CRYSTAL GROWTH & DESIGN
An Examination into the Effect of Stirrer Material and Agitation Rate on the Nucleation of L-Glutamic Acid Batch Crystallized from Supersaturated Aqueous Solutions
2004 VOL. 4, NO. 5 1039-1044
Kangping Liang,* Graeme White, and Derek Wilkinson Centre for Molecular and Interface Engineering, Department of Mechanical and Chemical Engineering, Heriot-Watt University, Edinburgh, UK
Leslie J. Ford and Kevin J. Roberts Institute of Particle Science and Engineering, Department of Chemical Engineering, University of Leeds, UK
Will M. L. Wood Formerly Process Studies Group, Syngenta Limited, Huddersfield, UK Received June 11, 2003;
Revised Manuscript Received September 10, 2003
ABSTRACT: The influence of stirrer material and agitation rate on the nucleation of batch crystallized L-glutamic acid from supersaturated aqueous solutions using temperature programmed cooling is investigated. Results obtained at the 450 mL scale size using a retreat curve impeller together with a single baffle reveal that stirrer material type and its surface morphology are important in the primary nucleation process having a significant influence on the nucleation order, as assessed via optical turbidity method, and being consistent with a surface-induced heterogeneous nucleation mechanism. 1. Introduction Solution cooling crystallization is a major technological process for manufacturing high value-added specialty materials particularly in the pharmaceutical and other fine chemical industries. It is well-known that even minor changes in crystallization process conditions and equipment, for example, supersaturation, temperature, impurity, cooling rate, or reactor hydrodynamics can result in significant variations in the crystal and downstream powder properties, notably, polymorphic form, particle size, shape, purity and defect structure. Such effects have been recognized as major batch-tobatch and source variation problems potentially leading to inconsistency of the product properties,1-5 e.g., tabletting behavior for a pharmaceutical. It is well-known that reactor stirrer materials are capable of affecting the crystallization process.6-8 Early investigations such as that by Ness et al.6 studied collision nucleation by seeding aqueous magnesium sulfate (MgSO4‚7H2O) solutions in a baffled crystallizer using both stainless steel and plastic Rushton impellers. Their results indicated that stirrer speed over the range from 310 to 460 rpm has a marked influence on the nucleation rate at different supercooling. Different power law correlations between nucleation rate and agitation rate were established for both stainless steel and plastic stirrers. The effects of hardness of the stirrer material and of crystal hardness on the generation of * To whom correspondence should be addressed: Dr. Kangping Liang, SH103, 3301 South Dearborn St., Chicago, IL, USA 60616. E-mail:
[email protected]. Tel.: 1-312-567-5093; Fax: 1-312-7567018.
secondary nuclei have been studied by several researchers.6,9 In general, it was found that a harder material is more effective in enhancing the secondary nucleation rate. Ness6 found a plastic stirrer reduced the nucleation rate by a factor of between 4 and 10, depending on the agitation rate when compared with a steel stirrer at the same degree of supercooling. Drawing on these previous works, the influence of stirrer material and its operational parameters (e.g., rotation rate) upon the primary nucleation of L-glutamic acid batch crystallized for aqueous solution at a scale size of 450 mL and agitated via a retreat curve impeller (Perspex or stainless steel) has been investigated. 2. Theoretical Background 2.1. Evaluation of Nucleation Kinetics. Ny´vlt10 proposed an empirical method for the evaluation of nucleation kinetics by measuring the width of the metastable zone. In this, the nucleation rate J was defined as:
J ) kn∆c m max
(1)
∆cmax ) c - c*
(2)
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
10.1021/cg034096v CCC: $27.50 © 2004 American Chemical Society Published on Web 10/15/2003
1040 Crystal Growth & Design, Vol. 4, No. 5, 2004
Liang et al.
