J. Phys. Chem. B 2001, 105, 10723-10730
10723
Nucleation, Growth, and Pseudo-Polymorphic Behavior of Citric Acid As Monitored in Situ by Attenuated Total Reflection Fourier Transform Infrared Spectroscopy Heidi Groen Centre for Molecular and Interface Engineering, Department of Mechanical and Chemical Engineering, Heriot-Watt UniVersity, Edinburgh EH14 4AS, U.K.
Kevin J. Roberts* Centre for Particle and Colloid Engineering, Department of Chemical Engineering, UniVersity of Leeds, Leeds LS2 9JT, U.K. ReceiVed: March 27, 2001; In Final Form: August 8, 2001
The crystallization, dissolution, and associated pseudo-polymorphic behavior of citric acid crystals from aqueous solution is investigated using temperature-programmed and isothermal batch experiments. Quantitative attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy is used to measure in situ the solution concentration and hence the reactant supersaturation over a wide range of solution undercoolings within the metastable zone. Detailed mapping out of the solubility-supersolubility diagram reveals poor nucleation behavior as characterized by a very wide metastable zone width (typical value, 55 °C for a cooling rate of 0.05 K/min). Simultaneous ATR FTIR and optical turbidometric measurements are used to crosscorrelate the supersaturation driving force to the nucleation behavior as followed prior to and during crystallization within the metastable zone. Both temperature-programmed and isothermal measurements reveal behavior consistent with spontaneous liquid-phase separation within the highly supersaturated mother liquor prior to crystallization, the occurrence of which is known as oiling-out, a phenomenon poorly understood in industrial crystallization reactions. Parallel examination of the phase of the product crystals, using in situ and ex situ powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC), reveals the formation of the anhydrous form of citric acid via temperature-programmed experiments and the monohydrate phase being crystallized via isothermal experiments. These results, which correlate with the solubility-supersolubility phase diagram, are rationalized in terms of the respective crystal chemistry of the anhydrate and monohydrate structures of citric acid, which is consistent with a solvent-mediated phase transformation mechanism effecting the change from the anhydrate to the monohydrate form.
Introduction The structural aspects associated with first-order phase transitions are among nature’s least understood phenomena, therefore being of significant interest to the scientific community. The transformation from either a melt or a dissolved phase into a solid crystalline phase, crystallization, is important in a wide range of scientific disciplines including mainly chemistry, physics, biology, and material science. Crystal formation from solutions is mediated by a degree of supersaturation providing the driving force for solute structuring and hence providing a source of fresh nuclei during processing.1 Because variation in solution supersaturation impacts on the crystal size, its measurement and control offer a route, in principle, to the control of the crystal size distribution (CSD) in batch reactors. Difficulty in realizing a reproducible batch crystallization step remains a substantial practical and fundamental challenge for a wide range of speciality materials, particularly organic solids such as pharmaceuticals.2,3,4 Often the poor nucleation ability of some solution systems can lead to heavily supersaturated mother liquor, which may fail to crystallize altogether resulting in the formation of an emulsion * To whom correspondence should be addressed. E-mail: K.J.Roberts@ leeds.ac.uk.
phase. The latter, often referred to as oiling-out, is exceedingly poorly understood as is, in general, solution-phase nucleation. Reflecting this perspective, the application of in situ process analytical measurements within chemical reactors has become a growing and topical area within current physical chemistry science. The challenge in controlled batch crystallization is to determine the most appropriate cooling profile that maintains an appropriate level of supersaturation over the batch cycle time to produce the desired CSD. To achieve this, measurement of supersaturation, in situ, is a prerequisite. Such measurements are essential because nucleation kinetics in particular can depend significantly on the system configuration, such as reactor size, geometry, and internals, as well as on dynamic process conditions, such as agitation speed. In this paper, we present a detailed examination of the crystallization and dissolution behavior of citric acid in aqueous solution, a compound previously studied for its poor nucleation behavior.5,6,7,8 In this, the mother-phase supersaturation and turbidity have been monitored on-line via simultaneous measurements using attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy and optical turbidometric detection, respectively.
