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Ind. Eng. Chem. Res. 2003, 42, 4888-4898
GENERAL RESEARCH Dynamic In-Process Examination of Particle Size and Crystallographic Form under Defined Conditions of Reactant Supersaturation as Associated with the Batch Crystallization of Monosodium Glutamate from Aqueous Solution Heidi Gro1 n,† Patricia Mougin,‡ Alistair Thomas, Graeme White, and Derek Wilkinson Centre for Molecular and Interface Engineering, School of Engineering and Physical Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, U.K.
Robert B. Hammond, Xiaojun Lai, and Kevin J. Roberts* Institute of Particle Science and Engineering, Department of Chemical Engineering, University of Leeds, Leeds LS2 9JT, U.K.
The use of in-process analytical techniques to give direct access to the processing parameters needed for the optimization of crystallization processes for new materials and to achieve process robustness for existing processes is presented. An integrated 2-L batch crystallization system incorporating advanced in-process analytical techniques (optical turbidimetry, ATR FTIR spectroscopy, ultrasonic spectroscopy, and X-ray diffraction) is described. Using this multitechnique facility, dynamic measurements of the onset of crystallization, supersaturation of the mother liquor, crystal size distribution of the particles produced, and pseudo-polymorphic form of the product crystals are obtained during the isothermal crystallization of monosodium glutamate monohydrate from supersaturated aqueous solutions. The results provide a useful insight into some of the mechanistic aspects of nucleation, growth, and breakage processes, as well as enabling the measurement of growth rate during a desupersaturation process. This development serves to enhance the understanding of crystal growth mechanisms at the molecular scale for industrial crystallization processes as carried out at a representative scale size. 1. Introduction Crystallization from solution is extensively used in the chemical industry. Diversification and innovation in a constantly expanding market means that new processes and systems, together with operational “best practice”, must be created to accelerate the manufacture of the new high-value-added chemicals that are entering the market. Whereas a thorough empirical approach to process design and optimization can be adopted in the first stage of the production of a material (solvent screening, polymorph and salts selection, process balances, etc.), the difficulties encountered in scaling-up a process mean that the traditional trial-and-error approach can be rather limited, particularly with respect to time scale. Recently, there has been interest in developing new and robust approaches to process design, focusing on developing new process analytical tools capable of * To whom correspondence should be addressed. E-mail:
[email protected]. † Current location: Process Technology, Degussa AG, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany. ‡ Current location: SSCI Inc., 3065 Kent Avenue, West Lafayette, IN 47906-1076.
enabling on-line monitoring of the process variables needed for system characterization. This involves (1) monitoring any changes of the batch process that cannot be predicted otherwise, (2) reacting accordingly for improved control of the process, and (3) facilitating a research tool to provide better understanding of the mechanisms involved in a crystallization process. The lack of such tools results in the crystallization step being, perhaps, an underexploited unit operation, i.e., consequent use of energy-inefficient processes such as spray drying for particle formation. Often, crystallization is used merely to purify or separate products rather than being fully optimized as a method for delivering the product in its desired final form and with its required end-use properties. The economic impact of poorly controlled crystallization processes can be significant. The resulting materials inevitably require further downstream processing, thus impacting both time to market for new products (and, as a result, patent revenue) and processing costs. Building on the development of a range of in-process techniques for batch crystallization monitoring,1-7 in this work, these techniques have been brought together, and used simultaneously, in a detailed study of the isothermal crystallization of monosodium glutamate
10.1021/ie021037q CCC: $25.00 © 2003 American Chemical Society Published on Web 09/09/2003
Ind. Eng. Chem. Res., Vol. 42, No. 20, 2003 4889
Figure 1. Schematic of the 2.6-L batch crystallizer integrating the in situ process analytical techniques of turbidity and ATR FTIR immersion probes, ultrasonic spectroscopy, and X-ray diffraction flow-through cells.
