CRYSTAL GROWTH & DESIGN
A Novel Batch Cooling Crystallizer for in Situ Monitoring of Solution Crystallization Using Energy Dispersive X-ray Diffraction Nicholas Blagden,*,†,# Roger Davey,† Mike Song,†,⊥ Mike Quayle,†,§ Simon Clark,‡ David Taylor,‡ and Alfie Nield‡
2003 VOL. 3, NO. 2 197-201
Molecular Materials Centre, Department of Chemical Engineering, UMIST, P.O. Box 88, Manchester M60 1QD, UK, Diffraction Group, Synchrotron Radiation Source, Daresbury Laboratory, Warrington Cheshire, WA4 4AD, UK, School of Pharmacy, University of Bradford, Bradford, West Yorkshire, BD7 1DT, UK, NV Orgonon, P.O. Box 20, 5340 BH Oss, Netherlands, and BNFL Technology Centre, Seascale, Cumbria, UK Received October 2, 2002
ABSTRACT: In situ X-ray diffraction monitoring of crystallization from solution is often hampered by a combination of the rather low levels of crystallized solid (typically 5 to 20 wt %) and the large background scattering that arises from the solution phase. In this work, we have attempted to overcome these limitations, first, by using high intensity dispersive X-rays available at the Synchrotron Radiation Source, Daresbury Laboratory, UK, and second by designing a novel batch classifying crystallizer. This crystallizer was designed to maximize the weight fraction of solid presented to the probe beam. In this configuration, solution crystallizations generating between 2 and 30 wt % of solids were monitored successfully. Three preliminary studies describe the application of this equipment to the simple real time monitoring of a crystallization event, the interconversion of two polymorphic crystalline forms, and the orientation of crystals in the fluid flow of the crystallizer. Introduction
Crystallizer Design
Energy-dispersive X-ray diffraction and scattering using synchrotron radiation has been widely used for the in situ study of a range of kinetic processes involving crystalline solids. For example, rapid solid-state reactions under various chemical and physical conditions,1 solid-state transformations and hydrations,2 study of particle orientation under flow,3 and the phase behavior of colloidal dispersions4 have all been studied. In the context of crystallization from liquids, however, the technique has been limited to application to melt crystallization of alkanes,5 and solution crystallization of TNT6, since such systems typically yield, after crystallization, slurries containing upward of 40 wt % crystalline solids, which are then easily detectable via their diffraction pattern. More recently, we have shown how the stopped flow technique and simple glass capillaries can be adapted to crystallization studies.7,8 For the many systems in which the yield of crystalline material is lower that 25 wt % this technique often cannot resolve the evolution of the crystalline phase above the scattering from the solution. To avoid this problem and hence improve the sensitivity of X-ray diffraction in studying liquid phase crystallization processes, a novel batch crystallizer has been designed that allows the classification of crystals into a well-defined zone through which the X-ray beam passes.
The cell, which was machined from a single Teflon block, is shown schematically in Figure 1. The cell volume is approximately 70 cm3 and the cell is filled with hot saturated solution, which upon cooling will crystallize. The crystallizer volume is divided into two partssin the upper part the majority of the crystallization takes place and, given the appropriate agitator speed, the crystals then settle and concentrate as a suspended sediment in the lower, narrow part of the vessel. The crystals are maintained in this location as a suspended plume of solid, and it is through this lower part of the cell that the probe synchrotron beam passes and where the crystallization processes are monitored. This approach of using sedimentation from the larger into the smaller volume is a simple means of achieving the required particle suspension weight fraction to generate a detectable signal. The optimum length of the lower portion was determined experimentally by use of a plunger arrangement, which allowed the length to be varied continuously from 1 to 10 cm. The agitation was obtained from 1/60 pitched two bladed steel impellor, set to rotate at 200 rpm, initially, and subsequently varied from 0 to 700 rpm using a digital Heidulph RZR 2000 overhead stirrer.
* To whom correspondence should be addressed. E-mail: nblagden@ brad.ac.uk. † UMIST. ‡ Synchrotron Radiation Source. # University of Bradford. ⊥ NV Orgonon. § BNFL Technology Centre.
Experimental The work presented here describes our initial findings during the commissioning of the cell using the dispersive instrument on Station 16.4 at Daresbury Laboratory, UK.9 Data on three systems, urea, citric acid, and glutamic acid, are reported. The initial solution loadings and yields used were urea, 77.05 g dissolved in 50 cm3 water, with 17.05 g crystal yield; citric acid 91.30 g dissolved in 50 cm3 water, with 3.24 g crystal yield; and glutamic acid 6.5 g dissolved in 100 cm3, with added 10 wt % slurry of R crystals. Unless otherwise stated, agitation was fixed at 200 rpm for crystallization runs.
