Ind. Eng. Chem. Res. 2004, 43, 1227-1234
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Examination of the Process Scale Dependence of L-Glutamic Acid Batch Crystallized from Supersaturated Aqueous Solutions in Relation to Reactor Hydrodynamics Kangping Liang,* Graeme White, and Derek Wilkinson Centre for Molecular and Interface Engineering, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, U.K.
Leslie J. Ford and Kevin J. Roberts Institute of Particle Science and Engineering, Department of Chemical Engineering, University of Leeds, Leeds, U.K.
Will M. L. Wood Formerly Process Studies Group, Syngenta Limited, Huddersfield, U.K.
The effects of reactor internals and reactant mixing on the measured metastable zone width (MSZW) associated with the batch crystallization of L-glutamic acid from supersaturated aqueous solutions are presented. The results of cooling crystallization experiments, as carried out at three reactor scales (450 mL, 2 L, and 20 L) agitated at various stirring speeds using an industrystandard retreat curve impeller with a single beaver-tail baffle, are shown. The observed MSZWs are mostly found to decrease with increasing stirring speed, with enhanced nucleation also being observed as the reactor scale increased; albeit hindered nucleation was found at higher stirrer speeds in the 450-mL reactor experiments. The MSZW data are correlated with Reynolds number to reveal a model reflecting the combined influences of hydrodynamics and scale on the overall nucleation process. 1. Introduction Batch cooling crystallization from solution is commonly used in the production of fine chemicals and pharmaceuticals. The standard equipment configuration is an agitated reactor. From an industrial point of view, reproducibility of product quality is critical. It has long been recognized that crystal formation processes and reactor hydrodynamics are closely related, with the latter affecting both reactant mixing and the spatial distribution of supersaturation and, as a consequence, the size distribution and morphology of final products.1-6 However, the interrelationship between hydrodynamics and crystallization is complex and poorly understood and, hence, a better understanding of the hydrodynamic influences on crystallization processes is of significant industrial importance. It is generally accepted that mechanical disturbances are capable of profoundly influencing the onset of nucleation.7-9 Agitation is frequently used to encourage crystallization. Unstirred solutions usually exhibit much broader metastable zones [the metastable zone is that (for cooling crystallization) between the thermodynamic dissolution temperature and the kinetically driven crystallization temperature] than stirred solutions. Hence, the supersaturation curve tends to approach the solubility curve more closely in agitated solution, as the width of the metastable zone is reduced. The early works of Mullin and Raven8,9 demonstrated that, for the * To whom correspondence should be addressed. Current address: SH103, 3301 South Dearborn Street, Chicago, IL 60616. Tel.: 1-312-567-7010. Fax: 1-312-756-7018. E-mail:
[email protected].
case of a cooling crystallization of aqueous inorganic salt solutions in a glass beaker (200 mL) equipped with a glass T stirrer and a vertical Perspex baffle, raising the stirrer speed was first found to reduce the supercooling required for nucleation, but further increases in agitation were found to actually retard the nucleation process. Finally, at the highest usable rates of agitation, nucleation is again enhanced. A similar behavior was observed for higher saturation temperatures. A combined effect of enhanced diffusion mass transfer and disruption of subnuclei due to agitation was believed to produce the complex interaction of nucleation versus agitation. However, the relative magnitudes of these two effects were not predicted.9 A theoretical explanation of the hydrodynamic effect on nucleation has been proposed by Ny´vlt and coworkers10 on the basis of a semiquantitative statistical model. Batch cooling crystallization of aqueous NaNO3 was carried out in a 250-mL Erlenmeyer flask fitted with a magnetic stirrer. Nucleation parameters were estimated from metastable zone width (MSZW) measurements, and their dependence on the stirrer speed was investigated. It was concluded that nucleation rate constant increases with rising stirrer speed. The order of nucleation was found to be practically independent of the rate of stirring and related only to the number of molecules needed to form a critical nucleus in a supersaturated solution.10-12 Liszi et al.13 studied the effect of the stirring speed on batch cooling crystallization of an aqueous solution of a sulfamide derivative in a jacketed glass reactor (500 mL) using a paddle stirrer. The MSZW and final crystal size distribution were measured. Their results showed
10.1021/ie0305014 CCC: $27.50 © 2004 American Chemical Society Published on Web 02/04/2004
