Effects of Cooling Rate and Solution Concentration on Solution

CRYSTAL GROWTH & DESIGN

Effects of Cooling Rate and Solution Concentration on Solution Crystallization of L-Glutamic Acid in an Oscillatory Baffled Crystallizer

2008 VOL. 8, NO. 8 2875–2881

Xiongwei Ni* and Anting Liao Centre for Oscillatory Baffled Reactor Applications (COBRA), School of Engineering and Physical Science, Heriot-Watt UniVersity, Edinburgh EH14 4AS, UK ReceiVed December 7, 2007; ReVised Manuscript ReceiVed February 20, 2008

ABSTRACT: In this paper, we report our systematic study on solution crystallization of an industrially important compound, L-glutamic acid, in an oscillatory baffled crystallizer (OBC). The effects of linear cooling rates and solution concentrations on metastable zone width (MSZW), nucleation parameters, and crystal polymorphism are investigated. The MSZW increases with an increase in the cooling rate, while it remains more or less unchanged for different solution concentrations. The metastable R crystals are favored for low to medium solution concentrations for all cooling rates, while β crystals are favored for relatively high solution concentrations. The OBC offers more uniform mixing and better heat transfer environment than traditional stirred tank vessels (STC), resulting in a higher crystallization temperature, suggesting that the OBC would be more effective in promoting nucleation, thus presenting a narrower MSZW during a cooling process than traditional STC. Introduction Solution crystallization is widely used in fine and specialty chemicals and pharmaceutical industries, and is affected by a number of process parameters, such as supersaturation, solute concentration, temperature, mixing, cooling profile, solvent/ additives, seeding, and so on. Since no complete theory is available to model nucleation/crystallization, their behaviors can only be anticipated by experimentation; accurate process measurements are essential in understanding crystallization processes. A number of techniques have been implemented to monitor crystallization/process variables at laboratory scale, for example, employing an optical turbidometric UV-vis probe for the measurement of metastable zone width (MSZW);1 X-ray diffraction (XRD) for polymorphs;2 Fourier transform infrared spectroscopy (FTIR) for supersaturation;3,4 ultrasound spectroscopy (USS) for crystal size;5 focused beam reflectance measurements (FBRM) for online chord length of crystals and crystal size distribution;6,7 differential scanning calorimetry for phase transition;8 particle vision measurements (PVM) for online crystal shape;9 particle image velocimetry (PIV) for local velocity and so on. These techniques/measurements have promoted significant advances in understanding laboratory scale batch crystallization and have assisted in designing better crystallization processes. However, these advances have not been matched by an equivalent increase in our ability and understanding in scaling up stirred tank reactors (STR), the workhorse of industrial crystallization. The scale-up of crystallization processes involves the net result of several independent, but interrelated, steps. A crystallization vessel is three-dimensional, so as the linear dimensions increase, the capacity of the system increases as the cube of the linear dimension. With this increase in scale, other variables rise on the linear scale with different exponents, which may vary from negative to zero to three and higher. As a result, the scale-up of STRs has always been very troublesome. The work reported in this paper involves a different type of crystallizer, that is, oscillatory baffled crystallizer (OBC), which * Corresponding author. Tel: 00441314513781; fax: 00441314513129; e-mail: [email protected].

has linear scale-up capability and could be used to bridge the gap between laboratory understanding and industrial operation. The OBC generally consists of a column containing periodically spaced orifice baffles superimposed with oscillatory motion. The mixing in an OBC is provided by the generation and cessation of eddies when flow interacts with baffles. With repeating cycles of vortices, strong radial motions are created, giving uniform mixing in each interbaffle zone and cumulatively along the length of the column. The power density (P/V) in an OBC can be evaluated via a quasi-steady-state approach taking into consideration the effects of static, inertial, and frictional forces,10 assuming that there is a uniform velocity throughout the column:

( )