10.1021/jp011128l CCC: $20.00 © 2001 American Chemical Society Published on Web 10/04/2001
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Figure 1. Schematic of the experimental setup: (a) ATR immersion probe, (b) colorimetric turbidity probe, (c) jacketed crystallizer, (d) PT100 temperature probe.
Previous work has shown that ATR FTIR spectroscopy can be used to measure supersaturation on-line.9,10,11,12 The in situ capability of this reflection technique provides a significant advantage over other techniques that have been used so far to measure supersaturation of organic substances in aqueous or organic solution so that its direct application to the determination of the dynamics of crystallization kinetics and to reactor control could be achieved. The possibility of extracting reliable quantitative calibration data from ATR FTIR spectra and the fact that the effective measurement depth of the reflection measurement, the depth of penetration (dp), can be kept very small, on the order of a wavelength,13 render this method ideal for extracting supersaturation data of the crystallized material slurried within the mother liquor. Materials and Methods Aqueous solutions of citric acid were prepared with distilled water, and citric acid monohydrate was purchased from Aldrich Chemical Co. In situ measurements of supersaturation and solubility were performed 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). Experiments were carried out using a 400 mL jacketed glass crystallizer, which could be rapidly cooled using two Haake F3 circulating water baths, which could be set to different temperatures and switched between temperatures via computercontrolled valves. Stirring was provided by a pitched four-blade glass stirrer at a constant speed of 330 rpm. Furthermore, the temperature and turbidity of the solution/slurry was measured by a platinum resistance thermometer (PT100) and a Sybron Brinkmann Lexan fiber optic probe, respectively. The reduction in the light transmittance upon the presence of crystals in the solution was observed on a Brinkmann PC700 colorimeter. A simple schematic of the experimental setup is given in Figure 1. Construction of Calibration Curves. To determine the concentration, solubility, and degree of supersaturation of citric acid in water, calibration curves of a specific transmittance ratio versus concentration of citric acid in water were developed as follows. Appropriate amounts of citric acid monohydrate and distilled water were heated by a Haake F3 circulating water bath and stirred to a homogeneous solution in the respective crystallizer. ATR FTIR spectra of the solution were scanned at
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Figure 2. ATR FTIR spectra of aqueous citric acid solutions compared to the ATR FTIR spectrum of water. The arrows indicate the changes of the spectra with increased concentration of citric acid in water from 0% (w/w) to 60% (w/w). Spectra recorded here were taken at 10 °C; spectra at 30, 50, and 70 °C follow the same trend.
thermal equilibrium at set temperatures of 10, 30, 50, and 70 °C. Measurement of Solubility in Slurries. The complete solubility curve of citric acid in water over a wide temperature range from 10 to 70 °C was determined using the ATR FTIR transmittance ratios of slurries at equilibrium at different temperatures. Slurries of citric acid in water were prepared in the batch crystallizer. An excess amount of citric acid monohydrate was stirred in an appropriate amount of distilled water for 24 h at 10 °C before the ATR FTIR spectra were taken. Three spectra of the slurries at equilibrium per setting were scanned. After that, the temperature was increased step by step, and the procedure was repeated. The temperature settings ranged from 10 to 70 °C. At each temperature, a sample of crystals was taken, damped dry, and then immediately measured using X-ray powder diffraction. Measurement of Supersaturation. A defined solution of citric acid in distilled water was placed in the 400 mL crystallizer. The solution was cooled by applying predetermined cooling rates. ATR FTIR spectra were accumulated every 60 s during crystallization and dissolution processes. Phase Determination via Powder X-ray Diffraction. Ex situ powder diffraction data of the recrystallized material were collected on a standard Bragg-Brentano Siemens D500 diffractometer with scintillation counter and CuKR radiation in the 2 Å range of 10°-40°. In situ X-ray diffraction patterns using an in situ cell first described by MacCalman et al.14,15,16 were recorded using an in-house X-ray diffractometer with an Inel CPS-120 curved detector.17 Differential Scanning Calorimetry (DSC) Measurements. The melting point of citric acid anhydrate and the melting range of citric acid monohydrate were determined using a Mettler DSC820 differential scanning calorimeter operated at a N2 gas flow of 200 mL/min in a temperature range from 50-170 °C at a heating rate of 4 K/min. Results and Discussion Strategy. ATR FTIR spectra of aqueous citric acid solutions are given in Figure 2. The changes in intensity of infrared transmission bands of citric acid (2600 cm-1, HOH scissoring, and 1200 cm-1, CO stretching) and water (3300 cm-1, OH stretching) with increasing concentration of citric acid in water are clearly evident. Spectra recorded at 30, 50, and 70 °C resemble those scanned at 10 °C given in Figure 2. When the ratio of the broad water band at 3279 cm-1 with the citric acid band at wavenumber 2611 cm-1 was taken,
ATR FTIR Studies on Citric Acid Nucleation
J. Phys. Chem. B, Vol. 105, No. 43, 2001 10725
Figure 3. Dependence of the depth of penetration, dp, into a sample of 30% (w/w) citric acid anhydrate in water on the wavenumber. This was calculated for a ZnSe internal reflection element with an angle of incidence of 45° at a temperature of 20 °C.