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that the nucleation rate is very small at low Reynolds numbers (Re < 1000) and then increases significantly up to a critical Re ≈ 4000 but remains constant at higher Reynolds numbers. Higher mixing intensity was also reported to significantly decrease the crystal size for Re < 3000, which then remained constant at higher Reynolds numbers. It was suggested that stronger mixing generally raises the nucleation rate by reducing the diffusion inhibition due to poor suspension. However, no explanation was given of the constant nucleation rate beyond the critical Reynolds number. In this paper, optical turbidometric methods have been used to examine the effects of reactor hydrodynamics and process scale size on the measured MSZW to nucleation for the case of the batch crystallization of L-glutamic acid from aqueous solutions. To investigate scale effects, cooling crystallization experiments were carried out at three reactor scale sizes, 450 mL, 2 L, and 20 L, each fitted with an industry-standard retreat curve impeller with a single beaver-tail baffle and agitated at various stirring speeds. 2. Theoretical Background Ny´vlt et al.12 proposed a method for the evaluation of nucleation kinetics by measuring the width of the metastable zone. The nucleation rate J was defined as
J ) kn∆cmaxm ∆cmax ) c - c*
(1)
where kn is a nucleation rate constant, ∆cmax is the maximum possible supersaturation, c is the solution concentration, c* is the equilibrium saturation concentration at a given temperature, and m is the order of nucleation. The maximum possible supersaturation ∆cmax can be written as a function of the maximum possible supercooling of the system ∆tmax (MSZW) as
∆cmax )
∆t (dc* dt )
max
∆tmax ) tsat - tcry
(2)
where t is the solution temperature, dc*/dt is the temperature dependence of solubility, tsat is the saturation temperature, and tcry is the crystallization temperature. It is assumed that the nucleation rate is equal to the supersaturation rate B at the moment when nuclei are first detected. B is defined as
B ) k1 b )
dt (dc* dt ) ( dτ)
(3)
where k1 is a constant, is a correction factor for the change in concentration in case the species is being hydrated and equal to 1 for our system, b is the cooling rate, and τ is the time. When eqs 1-3 are combined, an expression for the dependence of the MSZW ∆tmax on the cooling rate b can be obtained:
log b ) (m - 1) log
dc* + log kn + m log ∆tmax dt
(4)
Therefore, plotting log(b) against log(∆tmax) should
Table 1. Geometry of the Reactors Used in This Work reactor scale [L]
reactor diameter T [m]
liquid level H [m]
impeller diameter d [m]
impeller clearance C [m]
baffle diameter [m]
0.45 2 20
0.082 0.153 0.29
0.082 0.153 0.29
0.05 0.09 0.172
0.008 0.016 0.03
0.013 0.025 0.048
result in a straight line with a slope equal to the order of nucleation, m, and the nucleation constant kn can be evaluated from the intercept. While Ny´vlt et al.’s method has proven to be highly useful in providing a “good practice” assessment tool, it is true that there is a need for caution in overanalyzing all measured nucleation data. Mullin14 has highlighted the utility of such a method in comparative terms for understanding changes in crystallizing systems. Though variability in the experimental approaches of some of the earlier studies had a significant impact, nowadays, via the use of temperature computer-programmed crystallization reactors lead to much more reliable data.19-22 In this analysis, it should be noted that Ny´vlt et al.’s approach assumes that the detection of crystals provides a good assessment of the general phenomenological properties of nucleation. This assumption is usually valid, particularly for organic compounds, for cases where the nucleation process is slow compared to crystal growth processes. 3. Experimental Details Batch cooling crystallization of aqueous L-glutamic acid (C5H9NO4, molecular weight 147.13) solutions was carried out in the temperature range from 75 to 20 °C. A solute concentration of 45 g/1000 g of distilled water (saturated at 70 °C) was used in all runs. Three glass reactors were used, whose volumes were 450 mL, 2 L, and 20 L, respectively, fitted with an industry-standard retreat curve impeller and a single beaver-tail baffle. The beaver-tail baffle was produced by a cylindrical plastic rod. Various stirrer speeds were investigated. The hydrodynamics for each scale size was represented by a 1:1 ratio of the reactor internal diameter to the solution fill height with a retreat curve impeller of standard geometry (DIN 28-146).18 The detailed geometry of the reactors and internals is presented in Table 1. Cooling of the unjacketed, dished-bottom glass 450mL reactor, the smallest scale studied in this work, was realized by putting the reactor into the water compartment of a Haake F3 thermostatic bath, with a specially designed system being used to carry out cooling experiments for the two larger reactor