P 2FNb 1 - R2 3( xo 2πf )3 (W m-3) ) 2 V 3πC2 R D

(1)

where Nb is the number of baffles per unit length of OBC (m-1), CD is the coefficient of discharge of the baffles () 0.7 normally), F is the fluid density (kg m-3), xo is the oscillation amplitude (m), f is the oscillation frequency (Hz), and R is the baffle free area ratio (0.2-0.5). The OBC offers more uniform mixing than stirred tank devices, and this may have an impact on solution crystallization in general. This study forms a part of the systematic investigation on the suitability of the OBC in crystallization. Experimental Setup and Procedures The Oscillatory Baffled Crystallizer. Figure 1 shows the schematic set up of the OBC. The OBC was made of a jacketed glass column of 50 mm internal diameter and 500 mm height, making the full volume of 1000 mL. The OBC was flanged onto a metal frame with a supporting structure in order to minimize external mechanical vibrations. The opentop OBC was operated in batch mode at atmospheric pressure and room temperature. The jacket inlet and outlet were connected to a temperature controlled water bath (Techne RB-12A, UK). An inbuilt pump ensures the steady flow of water through the jacket of the crystallizer. The water bath was controlled through an external computer. A set of three equally spaced orifice baffles was used to generate the mixing, and was supported by two 5 mm diameter PTEF rods. The baffle set was oscillated by an electrical motor/gearbox ensemble (Leroy Somer Ltd.) associated with an inverter for speed control (Eurotherm Drives 601). Oscillation frequencies of 0.2-10 Hz can be obtained

10.1021/cg7012039 CCC: $40.75  2008 American Chemical Society Published on Web 06/25/2008

2876 Crystal Growth & Design, Vol. 8, No. 8, 2008

Figure 1. The schematic of the experimental setup (not drawn to scale).

Ni and Liao

Figure 3. Solution transmittance as a function of temperature at various cooling rates with a fixed heating rate (concentration ) 45 g/L, f ) 2 Hz, xo ) 10 mm). Table 1. Properties of L-Glutamic Acid

Figure 2. A typical profile of solution transmittance as a function of temperature in crystallization of L-glutamic acid in OBC (concentration ) 30 g/L, cooling rate ) 1.2 °C/min). using the speed controller, and the center-to-peak oscillation amplitudes of 1-10 mm by adjusting the off center (eccentric) position of the connecting rod in the stainless steel coupling wheel. Metastable Zone Width. The MSZW is a nucleation kinetic limited parameter that is highly dependent on process conditions.11–17 In order for a temperature-controlled solution crystallization to take place the solution must be supersaturated, and the main cooling cycle must be in the supersaturated state within the MSZW. In this work, the MSZW was determined by the turbidity measurement of the solution in the OBC using a fiber optic probe designed and built in-house. The measurement is based on the principle that the solution transmittance is inversely proportional to the concentration of the crystals within the solution, and thus the turbidity measurement can be related to the concentration of crystals.18 A number of procedures have been incorporated into the control software, LabView 5.1, in order to reduce the effect of electronic noise and experimental uncertainty on the measurements. In all experimental cycles of heating and cooling, the turbidity probe reflectance was calibrated using a clear (slightly undersaturated at 10 °C) solution for which the reflectance was set to the full scale.19 The probe was then connected to a colorimeter, which transferred signals to the computer through an analogue to digital converter. During the experiments, data of the turbidity as well as temperature were collected every 30 s. Figure 2 is the typical profile of the solution transmittance as a function of temperature obtained in the OBC at a given concentration and given cooling rate. Initially the signals of transmittance are low (the square symbols), indicating crystals are not yet dissolved in the solution. When the temperature increases over a certain point, a sharp rise in the transmittance signal is seen, where the circled “points” are generally referred to as the state of the on-set of dissolution. As the dissolution of crystals in solution further intensifies with an increase in the temperature, a maximum transmittance signal is recorded, suggesting a clear solution free of solid. It should be noted however that the turbidity measurements are not absolute; a reading of 100%

molecular formula

molecule weight

density (kg m-3)

isoelectric point (pH)