Figure 5. Calibration of RT at 10, 30, 50, and 70 °C. RT is the transmittance ratio of the transmission band at 3279 cm-1 to that at 2611 cm-1.
Figure 4. Calibration parameter RT for spectra taken of citric acidwater slurries at 25 °C for different solid densities. The RT values are constant thus indicating that there is no influence of the solid state on the ATR FTIR spectra taken.
instrumental and experimental deviations were eliminated and the calibration parameter RT was defined:10
transmittance of the water band at 3279 cm-1 RT ) transmittance of the citric acid band at 2611 cm-1 (1) This transmittance ratio is a function of concentration and temperature, which means it implicitly reflects crystallization variables. In addition, the exponential gain in RT given by the Lambert-Beer Law18 provides more sensitivity for the measurement of supersaturation than standard concentrationbased approaches. Influence of Solids. To obtain nonerratic concentration data from ATR FTIR measurements, it is critical that any solid particles produced during crystallization have no influence on the recorded liquid-phase concentration data. Figure 3 shows the depth of penetration, dp, as a function of wavenumber for an aqueous citric acid solution (concentration of 30% (w/w) citric acid anhydrate) at 20 °C as calculated according to literature.19 The refractive index of the aqueous citric acid solution20 was taken to be n2 ) 1.3744, the refractive index of the internal reflection element ZnSe13 was taken to be n1 ) 2.4, and the angle of incidence was taken to be 45° as used in the experimental setup. From this, it can be seen that the ATR FTIR measurement of RT probes around 0.7 µm into the sample solution. ATR FTIR experiments showed that undissolved particles in a crystal slurry did not influence the determination of the liquid-phase concentration of the solute. This is clearly demonstrated in Figure 4, which shows the calibration parameter RT for saturated solutions of citric acid in water at 25 °C in equilibrium with varying suspended solid contents, thus con-
Figure 6. Temperature dependency of the parameters a and b of the equation RT ) a ebc.
firming that the solution concentration was constant for all solid-liquid slurry densities. In addition, infrared bands in solid-state ATR FTIR spectra generally differ from those of the liquid-state spectra, as they show much narrower bandwidths and shifts in position reflecting the higher order of organization in the solid state.19 Features reflective of the solid state were not observed in any spectra accumulated in any of the crystallization experiments (slurry densities up to 2.25 kg of citric acid/kg of water) consistent with the absence of any crystal growth on the surface of the ZnSe ATR probe. Calibration. The plot of RT versus concentration of citric acid in water is shown in Figure 5. The temperature dependency of RT is expected reflecting inter- and intramolecular interactions such as hydrogen bonding. Figure 5 confirms the exponential gain in RT predicted by the Lambert-Beer Law.10,18 To measure supersaturation on-line, a three-variable grid is necessary to calibrate the measurements. The transmittance ratio RT was assumed to be a function of temperature and concentration as follows:
RT ) a ebc
(2)
where a and b are functions of temperature and c is the solute concentration. The result of modeling the temperature dependency of the parameter RT as polynomial curves for a and b as a function of temperature is presented in Figure 6. This calibration method applied to ATR FTIR spectroscopy enables, for the first time, a methodology for the real-time data acquisition of the solution concentration during the crystallization process.