sizes. Figure 1 shows the setup for the larger scale sizes comprising the glass reactors as supported in a rectangular glass tank, which was filled with tap water and served as a jacket for the reactors. A Haake N6 (3-kW) circulator head fitted in the tank provided heating and ensured that the water was well mixed within the tank. Cooling was supplied by a Neslab CFT100 chiller (3 kW at 20 °C) connected to cooling coils in the tank. A LABVIEW data acquisition and temperature control system was developed to record signals from a PT100 temperature sensor and turbidimetric optical probe and simultaneously control the solution temperature. All of the experimental conditions studied are summarized in Table 2. It is wellknown that glutamic acid can crystallize as two different polymorphs, depending on the system conditions.23-25
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Figure 2. Dependence of MSZW on the stirrer speed, cooling rate, and central vortex in a 450-mL reactor and comparison with those of an aqueous ammonium dihydrogen phosphate solution saturated at 42.9 °C with a cooling rate of 0.1 °C/min.9
Figure 1. Experimental setup of the reactor system used for 2and 20-L crystallization experiments. Table 2. Summary of Experimental Conditions Studied reactor scale [L]
stirrer speed N [rpm]
cooling rate b [°C/min]
0.45 2 20
200, 250, 300, 400, 500 100, 150, 200, 250, 300 80, 100, 150, 200, 250
0.2, 0.3, 0.5 0.2 0.2
However, powder X-ray diffraction showed that, in all of our experiments, only the stable β form of L-glutamic acid was formed under all of the conditions investigated. Nucleation kinetic parameters were evaluated by a linear regression fitting of experimental measurements to eq 4. The ability to detect crystals when they first appear is obviously dependent on the sensitivity of the turbidimetric optical probe to the nucleation event, and detection cannot occur until some time after nucleation, i.e., when the nuclei have grown to micron scale. Hence, turbidmetric measurements assess, in principle, both nucleation and growth processes. However, assuming low nucleation rates with respect to the growth rates, we believe that the errors in measurement of the MSZW, due to detector sensitivity, are likely to be small relative to the actual width. In another words, one would expect the time taken for nuclei to grow to a detectable size would be onthe order of a few minutes at most; it is significantly shorter compared with the cooling times in the metastable zone of an hour or more. Furthermore, repetition of the experiments to consistency of the outcome for at least three times ensures the reproducibility of the measured MSZW. 4. Results and Discussion 4.1. Nucleation Kinetics at the 450-mL Reactor Size. The effect of the stirrer speed on MSZW in the 450-mL reactor is illustrated in Figure 2. It can be seen that, at a cooling rate of 0.2 °C/min, MSZW first
Figure 3. Dependence of nucleation order on the stirrer speed in a 450-mL reactor compared with those of aqueous NaNO3 solutions.10
decreases significantly as the stirring rate increases, indicating that nucleation is enhanced because of a greater agitation intensity; as the speed exceeds a critical value of 400 rpm, MSZW is found to rise again, suggesting that nucleation was retarded at this stage. This phenomenon remains qualitatively the same at faster cooling rates. Identical behavior was observed by Mullin and Raven8,9 during cooling crystallization of aqueous ammonium dihydrogen phosphate solutions (saturated at 42.9 °C) in a 200-mL beaker, as illustrated in Figure 2. The results also revealed that the faster the solution was cooled, the wider MSZW became, reflecting the fact that the nucleation rate is kinetically limited with respect to the generation rate of solution supersaturation. The results of the kinetical analysis, shown in Figure 3, reveal the order of nucleation m to be independent of the agitation rate, a result consistent with those of Ny´vlt et al.10,11 The influence of mixing on the nucleation rate constant kn was also compared with Ny´vlt et al.’s results10 (see Figure 4), and a similar trend was found at low speeds (N e 300 rpm). As the speed increases further, the data show that the value of kn decreases sharply, but no equivalent data are available from Ny´vlt et al. at higher speeds for comparison. Ny´vlt et al. proposed that strong turbulence generated by agitation in the vicinity of nuclei wipes away the solution that has given up its supersaturation and continuously replaces it with
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Figure 4. Nucleation rate constant as a function of the stirrer speed in a 450-mL reactor compared with the results for aqueous NaNO3 solutions.10
Figure 6. Digital images illustrating the formation and development of the central vortex and aeration in a 450-mL reactor at various stirrer speeds showing that a stirring speed of less than 400 rpm is needed to avoid central vortex formation.