C5H9NO4

147.13

1.538

3.22

transmittance does not represent an absolutely transparent solution and nor does 0% respresent an opaque solution. Although it is almost impossible to eliminate all particulate matters from the crystallizing solution, it is feasible to minimize the number of foreign particles present by introducing some measures; for example, the temperature is raised above the saturated temperature and held for a period of time to ensure that any nuclei present are totally dissolved. By controlling the decrease of the solution temperature, a controlled cooling, that is, linear cooling profile, is created, and a sharp drop in the transmittance is noticed. The on-set of nucleation is regarded happening in the small region with the initial drops in the signals; and crystallization has occurred when the transmittance reading drops by more than a predefined value (e.g., 20% in this study, see the dotted line in Figure 2) from the maximum.20 The MSZW (∆Tmax) for a particular operational condition is then defined as

∆Tmax ) Tsat - Tcry

(2)

where Tsat is the saturation temperature (°C) and Tcry the crystallization temperature (°C) as shown in Figure 2. It is clear that the MSZW is dependent on operational conditions. L-Glutamic Acid. L-Glutamic acid (β form 99% CAS 5686-2, EEC 200-293-7) of white powders was purchased from Sigma-Aldrich Co. Ltd., and the physical properties of L-glutamic acid are given in Table 1. L-Glutamic acid crystals have two polymorphic forms: metastable R and stable β forms. The R form of L-glutamic acid has a distinctive prismatic morphology, which is easy to filter, generally preferred for industrial purposes, whereas the β is needle-like which is difficult to filter. Experimental Procedures. A known amount of L-glutamic acid was dissolved in 1 L of distilled water to give a specific solution concentration. The solution was heated up and kept at a temperature 10 °C higher than the saturation temperature for about 30 min in order to ensure complete dissolution of the solute material. The solution was then cooled to the final cooling temperature of 10 °C. After the crystallization process has completed, crystals were filtered, washed using a 95% ethanol solution, and dried overnight in an oven at 80 °C. The dry crystals were used for both analyses of polymorphism and crystal size distribution using a scanning electron microscope (SEM) and Malvern Master Sizer (Malvern instrument Ltd. Serial No. 33265140), respectively. Note that the latter analysis was applied to R crystals only. Effect of Cooling Rate on MSZW. In order to examine the effect of linear cooling rate on MSZW, seven cooling rates were tested while the concentration of L-glutamic acid was fixed at 45 g L-1, the oscillation amplitude at 10 mm, and frequency at 2 Hz. Figure 3 shows the solution transmittance as a function of temperature for these cooling rates. It can clearly be seen that the turbidity curves for crystallization

Crystallization of L-Glutamic Acid

Crystal Growth & Design, Vol. 8, No. 8, 2008 2877

Figure 4. Metastable zone width for different cooling rates (concentration ) 45 g/L, f ) 2 Hz, xo ) 10 mm).

Figure 5. Metastable zone width vs power density for both an OBC and a STC (stirrer speed from 200 to 500 rpm, oscillation frequency from 1 to 3 Hz, amplitude from 7.5 to 15 mm). varied for different cooling rates, while these for dissolution remained more or less the same, indicating that Tsat is close to constant. The overall effect is that the faster the cooling rate, the wider the MSZW becomes. This is expected, as faster cooling rates create higher supersaturation rates within the same time scale; thus, longer a relaxation time is required to achieve a quasi-steady-state distribution of molecular clusters and allow the appearance of the first nuclei cluster even at the same concentration.21 Hence, the MSZW becomes wider and acts effectively as the barrier for crystallization.22 The extracted MSZW data are plotted against the cooling rate in Figure 4, confirming that the MSZW is a function of cooling rate.23 With limited data from a stirred tank crystallizer (STC)13 a comparison of the MSZW is achieved using the power density as the basis. The power density for a stirred tank takes the form of