Figure 1. Schematic representation of industrial standard retreat curve impeller (DIN 28146) and cylindrical reactor: (a) 2D, and (b) 3D.
supercooling of the system ∆tmax, or metastable zone width (MSZW) as
∆cmax
dc* ) ∆tmax dt
( )
∆tmax ) tsat - tcry
(3)
dt (dc* dt )( dτ)
(5)
where k1 is a constant, is a correction factor for the change in concentration in case the species is being hydrated, equal to 1 for this system, b is the cooling rate, and τ is the time. By combining eqs 1, 3, and 5, 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 (6) dt
Therefore, plotting log(b) against log(∆tmax) should result in a straight line with slope equal to the order of nucleation, m, and the nucleation constant kn can be evaluated from the intercept. The validity of using the Ny´vlt’s method, in our view, is justified because the nucleation rate is slow compared to growth rate in the case of L-glutamic acid, the turbidmetric measurements provide a good assessment of the general phenomenological properties of nucleation. 2.2. Heterogeneous Nucleation and Contact Angle. According to nucleation theory, the overall free energy change associated with the formation of a critical nucleus under heterogeneous conditions ∆G′crit is lowered with respect to that associated with the corresponding free energy change ∆Gcrit associated with homogeneous nucleation by the presence of heterogeneous nuclei; thus11
∆G′crit ) φ∆Gcrit
reactor reactor liquid impeller impeller baffle scale diameter T level H diameter D clearance C diameter Db [L] [m] [m] [m] [m] [m] 0.45
(4)
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 ) k1b )
Table 1. Detailed Geometry of Reactor and Its Internals (DIN 28146) Used in This Work
(7)
0.082
0.082
0.05
0.008
0.013
where φ, the ratio of ∆G′crit and ∆Gcrit, is less than unity and depends on the contact angle between the crystalline deposit and the foreign heterogeneous nucleating solid surface. The value of φ can be easily calculated; thus:11
φ)
(2 + cosθ)(1 - cosθ)2 4
(8)
where θ is the measured contact angle for a specific surface. 3. Experimental Details 3.1. Batch Cooling Crystallization. Batch cooling crystallization of aqueous L-glutamic acid (C5H9NO4, molecular weight 147.13, Sigma-Aldrich 99% CAS 5686-2) solutions was carried out from 75 to 20 °C in an unjacketed glass reactor (450 mL) fitted with a retreat curve impeller (RCI) and a Beaver-tail baffle (in this case provided by a turbidity probe). As seen in Figure 1, the dimensions of the crystallizer and the stirrer are based on the industrial standard (DIN 2814621). Two materials were used to manufacture different stirrers: stainless steel and Perspex. The detailed geometry of the reactor and its internals is given in Table 1. Various stirrer speeds were investigated. Cooling of the dished-bottom glass reactor was realized by partially submerging the batch reactor into a Haake F3 thermostatic bath. An initial solute concentration of 45 g/L (saturated at 70 °C) was used in all runs. Hydrodynamics of vessel were represented by a 1:1 ratio of reactor internal diameter to solution fill height. During the batch cooling crystallization experiments, temperature and turbidity of the solution were measured by a platinum resistance thermometer (Pt100) and a Sybron Brinkman Lexan fiber optic probe, respectively. Using a previously described setup,12-15 the fiber optic probe was used to measure the presence of nuclei in the saturated solution through a 10mm path in the solution as reflected via a mirror at the probe end and detected using a Brinkman PC700 colorimeter. At the beginning of each cycle, the temperature was raised to 5 °C above the saturation temperature and held there for at least half an hour to ensure total dissolution of the solute. Turbidity readings at this point were calibrated to be those of a transparent solution. By controlled reduction of the solution temperature, this experimental setup induces supersaturation in the reactor leading eventually to nucleation with the
Nucleation of L-Glutamic Acid
Crystal Growth & Design, Vol. 4, No. 5, 2004 1041
Figure 2. Schematic illustration of the contact angle measurement apparatus with inset showing the definition of contact angle of a droplet on a flat surface.