10.1021/cg020053n CCC: $25.00 © 2003 American Chemical Society Published on Web 02/06/2003
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Blagden et al. (Icryst/Itotal)) is thus simply obtained by subtracting this estimated solution contribution to total probe peak intensity ratio from 1. This is also a simple and convenient way to accommodate for the decay in power of the synchrotron beam
Results and Discussion Overall, the crystallizer was found to operate successfully in providing time-resolved data for the systems studied in which the final solids contents were ca. 30, 10, and 2.5 wt % for urea, glutamic acid, and citric acid, respectively. Below, each system is considered in turn and data is presented relating to the time evolution of the crystallization of citric acid, the polymorphic transformation between R and β glutamic acid and the orientation of urea crystals within the flow field of the crystallizer. The Extent of Crystallization
Figure 1. A schematic of the crystallizer design, including approximate dimensions. Typically diffraction patterns were recorded every 30 s (Note: the detector collection on Station 16.4 is able to collect a frame every 10 ms, however higher frame rates result in lower resolution). In the case of urea crystallization was allowed to proceed to completion with agitation. The diffraction pattern was then monitored at a range of agitation speeds from 0 to 700 rpm. Data collection and analysis were undertaken using fixed detector angles of (top) 7.796°, (middle) 4.996°, and (bottom) 2.196°, from the parallel incident beam. A white light X-ray source was used (range 20-70 Kev). The position of the cell in the beam was adjusted using the computer-controlled xyzstage. The cell was initially positioned and calibrated using silicon dioxide and benzamide samples (the former is welldefined standard, and the latter has a number of significant reflections over the d spacing range of interest). All patterns obtained were adjusted for the signal from the Teflon cell (i.e., between 4.5 and 5 Å). The time-resolved patterns were recorded along with the pure solvent and pure solid patterns. The simulated diffraction patterns and morphologies of these systems where generated using Cerius2 software.10 The crystal structures used for this modeling were taken from Cambridge Crystallographic Database.11 For any diffraction peak of interest, the total intensity observed will be the sum of scattering from solution and the diffraction from the crystal lattice at the selected angle. To follow the kinetic and hydrodynamic processes associated with crystallization, it is clearly essential to make an estimate of contribution that crystal diffraction (intensity Icryst) makes to the overall sample scattering (Itotal). This was done in a simple way by estimating the solution scattering contribution from the background intensity (Isolution) recorded as close as possible to the diffraction peak of interest. Then
(Icryst/Itotal) ) 1 - (Isolution/Itotal)
(1)
The contribution of crystal diffraction to overall probe peak intensity (as a ratio, referred to as the extent of crystallization,
Figure 2a shows a series of (plot I), which describe the time evolution of the crystallization process of anhydrous citric acid. The gradual appearance and growth of diffraction peaks above the background scatter can be clearly seen. Figure 2a plot II shows the final total scattering and diffraction (indexed) and the initial solution scatter. To track the kinetic process more effectively using these data, eq 1 has been used to explore the evolution of the fastest growth direction12 [212 h ], and the extent of crystallization (I[212 h ]/Itotal) is then plotted as a function of time in Figure 2b. The resulting diffraction ratio profile clearly shows the induction time for the onset of nucleation followed by the overall increase in diffraction intensity as crystallization progressed. Examination of other significant reflections (viz (202), (002), and (201)) showed similar trends (Figure 2c). It is noted that all these data show maxima during the course of the crystallization. This may be attributed to preferred orientation effects due to the evolving crystal habit as the crystallization process proceeds. Future work would be needed to explore this area further. Polymorphic Transformation The solution mediated transformation of glutamic acid is well documented,13 and for this work was followed by monitoring a slurry of preformed R crystals over an 8 h period in which the significant part of the transformation was found to occur in the last 2 h. For glutamic acid R and β phases have pairs of characteristic XRD signature peaks at 3.34 and 3.75 Å and 4.02 Å, and 4.14 Å, respectively. Thus, for example, in Figure 3a the initial traces clearly result from crystals of the R form. Over the 110 min period shown, the peaks at 3.34 and 3.75 Å gradually decrease, while those due to the β form at 4.02 Å, and 4.14 Å increase in intensity. In this case, the transformation may be tracked using the time dependence of extent crystallization according to eq 1 for significant peaks (3.75 Å for alpha, and 4.14 Å for beta) for each form. The profiles of the extent of crystallization for these significant peaks are shown in Figure 3b. These profiles clearly reveals the overall kinetics of the transformation process, although it should be noted that
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Figure 2. The crystallization of citric acid: (a) plot I, diffractogram sequence for crystallization and plot II, initial (indexed) and final diffractograms, (b) tracking the process via the (212 h ) reflection, (c) tracking the process just after nucleation via the significant reflections.