P PoFN ) V VL

D5s

3

(3)

where Po is the power number of the stirrer used (-), N is the speed of stirrer (rps), Ds is the diameter of the stirrer (m), and VL is the volume of liquid in a STC (m3). The power number is a unique parameter relating to a specific type of impeller in a STC. A retreat curve impeller with three blades was used in Liang’s work,13 and the power number was estimated at 1.3.24 The diameter of the impeller was 50 mm, and the working volume of the STC was 450 mL. For the range of the stirrer speeds from 200 to 500 rpm, the power density for the STC spans 33 to 522 W m-3. Figure 5 compares the MSZW data for both the STC and OBC. Initially the MSZW in the STC decreased significantly with an increase in the power density (see the filled square symbols) and then increased after a minimum trough was reached. This phenomenon was later attributed to the generation of “unwanted” central vortices around the stirrer shaft that entrained air bubbles. When a secondary lid device was fitted with a rubble “O-ring” being placed above the liquid level in the STC, the central vortex surrounding the

Figure 6. SEM images of crystals (concentration ) 45 g/L, f ) 2 Hz, xo ) 10 mm). Table 2. Comparison of MSZW for Both OBC and STC at the Cooling Rate 0.5 °C min-1 and the Concentration of 45 g L-1 temp of dissolution (°C) temp of crystallization (°C) MSZW (°C)

OBC

STC13,14

75 61 14

70 32 38

rotational shaft and the associated unwanted aeration were minimized, and a decreasing trend of the corrected MSZW data with an increase in the power density was then displayed (see the diamond symbols) in Figure 5. The MSZW in the STC became generally narrower than that in the presence of central vortices. A similar decreasing trend of the MSZW with an increase in the power density can be seen for the OBC with much lower and narrower MSZW, indicating better controllability in the OBC.22 Table 2 compares the dissolution and crystallization temperatures in both the OBC and the STC13,14 at a concentration of 45 g L-1 and a cooling rate of 0.5 °C min-1. It is clear that the crystallization took place at a higher temperature in the OBC than in the STC, which is associated with smaller MSZW, that is, smaller nucleation barriers, in the OBC than that in the STC. Crystals in solution crystallization can only be formed when the temperature crosses the metastable zone.10,22,25 At similar power densities, the nucleation process for higher crystallization temperatures in the OBC would occur earlier than that in STC due to significantly improved mixing and heat transfer, which would mean that for a specific supersaturation ratio the OBC is more effective in promoting the nucleation, thus presenting a narrower MSZW during a cooling process.


Ni and Liao

Figure 7. Metastable zone width vs concentrations (f ) 2 Hz, xo ) 10 mm).

Figure 8. log b vs log ∆Tmax (f ) 2 Hz, xo ) 10 mm).

Figure 10. SEM images of crystals at 1 °C/min (left column) and 2 °C/min (right). Figure 9. Nucleation rate vs concentration (f ) 2 Hz, xo ) 10 mm). Effect of Cooling Rate on Polymorphism. Figure 6 is a snapshot of crystals from a large number of SEM images obtained from the slowest to the fastest cooling rate at a fixed solution concentration and mixing intensity. All images were taken with a magnification of ×200. At the slowest cooling process (0.5 °C min-1), the shape of crystals was long, narrow needle-like. With an increase in the cooling rate, the shape of β crystals changed gradually to wider and thicker plates. The crystals became fragmented with flower shape arrangements at faster cooling rates of 2.5 and 3.0 °C min-1. A faster cooling rate is generally associated with bigger MSZW, and in turn greater supersaturation and more rapid nucleation. As a result, a large amount of small nuclei are expected at the end of MSZW and the fast growth rate forces all small seeds searching for a platform to grow.26,27 The fragments grow on the rough surfaces of each other and the groups of the wide and thin fragments become attached to form the flower-like crystals.

Table 3. Nucleation Order and Nucleation Rate Constant concentration (g L-1)

nucleation order (-)

nucleation rate constant (kg1-m m3m-3 min-1)

15 30 35 40 45

7.1 4.4 6.1 2.8 1.8

0.0091 0.00094 0.00011 0.005 0.017

It is interesting to learn that only β crystals were produced in the OBC at the concentration of 45 g L-1 for various cooling rates, which are different from the literature under somewhat similar concentrations.28–30 The stagnant environment in a STC was preferred by R crystals according to Kitamura,29 and the polymorphism changed from R to β when the stronger mixing was applied. The results from the OBC suggest that the more uniform mixing and more uniform