Figure 3. Metastable zone width measured as a function of stirrer speed for stainless steel and Perspex retreat curve impellers compared with those of aqueous ammonium dihydrogen phosphate solution saturated at 42.9 °C at cooling rate of 0.1 °C/min.17 crystallization process being monitored by the colorimeter. In the case of L-glutamic acid crystallization was deemed to have occurred when the transmittance reading was found to drop by 10% from the transparent solution calibration. 3.2. Contact Angle Experiments. The contact angle of liquid droplets on various stirrer materials was measured using optical microscopy to evaluate the interfacial surface energy between the liquid phase and solid phase. A schematic representation of the experimental arrangement is shown in Figure 2 along with the inset providing the definition of the contact angle. Contact angles were measured of pure distilled water and two aqueous L-glutamic acid solutions, 10 and 18 g/L and for both types of solid flat surfaces investigated: Perspex and stainless steel, reflecting different stirrer materials. Liquid droplets were introduced by a microsyringe (2 mL) onto the various flat surfaces. Only the advancing contact angle, the contact angle on a dry surface, was recorded. At least five droplets were dispensed at different regions of the same piece of flat surface for contact angle measurement, and at least two different flat plates of each material were used, to obtain reliable contact angle data. Thus, at least 10 advancing contact angles were averaged for each type of solid surface as well as for each kind of liquid tested.
4. Results and Discussions 4.1. Metastable Zone Width. Figure 3 shows the results of MSZW measurements of both stainless steel and acrylic (“Perspex”) retreat curve impellers (RCI) as a function of stirrer speed. It can be seen that for Perspex RCI at a cooling rate of 0.2 °C/min, MSZW was
Figure 4. Effect of cooling rate on crystallization temperature for Perspex stirrer rotating at a rate of 400 rpm with inset showing the plot of log b against log ∆tmax.
initially found to decrease significantly as the stirring rate rises, indicating that nucleation is enhanced due to greater agitation intensity, until a minimum is reached at around 400 rpm, after which the MSZW was found to rise again, suggesting that nucleation is retarded at this stage. This phenomenon was found to become more pronounced as the cooling rate rises. Similar effects (see Figure 3) were observed by Mullin16,17 during cooling crystallization of aqueous ammonium dihydrogen phosphate solutions (saturated at 42.9 °C) with a constant cooling rate of 0.1 °C/min in a 200 mL beaker. Similar dependence of the measured MSZW as a function of stirrer speed was found for both stirrers, although the effect of increasing MSZW at stirring rate greater than 400 rpm was found to be less pronounced for the stainless steel RCI. However, for a given cooling rate, a narrower MSZW was observed for the stainless steel RCI for all stirrer speeds examined. It is also seen that the MSZW becomes much wider as the cooling rate increases, indicating that the crystallization process under those conditions to be kinetically limited rather than thermodynamically controlled. 4.2. Nucleation Order and Nucleation Rate Constant. Figure 4 shows the dependence of crystallization temperature on cooling rate at a stirrer speed of 400 rpm. It can be seen that the faster the rate of solution
1042 Crystal Growth & Design, Vol. 4, No. 5, 2004
Figure 5. Nucleation order as a function of stirrer speed: comparison between stainless steel and Perspex retreat curve impeller results along with those of aqueous NaNO3 solutions (Ny´vlt18).