(hereafter MSG). In this way, the crystallization onset, reactant supersaturation, crystal size distribution (CSD), and crystal structure of the product crystals have been monitored throughout an isothermal batch crystallization process. This has been achieved via the use of optical turbidity, attenuated total reflection (ATR) FTIR spectroscopy, ultrasonic spectroscopy, and X-ray diffraction techniques, respectively. MSG was chosen as a representative material for an industrial batch crystallization process, i.e., one that would be important in the pharmaceutical sector. Given that it is an organic salt and its nucleation kinetics are slow, it forms aqueous solutions with high (mass-transport-impeding) viscosity and crystallizes as a mixture of monohydrate and anhydrous crystallographic forms, both of which exhibit a needlelike morphology.8 2. Materials and Methods 2.1. Batch Crystallizer Setup. A double-jacketed 2.6-L glass reaction-calorimeter from Hazard Evaluation Laboratory (HEL) was used as the crystallizer in this work. Oil for heating or cooling was circulated through the inner jacket, while the outer vacuum jacket provided thermal insulation. The agitator was a 6-pitched-blade impeller, and the agitation speed was kept at 200 rpm throughout the crystallization processes. The circulating oil temperature and agitator speed were controlled by a control and data acquisition unit linked to a desktop PC. The temperature of the crystallizing solution, solution turbidity, and temperature of oil into and from the inner jacket were recorded every 20 s. The oil temperature was adjusted automatically by the PC/ control system to achieve a linear cooling rate. Figure 1 shows the experimental setup, including all of the analytical instruments integrated into the fully automated reactor system. The reactor loading was set to 2-L volume, producing a 1:1 height/width ratio defining the reactor hydrodynamics and mixing. 2.2. Crystallization Onset via Optical Turbidimetry. The use of optical turbidity to measure the crystallization onset using a fiberoptic reflectance immersion probe has been reviewed in previous papers.9-13 The turbidity probe reflectance can be calibrated using
a clear (slightly undersaturated) solution for which the reflectance can be set to full scale. Crystallization can thus be detected via the observation of substantial and rapid loss of transmittance due to crystallized material obscuring the probe reflector. In this work, the turbidity of the solution/crystal slurry was measured using a turbidometric fiberoptic probe designed and built in-house. 2.3. Supersaturation Measurements via ATR FTIR Spectroscopy. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy can be used to measure the solute concentration of a solution, and through this, if the solubility is known, the supersaturation can, in principle, be determined.14,15 The application of ATR FTIR spectroscopy to supersaturation measurements for organic materials has been described in previous papers.1-3 The ability of the ATR technique to measure solution concentration in situ without phase separation reflects the fact that the depth of IR penetration, typically in the 0.3-1 µm range (see, e.g., ref 17), is less than the solution-phase boundarylayer thickness, hence preventing solid particles from contacting the ATR probe surface.3 In this work, ATR FTIR measurements within the batch reactor were carried out using a Dipper-210 ATR FTIR immersion probe equipped with a ZnSe conical internal reflection element, manufactured by Axiom Analytical Incorporated, together with a Bomen WorkIR Fourier transform infrared spectrometer connected to a PC equipped with Grams software (Galactic Industries Corporation). The ATR FTIR immersion probe was inserted into one of the top ports of the crystallizer. 2.3.1. ATR FTIR Calibration. To determine the concentration, solubility, and degree of supersaturation of MSG in water, calibration curves of a specific absorbance ratio versus concentration of MSG in water were determined. ATR FTIR spectra (see, e.g., Figure 2) of the solutions at temperatures of 10, 30, 50, and 70 °C were measured, from which changes in the intensity of the absorbance bands due to variations in solute concentration can be seen, for example, in the vicinity of 1400 and 1558 cm-1. By taking the ratio of the broad water band at 3279 cm-1 to the above bands, two
4890 Ind. Eng. Chem. Res., Vol. 42, No. 20, 2003
Figure 2. ATR FTIR spectra of aqueous solutions of MSG at 70 °C for two different concentrations. The arrows indicate locations of peak intensity changes with increasing concentration of the solute in water.