Crystal Growth & Design, Vol. 8, No. 8, 2008 2879

Table 4. Polymorphisms of L-Glutamic Crystals at Various Concentrations and Cooling Rates

supersaturation within the OBC created a unique environment in which stable β crystals are produced even at the conditions favored by metastable R crystals in traditional STR. This implies overall much more uniform or stronger mixing in the OBC at the same power densities. Effect of Concentration on Nucleation Kinetics. Concentration of L-glutamic acid in solution is associated with supersaturation; to study the effect of concentration on the crystallization process, experiments were carried out covering solution concentrations of 15, 30, 35, 40, and 45 g L-1 at a fixed oscillation frequency of 2 Hz and an amplitude of 10 mm for cooling rates of 0.5, 1, 1.5, and 2.0 °C min-1, respectively. The effect of concentration on MSZW is presented in Figure 7 for different cooling rates. Generally the MSZW remained more or less unchanged for the range of concentrations tested in the OBC, except at the lowest cooling rate of 0.5 °C min-1 where the MSZW sharply decreased with an increase in concentration. While the general trend agrees with the previous study,15 we do not have any explanation for the data of 0.5 °C min-1. At a given solution concentration, the MSZW increased with an increase in the cooling rate, which echoes what was presented in Figure 4 earlier. Combining the MSZW data with the Nyvlt’s method,11,12 nucleation kinetic parameters can be evaluated given that the MSZW is associated with the cooling rate, b, by

log b ) (m - 1) log

dc/ - log ε + log kn + m log ∆Tmax dT

(4)

where m is the nucleation order (-), T is the solution temperature (°C), kn is the nucleation rate constant (unit is dependent upon the order), dc*/dt is the temperature dependence on solubility (kg °C-1 m-3), and ε is a correction factor for the change in concentration in case the species is being hydrated (unit depends on the nucleation order), and assumed to be 1 in this study. By plotting log b vs log ∆Tmax, a straight line is expected, and the slope is the nucleation order (m); the intercept equals (m - 1) log dc*/dT + log kn from which the nucleation rate constant kn can be evaluated. For example, when the cooling rates (b) of 0.5 and 2.0 °C min-1 are used in a 30 g L-1 solution, respectively, by calculating the slope of 30 ( 1 g L-1 divided by the solubility temperatures according to the literature25,26 we have dc*/dT ) 0.127177. From experiments the MSZW (∆Tmax) are determined as 13.76 and 30.27 °C, respectively. Hence the slope (m) of log b vs log (∆Tmax) is 1.7439 and the intercept is -2.2817. From these the kn is evaluated as 0.02424 under this condition. Figure 8 shows the characteristics of the plot of log b vs log (∆T max) with good linearity, which validates the type of analysis. With the determined nucleation order and rate constant, the nucleation rate, J, can then be estimated from m J ) kn∆cmax ) kn(c - c/)m -3

(5)

where c is the solution concentration (kg m ) and c* is the equilibrium concentration (kg m-3) at the crystallization temperature.