10726 J. Phys. Chem. B, Vol. 105, No. 43, 2001
Figure 7. Solubility-supersolubility diagram of citric acid in water. The dissolution temperatures of three differently concentrated aqueous citric acid solutions confirm the solubility data measured by ATR FTIR using the calibration parameter RT. Through these solutions being slowly cooled, the metastable zone (MSZ) limit of the anhydrous form was extracted.
Figure 8. XRD pattern of citric acid crystals from a slurry at 30 °C (solubility measurement) compared to the theoretical pattern of citric acid monohydrate calculated from structural data.32
Solubility-Supersolubility Diagram of Citric Acid in Water. Literature data on the solubility of citric acid in water are rather limited to single-concentration-point measurements.20-26 In good agreement with unpublished data by Mersmann et al.,21 it was found that below 34 °C the monohydrous form of citric acid has a lower solubility than the anhydrous form and is the thermodynamically stable form in the temperature range below 34 °C (Figure 7). At temperatures above 34 °C, the anhydrous form has a lower solubility and is the stable form in this temperature range. It was found that the crystals sampled at 40 °C and higher temperatures had transformed to anhydrous citric acid in aqueous solution (Figures 8 and 9). This was confirmed via DSC measurements determining the melting point of citric acid anhydrate to be 153 °C, whereas the dehydration onset of the monohydrate was found to be 71 °C. Combining on-line XRD and ATR FTIR monitoring of temperature-induced crystallization experiments of highly concentrated aqueous citric acid solutions showed that under the applied process conditions the anhydrate was formed (Figure 10). Hence, the metastable zone (MSZ) limit of citric acid
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Figure 9. XRD pattern of citric acid crystals from a slurry at 40 °C (solubility measurement) compared to the theoretical pattern of citric acid anhydrate calculated from structural data.33 This shows that citric acid monohydrate transforms in the solvent to the more stable anhydrous form above 34 °C.
Figure 10. On-line XRD pattern taken during crystallisation of citric acid from water (cooling rate of 0.05 K/min, concentration of 3717.3 g of anhydrate/kg of water) compared to the theoretical pattern of citric acid anhydrate and monohydrate calculated from structural data.32,33 As can be seen, the crystalline phase formed is anhydrous.
anhydrate was extracted from the ATR FTIR data, which led to the derivation of a solubility-supersolubility diagram for citric acid in water (Figure 7). From this can be seen that an aqueous solution saturated at temperatures between 60 and 90 °C, if it is cooled, will reach the MSZ limit of the anhydrate first, before reaching the MSZ limit of the monohydrate, thus explaining the observed crystallization of the anhydrate found in the slow-cooling experiments. When an aqueous solution of citric acid (80.75% (w/w) monohydrate) was crash-cooled to a set temperature beyond the MSZ limit of the monohydrate (isothermal experiment), crystallization of the monohydrate was found to take place. These results lead to the estimation of the MSZ limit of the monohydrate as given in Figure 7. Supersaturation Variation during Isothermal and Temperature-Programmed Experiments. The supersaturation profile, temperature, and optical transmittance of the solution during an isothermal crystallization experiment are shown in Figure 11. A decrease in the optical transmittance of the solution was detected after an induction time of 43.5 min at a supersaturation
ATR FTIR Studies on Citric Acid Nucleation
Figure 11. Supersaturation curve (S) of citric acid monohydrate in water during a crash-cool-induced crystallization process (concentration of 80.75% (w/w) monohydrate). Also shown is the turbidometric change of the solution transmittance and temperature. A decrease in optical transmittance of the solution is detected after an induction time of 43.5 min at a supersaturation value of 1.59; a decrease in solution concentration is only detected after 55 min.