Figure 6. Nucleation rate constant as a function of stirrer speed: comparison between stainless steel and Perspex retreat curve impeller results along with those of aqueous NaNO3 solutions (Ny´vlt18).
cooling (or the greater the rate of supersaturation generation), the lower the crystallization temperature becomes. This agrees with nucleation theory that states that a longer relaxation time is required to achieve a quasi-steady-state distribution of molecular clusters and formation of a stable nucleus with higher rate of supersaturation generation11. Consequently, the on-set of nucleation is delayed. A plot of log(b) against log(∆tmax) yields the nucleation order and nucleation rate constant (see eq 6); an example of this equation is shown in the inset of Figure 4. Nucleation order, as a function of agitating speed for the steel and Perspex stirrers, is given in Figure 5 which demonstrates that the nucleation order using the stainless RCI is higher than using the Perspex RCI. It can also be seen that the nucleation order does not vary greatly with increasing stirring rate for either impeller and is of the same order of magnitude as those given by Ny´vlt.18 On the basis of experimental results for 25 inorganic salts, Ny´vlt pointed out that the nucleation order depends neither on the presence of the solid phase, nor on temperature, but is approximately inversely proportional to the molecular weight of the solute. According to classical nucleation theory, the value of nucleation order is related to the number of molecules forming a critical nucleus, in other words, the energy barrier of nucleation.19 Figure 6 shows the variation of nucleation rate constant as a function of stirrer speed for the two impeller types. It is seen that values for the Perspex
Liang et al.
Figure 7. Nucleation rate as a function of stirrer speed: comparison between stainless steel and Perspex retreat curve impeller results.
are much higher than those observed for stainless steel stirrer. As the stirrer speed increases, the rate constant was found to rise in all cases; further increasing the speed, the value for the Perspex stirrer reduces while that for the steel impeller was observed to remain constant. Note that no data from Ny´vlt’s work18 were provided for the higher speeds, and hence a direct comparison could not be made. 4.3. Nucleation Rate. Dependence of nucleation rate on stirrer speed for both stirrers are shown in Figure 7. Nucleation rate can be seen to be less sensitive to agitation for both stirrers at the lowest investigated cooling rate of 0.2 °C/min. At the higher cooling rate of 0.3 °C/min, the nucleation rate can be seen to rise with greater stirrer speed for the steel stirrer, but for the Perspex stirrer it drops at a speed higher than 300 rpm. At the highest cooling rate examined, the nucleation rate is enhanced as the stirring rate increases. In general, the values of nucleation rate are higher for the stainless steel stirrer than those for the Perspex stirrer with the difference becoming more significant at higher cooling rates. 4.4. Nucleation Mechanism. Photographs of stirrers at the end of crystallization runs are given in Figure 8 revealing a high degree of crystal encrustment on the surface of the stirrers and impeller shaft. It can also be seen from these data that there are much denser crystal attachments on the blades of the stainless steel stirrer than on the Perspex one. These observations suggest that nucleation may occur initially on the surface of the stirrer rather than in the bulk solution. It can also be seen that there are more crystals on the top and bottom edges and tips of the Perspex stirrer, i.e., in areas where the surface was machined to achieve the curved shape. These parts are much rougher than the rest of the surface area, perhaps indicating that the roughness of the stirrer surface has also an important role to play in the nucleation process. It is noteworthy that similar crystal attachments are observed on the impeller shaft as shown in Figure 8. The same shaft was used in all runs, and only the impeller was changed for different crystallization runs. These data are consistent with the observed nucleation phenomena being due to a combination of initially surface-induced heterogeneous nucleation, immediately followed by the crystal growth process, then possibly secondary nucleation due to breakage of the crystals.
Nucleation of L-Glutamic Acid
Crystal Growth & Design, Vol. 4, No. 5, 2004 1043
Figure 8. Photographs of retreat curve impellers taken at the end of cooling crystallization illustrating the encrustation on the surface of stirrers: (a) Stainless steel, (b) Perspex, and on stirrer shafts.
Figure 9. Dependence of advancing contact angle and free energy ratio on surface types and concentration of aqueous L-glutamic acid solutions.