The evaluated nucleation rate is plotted against the concentration in Figure 9. It can be seen that the nucleation rate decreased with an increase in concentration. This is rather surprising, as higher concentrations relate to higher supersaturation, that is, higher driving forces for crystallization. However, as the effect of concentration on MSZW was not significant (Figure 7), the barrier for crystallization was similar for the range of solution concentrations tested, and the nucleation rate would depend upon both the nucleation order and the nucleation rate constant as shown in Table 3, which shows nonlinear dependence. The decreasing trend was the overall outcome. Effect of Concentration on Polymorphism. Selecting from a large number of SEM images of crystals obtained for five solution concentrations and four cooling rates, Figure 10 shows the image arrays for the cooling rates of 1 and 2 °C min-1, respectively. The transformation of polymorphism from the metastable R to the stable β form is seen from low to higher concentrations. Both R and β forms grew larger and became more obvious when the concentration was high as well as when the cooling rate was slow (images not shown here). Table 4 summarizes the matrix of polymorphism varying with concentration. Clearly the concentration and the cooling rates have a significant effect on crystal morphology. The R form was favorable at lower concentrations for all cooling rates, while the β crystals were preferred at higher concentrations. There seems to be an imaginary line separating the metastable and stable forms in Table 4. It is shown that the desired form can be created by controlling the combination of the concentration and the cooling rate in the OBC. The metastable and stable forms depend particularly on the method of creation of supersaturation. For a system in which two polymorphs exists, Ostwald’s rule stated that an unstable system does not necessarily transform directly into the most stable state, but into one which most closely resembles its own.22,31,32 Given that J1 and J2 are the nucleation rates of the metastable and stable phase; k1 and k2 are the kinetic coefficients for crystal growth respectively,33 the Ostwald’s rule becomes valid when J2k23 , J1k13. By using the evaluated nucleation rate constants as shown in Table 3 to substitute the kinetic coefficient for crystal growth, and using the nucleation rates in Figure 9 to represent these of the metastable and stable phases, approximate analysis can be performed. For example, at lower concentrations and higher cooling rates, the nucleation rate constant, k1, is high (Table 3), and so is the nucleation rate J1 (Figure 9). The product of J1k13 is thus high. While at higher concentration and high cooling rates, the nucleation rate constant, k2, is high (Table 3), but the nucleation rate J2 is low (Figure 9), leading the lower product of J2k23. We have J2k23 , J1k13; hence, the metastable or pseudo-stable crystals resulted at lower concentration. If the first nucleus is formed within the metastable zone, it is then likely to grow to metastable crystals, likewise the stable form. Similar results were also reported using the same analysis.27,29,34 Near to the imaginary line in Table 4, the nucleate rate constant is the lowest; the product of J1k13 may not be greater than the J2k23, leading to the coexistence of R and β crystals. By the approximate evaluation, the images of polymorph displayed in Figure 10 seemed in line with the nucleation kinetics extracted.


Ni and Liao Tcry VL xo R F

crystallization temperature (°C) volume of liquid in a STC (m-3) center-to-peak oscillation amplitude (m) ratio of baffle free area fluid density (kg m-3)

References

Figure 11. Sauter mean crystal size vs concentration (f ) 2 Hz, xo ) 10 mm). For R-crystals only, the crystal size distribution (CSD) were measured using the Melvern Sizer, from which the Sauter mean crystal sizes were obtained. Figure 11 is one of the typical mean crystal sizes plotted against the solution concentration. The mean crystal size increases with an increase in the concentration. In other words, the higher the supersaturation, the bigger the mean crystal size. The crystal size tends to grow through the slower cooling rate and higher concentration;22 the former allows fewer crystalline lattices to develop and hence increase the crystal size, while the latter offers more chances of diffusion through the boundary layer to the surface during crystal growth.30

Conclusions The results from this work indicate that the MSZW increased with an increase in the cooling rate, while it remained more or less unchanged for the range of solution concentrations employed. This suggests that the cooling rate had more influence on controlling the MSZW than the solution concentration. On the morphology, both the cooling rate and the solution concentration played a significant role: metastable R crystals were preferred for low to medium solution concentrations for all cooling rates, while β crystals were preferred for relatively high solution concentrations. By controlling the combination of the solution concentration and cooling rate, the desired form of crystal can be isolated in the OBC. With the limited data from the STC, a comparison of the MSZW as well as the temperatures of dissolution and crystallization between the OBC and STC indicates much a higher crystallization temperature in the OBC, suggesting that the more uniform mixing environment in the OBC would be more effective in promoting the nucleation, thus presenting a narrower MSZW during a cooling process than that in traditional STC. Acknowledgment. A.L. wishes to thank for the Heriot-Watt University for the Scholarship. Nomenclature b c CD Ds f J kn N Nb m Po P/V Tsat

cooling rate (°C min-1) concentration (kg m-3) discharge coefficient diameter of a stirrer (m) oscillation frequency (Hz) nucleation rate (unit depends on order) nucleation rate constant (unit depends on order) rotational speed of a stirrer (s-1) number of baffles per unit length (m-1) nucleation order power number of a stirrer power density (W m-3) saturation temperature (°C)

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CG7012039

Effects of Cooling Rate and Solution Concentration on Solution

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