of 1.59, followed by a depletion of solution concentration as measured by ATR FTIR after 55 min, thus indicating an intermediate state within the mother liquor prior to nucleation. Figure 12 shows the change of supersaturation and solution transmittance during a slow-cooling crystallization process of citric acid anhydrate in water, determined in situ by ATR FTIR spectroscopy. The temperature program for the slow cooling crystallization process was initiated at a temperature of 70 °C at a cooling rate of 0.05 K/min (A in Figure 12). We note, with interest, the cross-correlation between the turbidity and ATR FTIR data close to the crystallization onset point (B in Figure 12), which is shown in enlarged form in Figure 13. From this, we can see that the onset point to the overall process, as evidenced through the rapid decrease in optical transmittance, appears to precede the depletion of solution concentration due to crystal growth measured using the ATR FTIR data. The critical levels of supersaturation for the turbidity rise and the nucleation onset during the temperature-programmed crystallization experiment were found to be 1.384 and 1.395, respectively. Also of interest is the apparent loop in the turbiditytemperature profile (C1 in Figure 12) showing a temperature increase of 2.4 °C, which directly maps out onto the ATR FTIR
J. Phys. Chem. B, Vol. 105, No. 43, 2001 10727
Figure 13. Enlargement of region B from Figure 12. Cross-correlation of supersaturation (ATR FTIR data) and solution transmittance (turbidometric data) of citric acid anhydrate during a temperature-induced crystallization process (cooling rate of 0.05 K/min, concentration of 75% (w/w) monohydrate) showing the critical supersaturation for the decrease of solution transmittance (1.384) and subsequent concentration (1.395).
profile (C2 in Figure 12) and which would be consistent with the release of the enthalpy of crystallization. Within the growth stage, the supersaturation instantly drops to equilibrium and then rises again to a value of 1.11, perhaps indicating dissolution of fines (D in Figure 12). This is not an unexpected occurance near the thermostated walls of the reactor, as the initial crystal size is very small reflecting the high supersaturation at the nucleation onset. Finally, supersaturation goes toward equilibrium until the solid phase dissolves again at 61 °C during the heating cycle (E in Figure 12). The two distinct onset points for the temperature-programmed and isothermal crystallization processes as monitored, respectively, by optical turbidometric measurements and ATR FTIR spectroscopy are interesting. The onset of optical turbidity can only be explained by the formation of either clusters or liquid droplets of at least 0.5 µm in size (wavelength of light used for the turbidometric measurement) within the mother liquor. The lack of supersaturation depletion at the onset point to the overall process as evidenced through an increase in turbidity
Figure 12. Supersaturation curve of citric acid anhydrate in water during a temperature-programmed crystallization process (cooling rate of 0.05 K/min, concentration of 75% (w/w) monohydrate). Also shown is the turbidometric change of the solution transmittance.
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Figure 14. Micrograph of citric acid crystals recrystallized at 6 °C (concentration 75% (w/w), cooling rate 0.05 K/min) showing the prismatic morphology.