Figure 9 shows the measured advancing contact angle of L-glutamic acid aqueous solutions on both Perspex and stainless steel flat plates. It can be clearly seen that saturated solution droplets on the surface of Perspex have much higher contact angle than those observed on stainless steel surface. Higher advancing contact angles were observed for aqueous L-glutamic solutions compared with those measured for pure distilled water with a greater increase being recorded in the case of stainless steel. However, no significant variation in the values of contact angle was found as the solute concentration rises in the limited concentration range investigated. Studies of any further increase of solution concentration were prevented by the low solubility of L-glutamic acid at room temperature. The free energy ratio φ can be readily calculated using eq 8. The results are also given in Figure 9. Values of contact angles on rough Perspex and rough stainless steel surfaces have been measured. The results indicate that the contact angle on a rough surface would be smaller than on a smooth surface giving a lower free energy ratio. These observations are consistent with the conclusion that the free energy change associated with the formation of a critical nucleus on the Perspex stirrer surface would be greater than that for the surface of a stainless steel stirrer. Similarly, nucleation on a rough surface would be expected to be much easier than on a smooth surface due to the smaller contact angle of the
former. The images in Figure 8 are consistent with this model. Together these observations are consistent with the stirrer surface providing preferred nucleation sites in L-glutamic acid crystallization with both the stirrer material and its surface roughness being important factors dictating the nature of the primary nucleation process. It also appears that nucleation occurs first on the surface of the stirrer, where, according to mixing studies,20 the strongest turbulent kinetic energy is present. Hence, it is reasonable to conclude that these newly formed nuclei grow continuously to critical nuclei as freshly supersaturated solution is transported to the region due to better micromixing compared to that in the rest of the bulk. These stable nuclei may then be washed away by the strong fluid shear force and quickly dispersed into other parts of the bulk in the crystallizer and then the overall nucleation event is triggered. Therefore, the nucleation events during these batch cooling experiments reflect a surface-induced heterogeneous nucleation mechanism. 5. Conclusions It is well-known that secondary nucleation depends on the hardness of the stirrer as the crystals may be broken into fines due to crystal and stirrer collision. However, it is rarely reported that primary nucleation may also be affected by stirrer material. In this study, batch cooling crystallizations of L-glutamic acid aqueous solutions were carried out in a 450 mL reactor using stirrers with identical geometry but made from different materials: stainless steel and Perspex. Nucleation kinetics was evaluated using measured MSZW. Experimental results suggest that both stirrers show similar MSZW profiles as a function of stirring rate, though nucleation was found to be much easier in the case of the stainless steel stirrer. Nucleation order for crystallization experiments carried out using the stainless steel stirrer were found to be greater than those carried out using the Perspex stirrer, i.e., consistent with a much lower energy barrier for nucleation in the case of the stainless steel stirrer. However, the data also show that the nucleation rate constant for experiments carried out using the Perspex stirrer were much higher than those when using the stainless steel impeller for
1044 Crystal Growth & Design, Vol. 4, No. 5, 2004