calibration parameters RA1 and RA2, respectively, were determined. The temperature (T) dependency of the calibration parameters over the concentration range from 250 to 1200 g/L was modeled by defining calibration curves relating solution concentrations (c) using the general equation
RA ) a(T)cb(T)
(1)
where a and b are both functions of temperature. Using this expression, the more reliable and accurate results for the solution concentration were obtained using calibration parameter RA2. This is most probably due to the fact that the peak at 1558 cm-1, as used for the calculation of RA1, overlaps significantly with a water band in its vicinity, making it more sensitive to small peak shifts caused by slight variations in the solution structure. Therefore, the calibration curve for RA2
c(RA2,T) )
(142.5 -RA20.2563T)
-1/(0.7466+0.0001T)
(2)
was used for the quantitative analysis of variations in supersaturation occurring during crystallization. 2.3.2. Determination of Solubility Curves. The solubility curves of both the aqueous MSG monohydrate and the recrystallized MSG anhydrate and monohydrate mixtures were determined in a manner similar to the solution calibration curves, this time via isothermal equilibrium ATR FTIR measurements as carried out in situ within the saturated solution component of a crystal/solution slurry. For the MSG monhydrate, an excess amount of MSG monohydrate was stirred into an appropriate amount of distilled water for 2 h at 30 °C before the measurements of the RA2 peak ratio were made. The equilibrium was defined by the fact that no changes in the FTIR spectra were observed for equilibration times beyond 2 h. Three spectra of the slurries were recorded at equilibrium. Afterward, the temperature was increased to the next step and the procedure was repeated. For the recrystallized MSG anhydrate and monohydrate mixtures, slurries of MSG in water, recrystallized at each temperature, were kept at this equilibrium temperature. Three spectra were scanned after 24 h at equilibrium for each temperature. Unfortunately, solubility curves for the anhydrous phase, which is not commercially available, were not determined, reflecting experimental difficulties associated with the inherent hydroscopic nature of this phase.
Figure 3. ATR FTIR data for aqueous MSG solutions: (a) calibration curves based on RA2 ratio as functions of concentration and temperature, (b) solubility determinations for monohydrate and recrystallized anhydrate/monohydrate mixtures.
Using the ATR FTIR calibration curve RA2, given in Figure 3a, the solubility curves for both the MSG monohydrate and the mixed monohydrate/anhydrous slurry were extracted as a function of temperature (see Figure 3b). Combining these data with similar ATR FTIR data collected on-line during crystallization (nucleation and growth) experiments enabled direct measurement of the relative supersaturation (S), which is given by
S ) c/c*
(3)
where c and c* are the solution concentration during crystallization and at the equilibrium state of saturated mother liquor, respectively. 2.4. Crystal Size Distribution via Ultrasonic (Attenuation) Spectroscopy. Ultrasonic spectroscopy (USS), which involves measurement of the attenuation of transmitted acoustic waves (frequency range of ca. 1-150 MHz) through solid/liquid suspensions, allows the CSD (size range of ca. 0.1-1000 µm) and solid content (up to ca. 50 vol %) to be examined in situ18,19 during crystallization processes.4-6 The deconvolution of ultrasonic attenuation spectra, to obtain the CSD and solids concentration, can be carried out using the ECAH model.20,21 USS, validated with respect to previous measurements,1-7 has also been used for in-process measurements of batch crystallization at the 2-L scale size.22 In this work, an on-line USS spectrometer,30 designed and constructed in collaboration with Malvern Instruments Ltd., was used. In this instrument, a 470-mL stainless steel flow-through USS measurement cell drew
Ind. Eng. Chem. Res., Vol. 42, No. 20, 2003 4891
Figure 4. Ultrasound attenuation spectra of a MSG aqueous solution at different temperatures.