Figure 5. Calculated nucleation rate as a function of the stirrer speed in a 450-mL reactor.
fresh saturated liquor. Consequently, the probability of survival of nuclei would be expected to be much higher. However, as the diffusional mass-transfer rate reaches a maximum as the stirrer speed is increased and then becomes independent of the agitation, this factor is clearly not the only controlling factor for this behavior, and hence some other factors must be considered to rationalize the reduction of kn at high stirrer speeds. The calculated nucleation rate (seen in Figure 5) was found to increase with the stirring rate to a maximum at 400 rpm and then go down slightly, except at 0.3 °C/ min, where the maximum was found at 300 rpm. The phenomenon was found to become more pronounced at higher cooling rate. 4.2. Vortex Formation at 450-mL Scale Size. Figure 6 shows photographic images of the 450-mL reactor at four stirrer speeds, revealing the fact that a central vortex was found to form on the surface of the crystallizing solution at agitation rates greater than 250 rpm. As the agitation rate reaches 400 rpm, air was clearly observed to be drawn into the solution by this central vortex, with air bubbles being seen in the region close to the impeller shaft. At 500 rpm, more air bubbles were found to be generated and dispersed into most of the bulk solution, with a state of widespread aeration being achieved at 600 rpm. Upon a closer look at these observations, aeration was found only at stirrer speeds beyond the critical value of 400 rpm. At high agitation rates, the presence of air bubbles was found to introduce greater noise into the turbidity data. A filter was applied to eliminate the noise from the raw data set, with each
experimental condition being repeated at least three times to ensure the reproducibility of the results. There is evidence (Figure 2) that a central vortex also formed in the stirring rate range (400 rpm < N < 800 rpm) in the setup used by Mullin and Raven because an inhibiting effect on nucleation was reported over that speed range.9 Therefore, these results would be consistent with a model in which solution aeration and cavitations as induced via vigorous agitation serve important roles in inhibiting the nucleation process. The exact mechanism for this process is not fully defined, but it is clear that, with the gas phase present within the supersaturated solution, mixing in the bulk fluid is bound to be extremely complicated and the continuous formation and collapse of the air bubbles incorporated via the vortex can be expected to have a profound impact on diffusional mass transfer in the vicinity of nuclei and hence may have a disruptive effect on nucleation cluster formation. To further clarify these vortex phenomena, a set of batch cooling crystallization experiments were carried out in which the central vortex was suppressed while the temperature, solute concentration, and the crystallizer internals (stirrer and baffle) were kept the same. To eliminate the influence of the central vortex on the studied system, a secondary lid fitted with a rubber O ring was placed just above the liquid level in the 450mL reactor to suppress the central vortex and aeration. Batch cooling crystallization experiments were carried out in this vortex-free system at various speeds using a Perspex retreat curve impeller and a single baffle. The measured MSZWs with a suppressed vortex are presented in Figure 2 for comparison with those with a central vortex at a cooling rate of 0.5 °C/min. It can be clearly seen that, in the presence of the vortex, MSZW first reduces as the stirring rate rises but increases beyond a minimum at 400 rpm. In contrast, results of
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Figure 7. MSZW as a function of the stirrer speed in 450-mL, 2-L, and 20-L reactors at a cooling rate of 0.2 °C/min.
the batch cooling crystallization experiments carried out in the vortex-free system show that MSZW continuously decreases with greater agitating rate. The values of MSZW are also found to be generally narrower than those of the system with a central vortex. This result suggests that the suppression of air bubbles in the bulk solution may enhance the mass transfer and, hence, aid the nucleation process. However, an alternative explanation is that the extra interfacial area provided in the system by the presence of the close-filling second lid had introduced heterogeneous nucleation, which according to nucleation theory14 would require much lower supercooling, leading to the inability to eliminate the narrower MSZW (0.5 °C/min no vortex) observed in Figure 2. This result also demonstrates that reactor hydrodynamics is capable of affecting nucleation phenomena not only via enhancing/hindering the rate of nucleation but also possibly by altering the nature, or mechanism, of the nucleation event. This finding again confirms the complex and subtle interplay between reactor hydrodynamics and the nucleation process. As a rule of thumb, extra caution may be needed to choose the stirring rate to avoid the undesirable central vortex. Hence, fully baffled reactors may be preferable in cases where a higher degree of agitation is necessary to achieve satisfactory solid suspension particularly in the case of high solid loading. 4.3. Scale-Up Model Spanning 450-mL, 2-L, and 20-L Reactor Scale Sizes. Batch cooling experiments at two larger scales were carried out and lower stirrer speeds (