and the lack of any other compounds that could precipitate provide compelling evidence in support of phase separation within the heavily supersaturated mother liquor. This formation of a microscale dispersion could be associated with a thermodynamic relaxation process taking place within the highly concentrated mother phase, perhaps via the formation of some kind of colloidal structure within this highly supersaturated phase. This might involve phase separation into a highly concentrated dispersed phase stabilized within a less concentrated continuous phase. Such observations (oiling-out), which are commonplace in large-scale industrial crystallization reactions for products that poorly nucleate, e.g., pharmaceuticals and surfactants,27 would be consistent with the nucleation stage being initiated at the interfacial boundary between the dispersed
Groen and Roberts and continuous phase. It has been found that, for this kind of emulsification process prior to crystallization, the cloudiness of the solution as measured by optical turbidometric methods during the emulsification step appears to be higher than during the crystallization step.28 This would be consistent with the initial increase in cloudiness prior to the supersaturation drop as apparent in the turbidity-temperature profile (C1 in Figure 12). The temperature and time differences between the two onset points for the isothermal crystallization experiment of 11.5 min and for the temperature-programmed crystallization run of 24.8 min preclude the observed effects being due to the sensitivity difference of the turbidometric and ATR FTIR measurements. As to the onset of turbidity, no obvious change in the ATR FTIR data was found. This would be consistent with liquidliquid phase separation associated with an actual difference in concentration between the dispersed and the continuous phase of about 1% (w/w) to facilitate nucleation, i.e., the peak-topeak noise of the ATR FTIR signal. Examination of the micrograph of the recrystallized citric acid crystals (Figure 14) reveals a prismatic morphology thus making it difficult to distinguish whether the crystals grew from one single nucleation site within the mother liquor. Such an observation would be easier to demonstrate if the observed crystal habit was, for example, needlelike, for which one could recognize the spherulitic growth form of crystal bundles confirming nucleation at an interfacial phase boundary. Clearly the results, while interesting, demand further study to quantify the exact nature of the observed dispersion behavior and its
Figure 15. Crystal packing of citric acid anhydrate, view along the b axis, showing the centrosymmetric dimers forming eight-membered ring structures (A) and the helical arrangement of the molecules due to intermolecular hydrogen bonding between two of the carboxylic groups of each molecule (B).
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J. Phys. Chem. B, Vol. 105, No. 43, 2001 10729
Figure 16. Crystal packing of citric acid monohydrate, view along the b axis and a axis, showing a linear arrangement of the molecules facilitated by water molecules bridging between the citric acid chains along the b axis.
mechanism of formation. However, freeze-fractured SEM investigations on the microstructure of citric acid solutions have shown that cluster networks of several microns are formed in supersaturated solutions resembling an emulsion-like solution structure, which finally rearranges into an ordered crystal structure associated with a turbidity drop.29-31 This would be consistent with our observations; however, according to our data, the network structures seem to be homogeneously distributed throughout the solutions as no increase in noise in the ATR FTIR data can be detected at the onset of turbidity.
Phase Transformation Behavior. The recrystallized citric acid anhydrate slurry was kept at 4 °C for 14 days and then analyzed by XRD. The crystals were found to have transformed to the monohydrate. Dry anhydrous crystals were not found to transform to the monohydrate when kept at 4 °C for the same length of time. These two observations are consistent with a solvent-mediated transformation between the two forms taking place. Examination of the crystal structure for citric acid anhydrate and monohydrate (monohydrate, P212121, orthorhombic;32 an-