crystal/solution slurry directly from the crystallizer for size analysis. Slurry pumping lines to and from the reactor were jacketed using a coaxial piping arrangement, with the outer pipe being maintained at the reactor temperature using a thermostatic recirculating bath (Haake F3) to prevent size enlargement/reduction due to temperature variability in the pumping lines. 2.4.1. USS Calibration. Experiments were carried out to assess the temperature and solute concentration dependence of the liquid media used during the crystallization experiments. Appropriate amounts of MSG and distilled water were heated within the HEL reactor and rapidly cooled. Ultrasonic attenuation measurements were carried out at temperatures within the range 1040 °C and for solutions at solute concentrations between 980 and 632 g per 1000 g of water (corresponding to saturated solutions at 65 and 15 °C, respectively). Figure 4 shows the effect of temperature on the acoustic attenuation of an MSG aqueous solution saturated at 15 °C (solution at 632 g/1000 g of water). A curve of the form
R ) rf s
(4)
where f is the frequency and constants r and s are fitting parameters, characteristic of the frequency dependence of the attenuation of a liquid medium,32 was leastsquares fitted for each temperature. The results obtained for the attenuation coefficient factor, r, and exponent, s, for a solution of fixed concentration (saturated at 15 °C) at various temperatures are listed in Table 1. A linear relationship was found to accurately describe the relation between the attenuation coefficient factor r and temperature. In contrast, only a weak dependence was found between the attenuation coefficient exponent s and temperature, leading to the following calibration curves for attenuation in aqueous solutions of MSG with concentrations of 632 and 980 g per 1000 g of water
R632 ) (-0.001T + 0.0531)f1.9
(5)
R980 ) (-0.0018T + 0.0856)f1.95
(6)
where R632 and R980 are the acoustic attenuations of the aqueous solutions of MSG at the corresponding concen-
Table 1. Temperature Dependence of Ultrasound Attenuation for an Aqueous Solution of Monosodium Glutamate Saturated at 15 °Ca: Parameters r and s in the Relationb r ) rf s temperature (°C)
r (dB/in.)
s
16.4 17.6 19.4 21.5 23.9 26.5 29.2 31.7 34.0
0.039 12 0.038 41 0.035 32 0.033 35 0.028 73 0.027 03 0.024 73 0.022 64 0.021 17
1.886 1.872 1.874 1.866 1.879 1.872 1.873 1.878 1.889
a Concentration of 632 g/1000 g of water. b Regression parameter R2 > 0.996 for all curve fits.
trations, expressed in decibels per inch, with T in degrees Celsius and f in megahertz. Because of the solute concentration dependence of the ultrasonic attenuation of the liquid medium, and hence the shifting of the attenuation spectra due to the change in the liquid medium rather than in the solid content, ATR FTIR measurements of solute concentration were used to obtain the appropriate liquid acoustic properties and, so, to retrieve CSD and solid concentration data. 2.5. Crystallographic Form via X-ray Diffraction. Characterization of crystallographic form downstream of crystallization is routinely carried out, ex situ, in the laboratory using powder X-ray diffraction (XRD) techniques that have also been extended to in-process characterization of crystallizing forms.7,23-29 In favorable situations, in situ XRD also has the potential capability of yielding the particle strain and/or the degree of crystallinity of crystallized particles, thus enabling a crystallization process to be optimized to maximize the product quality. This latter aspect, however, is not adressed here. In this work, in-process XRD patterns were recorded using a purposely designed on-line XRD system31 comprising a conventional Cu X-ray tube and Nonius X-ray generator, an INEL CPS120 curved position-sensitive detector (PSD), and a PC-based Nonius multichannel analyzer data acquisition system. In this setup, X-rays passing through the X-ray-transparent window of an in situ cell were diffracted onto the curved PSD. To restrict crystallization in the sample flow loop, the flow-through
4892 Ind. Eng. Chem. Res., Vol. 42, No. 20, 2003
Figure 6. On-line XRD patterns taken during isothermal crystallization of MSG at TS ) 12.5 °C. The data collection time for each pattern was 20 min. The monohydrate and anhydrous peaks of MSG are marked by arrows in the figure as M and A, respectively. Figure 5. Reference ex situ powder XRD patterns of the monohydrate (top) and anhydrous forms of MSG.