the same agitation rate. Observations of crystal attachment on these two stirrers strongly indicated that the nucleation process initially started on the surface of the stirrer rather than in the preferentially cooled regions adjacent to the reactor wall as would be more conventionally accepted. This observation together with experimental measurements of contact angle for different stirrer materials, from which the free energy ratio was calculated, confirm that the energy needed to form critical nuclei on the stainless steel surface would be much lower than on Perspex. Surface roughness is also believed to play an important role. Overall, this study reveals a heterogeneous nucleation mechanism involving a surface-induced process on the stirrer surface with the surface properties and its material of construction playing an important role by the overall crystallization process. Acknowledgment. This work which forms part of the doctoral studies20 of one of us (K.L.) has been carried out as part of Chemicals Behaving Badly, a collaborative project funded by EPSRC (Grant GR/L/68797) together with industrial support from Astra-Charnwood, BASF, Glaxo-Wellcome, SmithKline Beecham, ICI, Malvern Instruments, Pfizer, and Zeneca. The cooperation of colleagues at the Centre for Molecular and Interface Engineering at Heriot-Watt University is gratefully acknowledged. Authors are also grateful to Dr. Zhiyi (Steven) Cao for writing a LABVIEW program for reactor control and to Professor John I. B. Wilson, Dr. John Andrews, and Suzanne Jardine for kind assistance on contact angle measurements. Nomenclature B b c c* ∆cmax D ∆G′crit ∆Gcrit J k1 kn m N T
supersaturation rate, kg m-3 min-1 cooling rate, °C/min solution concentration, kg m-3 equilibrium saturation concentration, kg m-3 maximum possible supersaturation, kg m-3 stirrer diameter, m free energy change associated with heterogeneous nucleation, J free energy change associated with homogeneous nucleation, J nucleation rate, kg m-3 min-1 constant nucleation rate constant order of nucleation stirrer speed, rpm reactor diameter, m
Liang et al. t tsat tcry ∆tmax
solution temperature, °C saturation temperature, °C crystallization temperature, °C metastable zone width, °C
Greek symbols correction factor for the change in concentration if the species is hydrated τ time, min φ energy ratio
References (1) Tavare, N. S. Can. Metall. Q. 1988, 27, 261-266. (2) Myerson, A. S. Handbook of Industrial Crystallisation; Butterworth-Heinemann, Oxford, 1993. (3) Rodriguez-Hornedo, N.; Murphy, D. J. Pharm. Sci. 1999, 88, 651-660. (4) Garside, J. Chem. Eng. Sci. 1985, 40, 3-26. (5) So¨hnel, O.; Garside, J. Precipitation: Basic Principles and Industrial Applications; Butterworth-Heinemann Ltd.: Oxford, 1992. (6) Ness, J. N.; White, E. T. Analysis and Design of Crystallization Process; American Institute of Chemical Engineering Symposium Series 153; American Institute of Chemical Engineering: New York, 1976; pp 65-73. (7) Randolph, D.; Sikdar, S. K. AIChE J. 1974, 20, 410-412. (8) Garside, J.; Davey, R. J. Chem. Eng. Commun. 1980, 4, 393-424. (9) Jancic, S. J.; Grootscholten, P. A. M. Industrial Crystallization; Delft University Press: Delft, 1984. (10) Ny´vlt, J.; Rychly, R.; Gottfried, J.; Wurzelova, J. J. Cryst. Growth 1970, 6, 151-162. (11) Mullin, J. W. Crystallization, 3rd ed.; Butterworth-Heinemann: Oxford, 1997. (12) Gerson, A. R.; Roberts, K. J.; Sherwood, J. N.; Powder Technol. 1991, 65, 243-249. (13) van Gelder, R. N. M. R.; Roberts, K. J.; Chambers, J.; Instone, T. J. Cryst. Growth 1996, 166, 189-194. (14) Smith, L. A.; Roberts, K. J.; Machin, D.; McLeod, G. J. Cryst. Growth 2001, 226, 158-167. (15) Meenan, P.; Roberts, K. J. J. Mater. Sci. Lett. 1993, 12, 1741-1744. (16) Mullin, J. W.; Raven, K. D. Nature 1961, 15, 251. (17) Mullin, J. W.; Raven, K. D. Nature 1962, 7, 35-38. (18) Ny´vlt, J.; Skrivanek, J.; Gottfried, J.; Krickova, J. Collect. Czech. Chem. Commun. 1966, 31, 2127-2136. (19) Ny´vlt, J. J. Cryst. Growth 1968, 3, 377-383. (20) Liang, K. Process Scale Dependence of L-Glutamic Acid Batch Crystallised from Aqueous Solution in Relation to Reactor Internals, Reactant Mixing and Process Conditions, Ph.D. Thesis, Heriot-Watt University, 2002. (21) American National Standards Institute. Glass-Lined Steel Baffles for Mixing Vessels for Use in Process Engineering Mounting Dimensions (foreign standard). Document No. DIN 28146. http://webstore.ansi.org/ansidocstore/default.asp.
CG034096V