10730 J. Phys. Chem. B, Vol. 105, No. 43, 2001 hydrate, P21/a, monoclinic)33 reveals that these two structures are not related through any group or subgroup symmetry as would be consistent with an undisruptive solid-solid phase transition. Visualization via molecular modeling (Figures 15 and 16) of the two structures supports this initial hypothesis. In the centrosymmetric anhydrate (Figure 15), the acid molecules form right-handed helices along the b axis (B in Figure 15) and dimers related by inversion (A in Figure 15). Two of the carboxylic groups of each molecule participate in two adjacent helical arrangements. This is stabilized by two intramolecular hydrogen bonds between the -OH and one -CdO end group and the -OH and the -CdO middle group. This -OH group also gives rise to a third intermolecular hydrogen bond with the -O- of the carboxylic end group of the adjacent molecule. As a result, the carboxylic group of the dimers not participating in the helices form eight-membered rings parallel to the {101} plane (A in Figure 15). Thus, hydration appears to proceed via the insertion of water molecules, which breaks the hydrogen-bonded helices. The water molecules facilitate a linear arrangement by forming bridges between the citric acid chains along the b axis. The result is a structure dominated by noncentric strings of hydrogenbonded citric acid molecules along the b axis and hydrogen bonds facilitated by the water molecules along the c axis (Figure 16). No such helical structure is observed in the monohydrate. Conclusions Examination of the solubility, supersolubility, and therewith phase diagram of the anhydrate and monohydrate phases of citric acid in water using ATR FTIR spectroscopy reveals a very wide metastable zone width (55 °C for a cooling rate of 0.05 K/min). In situ measurements of the solution supersaturation using ATR FTIR spectroscopy and the pseudomorphology of the produced crystals using XRD during temperature-induced crystallization and dissolution processes reveal the anhydrate phase being crystallized by temperature-programmed crystallization runs and the monohydrate phase being formed by isothermal batch crystallization experiments. Visualization of the crystal structures of the anhydrate and monohydrate form provides a detailed understanding of the interconversion between the anhydrous and monohydrous form of citric acid when crystallized from aqueous solution. ATR FTIR spectroscopy in combination with optical turbidometric measurements provides direct experimental evidence for a crystallization mechanism involving nucleation at the phase boundaries of a microscale dispersion formed via liquid-liquid phase separation within the highly supersaturated mother liquor. On-line ATR FTIR spectroscopy has revealed new physical insights into molecular scale processes prior to and during nucleation and crystal growth. This advance is extremely promising given the current interest in understanding, predicting, and controlling the batch manufacture of organic fine chemicals such as pharmaceuticals. Acknowledgment. This work, which forms part of the Ph.D. work of one of us (H.G.), was carried out as part of the Chemicals Behaving Badly project financially supported by Grant GR/L/23055 provided by the U.K.’s Engineering and Physical Science Research Council (EPSRC) together with an industrial consortium including Astra Charnwood, BASF, Glaxo Wellcome, ICI, Malvern Instruments, Pfizer, SmithKline Beecham, and Zeneca. We also appreciate the continuing support from Lesley Ford (project coordinator) and the Chemicals Behaving Badly project team as well as Elena Ferrari, who provided help with the molecular modeling work.