cell and slurry pumping line were jacketed and controlled at the reactor temperature in a manner similar to that used for the USS measurements. Preliminary experiments were conducted to characterize each pseudo-polymorphic form of MSG in terms of its respective XRD pattern. The commercially available MSG monohydrate was used to obtain the X-ray powder patterns of the monohydrate. The MSG anhydrous form was prepared by heating a sample of MSG monohydrate to 155 °C in a vacuum oven for 24 h. Figure 5 shows the XRD powder patterns of the monohydrate and anhydrous forms of MSG. Unfortunately, the absence of crystal structure data for anyhydrous MSG precluded the use of XRD pattern simulation for pattern identification. 2.6. MSG Crystallization Protocol. Monosodium glutamate (99% pure) was obtained from BDH. Experiments were carried out using an aqueous solution of 980 g of MSG in 1000 g of water, conditions characterized by a saturation temperature of 65 °C. MSG at this high concentration nucleates extremely poorly, and large undercoolings (high supersaturations) are needed to promote crystallization. Crystallization experiments were carried out isothermally (constant initial supersaturation) at crystallization temperatures (TS) of 10.0, 12.5, 15.0, 17.5, and 20.0 °C. For each temperature, the induction time to nucleation, as revealed from the turbidity monitoring, and the mother liquor supersaturation, as revealed via ATR-FTIR spectroscopy, were determined. Following the nucleation stage, the growth rate and crystallographic form of the MSG crystals were monitored using the on-line USS and XRD instruments, respectively. At the same time, ATR FTIR spectroscopy was used to monitor changes in reactor supersaturation during the desupersaturation process postnucleation resulting from the depletion of the excess solute concentration that had been maintained during the isothermal nucleation stage. Technical difficulties with the on-line instrumentation precluded the collection of useful data for the isothermal experiment carried out at 15.0 °C after the onset of nucleation. Samples of crystals prepared in the crystallization reactions were analyzed ex situ via the use of conventional reflected-light digital microscopy aided by digital image analysis methods.
Table 2. Calculated Values of Peak Intensity Ratios between Areas under Peaks at Diffraction Angles 33.3° for Anhydrous MSG and 35° for Monohydrate MSG at the Beginning and End of the Process: Comparison of Results for the Isothermal Crystallizations at 12.5 and 17.5 °C ratio of anhydrous form (2θ ) 33.3°) to monohydrate form (2θ ) 35°) T (°C)
initial
final
12.5 17.5
1.39:1 2.00:1
1.35:1 1.39:1
3. Results and Discussion 3.1. Analysis of Pseudo-Polymorphic Form Composition via XRD Measurements. Figure 6 shows a representative example of the on-line XRD patterns recorded during isothermal crystallization runs at TS ) 12.5 °C. In all of the crystallization experiments, the XRD patterns showed peaks representative of both the monohydrate and anhydrous forms of MSG, as expected from the literature.8 Accurate composition analysis, differentiating between the two forms, proved to be difficult because of the poor signal-to-noise ratio obtained for an XRD scan of only 20 min. This highlights one of the current problems of the technique, in that each on-line XRD pattern of a crystal slurry needs to be collected over a period of time to provide a reasonable signal-to-noise ratio for the data. Although increasing the scanning time would, in principle, improve the signal-to-noise ratio, it would reduce the currently rather limited temporal information about any changes in the MSG mixture composition. Thus, during the XRD data collection time, the crystallization process and potentially the product’s phase composition are bound, in principle, to vary continuously. Therefore, at present, the technique reflects only the crystallographic phase information as summed over a time period, a process through which the “instantaneous” polymorph composition information is lost. The peak areas of two diffraction peaks indicative of the anhydrous and monohydrate forms of MSG at 33.3 and 35° 2Θ, respectively, were examined (see Table 2). Comparing the ratios of these peak areas allowed the relative amounts of the anhydrous and monohydrate forms to be estimated as a function of time following the onset of crystallization. It should be noted here that this analysis proved problematic particularly given the poor signal-to-noise ratio, and hence, the data presented here reflect the more favorable, less noisy data. Thus,
Ind. Eng. Chem. Res., Vol. 42, No. 20, 2003 4893 Table 3. Induction Times as Measured as a Function of Crystallization Temperature and Level of Supersaturation and Constants Obtained from Empirical Fitting to the Kinetics Data, Together with Supersaturation Ranges Applied nucleation stage
a
growth stage
temperature (°C)
nucleation supersaturation S
induction time to nucleation (h)
kinetic rate constant kg (m/s × 10-10)
g
growth supersaturation range
10 12.5 15.0 17.5
1.48 1.43 1.42 1.33
9.8 9.2 11.8 15.4
20
1.30
36.4
38.5 37.0 no data3 8.2 41.5 4.1 53.4
1.64 1.49 no dataa 0.64 1.49 0.27 1.32
1.02 < S