Effect of Solution Hydrodynamics
Figure 3. The transformation from R to β glutamic acid: (a) the time-resolved diffractograms, (b) tracking the process via significant reflections of each form.
since this process involves crystal dissolution and growth that no detailed mechanistic information can be derived from such data.14
In the case of urea crystallized from aqueous solution, the crystals are c-axis needles15 of aspect ratio approximately 100:1. Small {111} facets with {110} side faces bound the needles. This is shown in Figure 4a. The effect of agitation on the orientation of the suspended crystals (once crystallization has gone to completion) is then seen in the accompanying diffractograms, see Figure 4b. At 0 up to 80 rpm, only the {111} reflections are observed. As the agitator speed increases through 100 to 200 rpm, the {110} reflection becomes dominant with the {002} just appearing. Above 300 rpm, only the {002} reflection is seen. These data imply that the orientation of the needle crystals is very sensitive to the combined gravitational and hydrodynamic forces, which govern the movement of crystals in the suspension. Three significant stages in this orientation process were identified from the diffractograms, (i) no stirring, (ii) intermediate agitation, and (iii) high agitation, and these stages in the orientation process are shown schematically in Figure 4c. Without stirring the crystals appear to settle under gravity with their long axis inclined slightly off from the vertical. As the agitator speed rises, the rotation of the fluid lifts the crystals up such that the needle axes lie with increasing incline to the horizontal. At higher agitator speeds where vertical and horizontal movement of the liquid occurs the crystals realign with their c-axes horizontal. This sensitivity of the diffraction pattern to crystal orientation suggests its application in defining the hydrodynamic regimes in agitated vessels. Conclusions This work has reported the successful design of a novel classifying crystallizer, which when used in
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Figure 4. The influence of hydrodynamics on crystal orientation of urea: (a) the habit of urea crystals, (b) a series of diffractograms recorded at different agitation speeds, (c) schematic representation of the three stages of orientation under various flow conditions.
Novel Batch Cooling Crystallizer
conjunction with dispersive X-ray diffraction, was found to extend the in situ study of solution crystallization down to suspension densities as low as 3 wt %. Initial data suggest that it is possible to track the onset and extent of crystallization, the solution mediated transformation of polymorphs, and the effect of habit and agitation on the hydrodynamics of the crystallites. The preliminary results reported here indicate that studies of solution crystallization using this approach may generate new insight into the crystallization process. Future work would focus on developing and refining the cell design to allow controlled cooling and the simultaneous use of other in situ probes such as turbidometry and FT-IR/FT-Raman. References (1) Walton, R. I.; Ohare, D. Phys. Chem. Chem. Phys. 2000, 2(23), 2283-2291. (2) Barnes, P. J. Phys. Chem. Solids 1991, 52(10), 1299-1306. (3) Brown, A.; Clarke, S. M.; Convert, P.; Rennie, A. R., J. Rheol. 2000, 44, 221-233. (4) Luggar, R. D.; Gilboy, W. B. Radiat. Phys. Chem. 1999, 56, 213-227.
Crystal Growth & Design, Vol. 3, No. 2, 2003 201 (5) Doyle, S. E.; Gerson, A. R.; Roberts, K. J.; Sherwood, J. N.; Wroblewski, T. J. Cryst. Growth 1991, 112(1), 302-307. (6) Vrcelj, R. M.; Gallagher, H. G.; Sherwood, J. N., J. Am. Chem. Soc., 2001, 123(10), 2291-2295. (7) Quayle, M. J.; Davey, R. J.; McDermont, A. J.; Tiddy, G. J. T.; Clarke, D. T.; Jones, G. R. PCCP 2001, 4, 416-418. (8) Davey, R. J.; Liu, W.; Quayle, M. J.; Tiddy, G. J. T. Cryst. Growth Des. 2002, 2, 269-272. (9) Barnes, P.; Jupe, A. C.; Colston, S. L.; Jaques, S. D.; Grant, A.; Rathbone, T.; Miller, M.; Clark, S. M., Cernik, R. J. Nucl. Instrum. Methods Phys. Res. 1998, 134, 310-313. (10) Morphology and Diffraction modules of Cerius 2, Ver 4.6, Accelrys, Cambridge, UK. (11) Allen, F.; Kennard, O. Chem. Des. Autom. News, 1993, 8, 1-31 (12) The fastest growth direction was identified using attachment energy calculations in the Morphology module of Cerius 2, Ver 4.6, Accelrys, Cambridge, UK. (13) Davey, R. J.; Blagden, N.; Potts, G. D.; and Docherty, R. J. Am. Chem. Soc. 1997, 119(7), 1767-1772. (14) Cardew, P. T.; Davey, R. J. Proc. R. Soc. (London) 1985, A393, 415-428. (15) Docherty, R. J.; Roberts, K. J.; Saunders: V.; Black, S.; Davey, R. J. Faraday Discuss. 1993, 95, 11-25.
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