Groen and Roberts References and Notes (1) Larson, M. A.; Garside, J. Chem. Eng. Sci. 1986, 41, 1285-1289. (2) Groen, H., Hammond, R. B., Lai, X., Mougin, P., Roberts, K. J., Savelli, N., Thomas, A., White, G., Williams, H. L., Wilkinson, D., Baker, M., Dale, D., Erk, P., Latham, D., Merrifield, D., Oliver, R., Roberts, D., Wood, W., Ford, L., Hoyle, W., Eds.; Pilot Plants and Scale-up of Chemical Processes II; Special Publication 236; Royal Society of Chemistry: Cambridge, 1999; pp 40-61. (3) Cao, Z.; Groen, H.; Hammond, R. B.; Lai, X.; Liang, K.; Mougin, P.; Roberts, K. J.; Savelli, N.; Thomas, A.; White, G.; Wilkinson, D.; Baker, M.; Dale, D.; Erk, P.; Latham, D.; Merrifield, D.; Oliver, R.; Roberts, D.; Wood, W.; Ford, L. Presented at the 14th International Symposium on Industrial Crystallization and 6th International Workshop on Crystal Growth of Organic Materials (CGOM-6), Cambridge, U.K., 1999; Paper 171, IChemE ISBN 0 85295 424 7. (4) Cao, Z.; Groen, H.; Hammond, R. B.; Lai, X.; Liang, K.; Mougin, P.; Roberts, K. J.; Savelli, N.; Thomas, A.; White, G.; Wilkinson, D.; Baker, M.; Dale, D.; Erk, P.; Latham, D.; Merrifield, D.; Oliver, R.; Roberts, D.; Wood, W.; Ford, L. J. Mol. Cryst. Liq. Cryst. 2001, 256, 273-288. (5) Dorokhov, I. N.; Gordeev, L. S.; Vinarov, A. Yu.; Leont’eva, L. V.; Bocharova, Yu. V. Theor. Found. Chem. Eng. 1997, 31, 224-231. (6) Mullin, J. W.; Leci, C. L. Philos. Mag. 1979, 19, 1075-1077. (7) Ueda, M.; Hirokawa, N.; Harano, Y.; Moritoki, M.; Ohgaki, K. J. Cryst. Growth 1995, 156, 261-266. (8) Mullin, J. W.; Leci, C. L. J. Cryst. Growth 1968, 5, 75-76. (9) Groen, H.; Roberts, K. J. Presented at the 14th International Symposium on Industrial Crystallization and 6th International Workshop on Crystal Growth of Organic Materials (CGOM-6), Cambridge, U.K., 1999; Paper 77, IChemE ISBN 0 85295 424 7. (10) Dunuwila, D. D.; Carroll, L. B.; Berglund, K. A. J. Cryst. Growth 1994, 137, 561-568. (11) Dunuwila, D. D.; Berglund, K. A. J. Cryst. Growth 1997, 179, 185-193. (12) Lewiner, F.; Klein, J. P.; Fe´votte, G. Chem. Eng. Sci. 2001, 56, 2069-2084. (13) Mirabella, F. M., Jr. Internal Reflection Spectroscopy, 1st ed.; Dekker: New York, 1993; Chapter 2. (14) MacCalman, M. L.; Roberts, K. J.; Kerr, C.; Hendriksen, B. J. Appl. Crystallogr. 1995, 28, 620-623. (15) MacCalman, M. L.; Roberts, K. J.; Hendriksen, B. Proc. World Congr. Chem. Eng., 5th 1996, 698-703. (16) MacCalman, M. L. Studies of the crystallisation of some pharmaceutically important materials in relation to polymorphic structural stability, Ph.D. Thesis, University of Strathclyde, Glasgow, Scotland, 1996. (17) Hastings, S. Application of in-situ X-ray diffraction to the examination of the on-line processing of organic fine chemical products, Ph.D. Thesis, Heriot-Watt University, Edinburgh, Scotland, 2000. (18) Smith, A. L. Applied Infrared Spectroscopy, 1st ed.; John Wiley & Sons Inc.: New York, 1979; Chapter 4. (19) Stuart, B.; George, W. O.; McIntyre, P. S. Modern Infrared Spectroscopy, 1st ed.; John Wiley & Sons Inc.: New York, 1996; Chapter 3. (20) Weast, R. C. Handbook of Chemistry and Physics, 57th ed.; CRC Press: Cleveland, OH, 1976. (21) Mersmann, A. et al. Private communications. (22) Landolt, H., Boernstein, R., Eucken, A., Eds. Zahlenwerte und Funktionen aus Physik, Chemie, Astronomie, Geophysik, Technik, 6. Aufl.; Springer: Berlin, Goettingen, Heidelberg, 1962; Band II/2b. (23) D’Ans, J.; Lax, E. Taschenbuch fu¨ r Chemiker und Physiker, 1. Aufl.; Springer: Berlin, Heidelberg, 1967; Band 1/2. (24) D’Ans, J. Die Lo¨ sungsgleichgewichte der Systeme der Salze ozeanischer Salzablagerungen; Kali-Forschungs-Anst. GmbH: Berlin. Reprinted on demand, authorised facs. d. Ausg. Berlin; Ann Arbor, Michigan; University Microfilms Internat.: London, 1982. (25) Mullin, J. W. Crystallization, 3rd ed.; Butterworth-Heinemann: Oxford, 1997; Chapter 3. (26) Broul, M.; Ny´vlt, J.; Soehnel, O. Solubility in inorganic twocomponent systems; Elsevier Scientific Publishing Company: Amsterdam, Oxford, New York, 1981. (27) Wood, W. Private communications. (28) Maeda, K.; Aoyama, Y.; Fukui, K.; Hirota, S. J. Colloid Interface Sci. 2001, 234, 217-222. (29) Ueda, M.; Hirokawa, N.; Harano, Y.; Moritoki, M.; Ohgaki, K. J. Cryst. Growth 1995, 156, 261-266. (30) Ohgaki, K.; Makihara, Y.; Morishita, M.; Ueda, M.; Hirokawa, N. Chem. Eng. Sci. 1991, 46, 3283. (31) Ohgaki, K.; Hirokawa, N.; Ueda, M. Chem. Eng. Sci. 1992, 47, 1819. (32) Roelofsen, G.; Kanters, J. A. Cryst. Struct. Commun. 1972, 1, 2326. (33) Glusker, J. P.; Minkin, J. A.; Patterson, A. L. Acta Crystallogr. 1969, B25, 1066-1072.
