Metastable zone

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

Within the metastable regioa, primary aucleatioa will aot occur, and the width of the metastable zone, as reflected by — c or T —, varies... 

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... 

Systems also vary in the extent of the metastable zone width, the point after whieh spontaneous nueleation is said to oeeur. Within the metastable zone, however, seed erystals may grow. Metastable zone width is therefore an important faetor in assessing the propensity of a system to erystallize and in deeiding the appropriate erystallization teehnique. Kim and Mersmann (2001) provide a review of methods for estimation for metastable zone widths both unseeded and seeded systems. 

Reeognizing that seeondary nueleation ean oeeur even within the metastable zone, the eoupled population and mass balanee equations for bateh eooling erystallization in moment form... 

Whilst programmed eooling (i.e. operation at eonstant nueleation rate within the metastable zone) inereases the mean produet erystal size ef. natural eooling, is it the optimum in produeing the largest possible erystals The problem is to find the maximum of the integral of erystal growth over the bateh time. Thus beeause bateh operation is by definition transient, a funetional has to be maximized over time rather than just a funetion at some point in time. Jones (1972, 1974) addressed this problem by applieation of a partieular result in... 

Solution characteristics eomposition, equilibrium relationships (solubility), metastable zone width, purity, partition eoeffieient, liquid density, viseosity, and their temperature dependenee (Chapter 3). 

The most frequent site for erystal enerustation is on a eompatible solid surfaee within a zone of high supersaturation and low agitation. Seleetion of a less eompatible material having a smooth surfaee ean avoid the major exeesses of enerustation. Dunean and Phillips (1979) and Shoek (1983), respeetively, reveal a eonneetion between the metastable zone width of erystallizing solutions and their propensity to enerust. It is well known that judieious erystal seeding ean also help minimize enerustation. Simple laboratory tests are reeommended to determine all these issues before the plant is built. 

Kim, K.-J. and Mersmann, A., 2001. Estimation of metastable zone width in different nucleation processes. Chemical Engineering Science, 56(7), 2315-2324. 

Sohnel, O. and Mullin, J.W., 1988. The role of time in metastable zone width determinations. Chemical Engineering Research and Design, 66, 537-540. 

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. 

The extrapolated value of aTi// ) on this plot corresponds to the width of the metastable zone as expressed in terms of temperature, The width of the metastable zone expressed in... 

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... 

The width of the metastable zone is system dependent and generally increases as the solute molecules become more complex and flexible. For inorganic salts the metastable zone may be 1 to 2 °C, however in pharmaceutical systems it is typically 20 to 40 °C, and in some instances it can be much larger. 

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. 

Parsons, A.R., Black, S.N., Colling, R., 2003, Automated Measurement of Metastable Zones for Pharmaceutical Compounds, Trans IChemE, 81, 700-704. 

In considering the state of supersaturation, Ostwald(20) introduced the terms labile and metastable supersaturation to describe conditions under which spontaneous (primary) nucle-ation would or would not occur, and Miers and Isaac(21) have represented the metastable zone by means of a solubility-supersolubility diagram, as shown in Figure 15.8. 

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. 

Figure 15.10. Simple apparatus for measuring metastable zone widths 36 ...

Figure 15.11. Metastable zone width of aqueous ammonium1-3)...

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... 

In an ideal experiment, once nuclei have formed, the concentration of protein in the solute will drop, thereby naturally leading the system into the metastable zone (Fig. 3.1) where growth should occur, without the formation of further nuclei (McPherson, 1999 Ducruix and Giege, 1992 ... 

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