical and chemical impurities and the surface quality of the crystallization vessel. This leads to uncertainty in process scale up. 

Whenever the solubility curve is crossed for the less stable Form II there is a risk that it will nucleate and contaminate the product. This situation is very probable when the solubility curves of the two polymorphs lie close together, as shown in Figure 21 of the Cimetidine case study. The addition of seed crystals of Form I, close to its solubility curve, and minimization of the supersaturation during the growth process is a good method of control in this instance. Solvent selection to extend the width of the Form II metastable zone would also be desired, as discussed in section 2.4.4. 

The measurement of the width of the metastable zone is discussed in Section 15.2.4, and typical data are shown in Table 15.2. Provided the actual solution concentration and the corresponding equilibrium saturation concentration at a given temperature are known, the supersaturation may be calculated from equations 15.1-15.3. Data on the solubility for two- and three-component systems have been presented by Seidell and Linkiv22 , Stephen et alS23, > and Broul et a/. 24. Supersaturation concentrations may be determined by measuring a concentration-dependent property of the system such as density or refractive index, preferably in situ on the plant. On industrial plant, both temperature and feedstock concentration can fluctuate, making the assessment of supersaturation difficult. Under these conditions, the use of a mass balance based on feedstock and exit-liquor concentrations and crystal production rates, averaged over a period of time, is usually an adequate approach. 

Carefully selected seed crystals are sometimes added to a crystalliser to control the final product crystal size. The rapid cooling of an unseeded solution is shown in Figure 15.20a in which the solution cools at constant concentration until the limit of the metastable zone is reached, where nucleation occurs. The temperature increases slightly due to the release of latent heat of crystallisation, but on cooling more nucleation occurs. The temperature and concentration subsequently fall and, in such a process, nucleation and growth cannot... 

The area of conditions called the metastable zone is situated between the solubility and supersolubility curves on the crystallization phase diagram (Fig. 3.1). The supersolubility curve is defined as the line that separates the conditions where spontaneous nucleation (or phase separation or precipitation) occurs, from those where the crystallization solution remains clear if left undisturbed (Ducruix and Giege, 1992 Ducruix and Giege, 1999). 

Figure 14.2 Solubility diagram. During equilibration, the concentration of both precipitant and macromolecule increase until precipitation occurs. The formation of crystal nuclei reduces the amount of solvated macromolecule and allows the system to remain in the metastable zone where crystals can grow.

Metastable zone width should be less than 25°C for efficient crystallization. 

If ice-cream is warmed or the temperature fluctuates, some ice will melt, and an infinite variety of lactose concentrations will emerge, some of which will be in the labile zone where spontaneous crystallization occurs while others will be in the metastable zone where crystallization can occur if suitable nuclei, e.g. lactose crystals, are present. At the low temperature, crystallization pressure is low and extensive crystallization usually does not occur. However, the nuclei formed act as seed for further crystallization... 

These principles have been used to detect crystals of a-hydrate, /3-lactose, or both in various products. A supersaturated solution in the metastable zone prepared with respect to the form being tested is unsaturated with respect to the other. When the product in question contains crystals, the solution will become cloudy with newly formed crystals as a result of seeding. If crystals are not present in the material, the solution will remain stable and clear. 

Sugar-boiling for proper crystallization is done in the metastable and intermediate phase below the metastable zone, crystals dissolve and inefficiencies result above the intermediate phase, uncontrolled false grain or extra, small, and agglomerated crystals form, resulting in poor-quality crystals. When the syrup is in the metastable phase, it is seeded that is, a predetermined amount... 

For crystals to form from a liquid state, the molecules of the crystallizing species must come together in sufficient number (form a cluster) to overcome the energy cost of forming a surface. Once this energy barrier is overcome, the latent heat associated with crystallization is released, and further nucleation is strongly promoted. Thus, there often is a metastable zone where a supersaturated or subcooled system may not nucleate for a very long time. 

Both types of US effects (namely physical, which facilitate mixing-homogenization, and chemical, resulting from radical formation through cavitation) influence crystallization by altering the principal variables involved in this physical process (namely induction period, supersaturation concentration and metastable zone width). These effects vary in strength with the nature of the US source and its location also, their influence is a function of the particular medium to which this form of energy is applied. 

Figure 5.13. Effects of US on crystallization parameters. (A) Influence of US on the induction period of roxithromycin. (B) Variation of the induction time as a function of the relative supersolubility. (C) Variation of the induction time as a function of the supersaturation ratio. (D) Effect of US on the metastable zone of roxithromycin. (A.) with US, ( ) without US, (A) solubility curve (Reproduced with permission of Elsevier, Ref [141])... 

Even a few seed crystals, mechanically separated, can be used to produce larger quantities of resolved enantiomerically pure material. A second method of resolution by direct crystallization involves the localized crystallization of each enantiomer from a racemic, supersaturated solution. With the crystallizing solution within the metastable zone, oppositely handed enantiomerically pure seed crystals of the compound are placed in geographically distant locations in the crystallization vessel. These serve as nuclei for the further crystallization of the like enantiomer, and enantiomerically resolved product grows in the seeded locations. 

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