Study of the Crystallization of Mandelic Acid in Water Using in Situ ATR-IR Spectroscopy Profir,†
Veronica M. Erik Åke C. Rasmuson*,†
Furusjo¨,‡
Lars-Go¨ran
Danielsson,‡
and
CRYSTAL GROWTH & DESIGN 2002 VOL. 2, NO. 4 273-279
Department of Chemical Engineering and Technology, and Division of Analytical Chemistry, Department of Chemistry, Royal Institute of Technology, SE-100 44 Stockholm, Sweden Received April 16, 2002;
Revised Manuscript Received May 17, 2002
ABSTRACT: Different aspects related to the separation of enantiomers of mandelic acid by direct crystallization are explored. Solubility, nucleation, and solid-phase transformation in aqueous solutions are investigated. Results show that a metastable conglomerate can be formed for a substance known to appear as a racemic compound. After a time-lag, the conglomerate transforms into the stable racemic compound. The time-lag ranges from a few minutes to 8 h depending on the operation conditions. The time-lag decreases at increasing concentration/temperature and in the presence of micrometer-sized particles. In situ attenuated total reflectance infrared (ATR-IR) spectroscopy and a partial least squares (PLS) calibration model are used to record the concentration of dissolved mandelic acid. Since no sampling is required and the calibration set, which is used on both racemic and enantiomerically pure solutions, can be built using the cheaper racemate, the technique should be of particular interest in applications involving chiral substances. Introduction Stereochemical purity is of rapidly growing importance in the development of new drugs. In 1990, 44% of the drugs on the market were nonchiral, 25% were racemates, and 31% were pure enantiomers.1 Since then, these numbers have dramatically changed both in favor of chiral over achiral compounds, and in favor of pure enantiomers over racemates. In the early stages of the product development, any method of producing the enantiomers in a pure form might be employed. However, when an enantiomerically pure product is introduced on the market, cost-effective full-scale production methods are required. Today, the most costeffective methods of producing pure enantiomers are usually methods where synthetically produced racemates are separated. The classical resolution via the formation of diastereomeric salts is the most commonly used method in industry today.2 However, a possibly more cost-effective resolution method is separation by direct crystallization.3 In this process, the crystallization conditions are adjusted so that pure crystalline material of either one of the enantiomers is crystallized directly from the racemic solution. The method can only be used when a conglomerate is formed. When crystallizing from a racemic solution, three different solid forms can be obtained: a conglomerate, a racemic compound, or a solid solution. A conglomerate is a physical mixture of crystals where each crystal is enantiomerically pure. In a racemic compound, equal amounts of the enantiomers are arranged in an alternating pattern in the unit cell, while in a solid solution, this arrangement is random. According to the literature, only 10% of all chiral organic compounds form conglomerates, while 89% are believed * To whom correspondence should be addressed. E-mail: rasmuson@ ket.kth.se. † Department of Chemical Engineering and Technology. ‡ Division of Analytical Chemistry.
to form a racemic compound.3 However, quite often the experimental conditions are not clearly reported, and it is difficult to elucidate to what extent the result reflects the thermodynamics of the system or whether kinetic limitations play a role. We therefore believe that the actual possible applicability of separation by direct crystallization might be broader than commonly expected. In this paper, we study the crystallization of racemic mandelic acid. Mandelic acid is used as a reagent in classical resolutions, and is reported to form a racemic compound upon crystallization of the racemic mixture. The goal of the work is to establish whether a conglomerate can be formed under certain conditions. The solubility of enantiomerically pure and racemic mandelic acid is measured, and the nucleation and transformation of the racemate are studied. The work also includes applying in situ attenuated total reflectance infrared (ATR-IR) spectroscopy combined with a multivariate partial least squares (PLS) calibration to measure the solute concentration. The in situ recording is of particular value in studies of kinetics, and in general for concentration monitoring in crystallization processes. The intermolecular interactions between like and opposite enantiomers are different, which is reflected in the properties of the solid racemates as different arrangements in the crystal lattices, different physical properties such as melting point, heat of fusion, and solubility, different X-ray diffraction pattern, IR spectra, etc. A rule of thumb for distinguishing between the solid racemates is the double solubility rule, which states that a conglomerate has a solubility that is double the solubility of the pure enantiomer in ideal solutions of nondissociated organic compounds.3 Another method of identifying solid racemates is by using IR spectroscopy. The solid-state IR spectra of a pure enantiomer and a
10.1021/cg025519g CCC: $22.00 © 2002 American Chemical Society Published on Web 06/06/2002
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Mandelic Acid
racemate will be identical if the racemate is a conglomerate. The solid-state IR spectrum of a racemic compound is most often very different.3,4 In solution, it is not possible to differentiate between two enantiomers by molecular spectroscopy as long as the solvent is achiral, and hence only the total concentration can be measured. Quantitative determination of the total concentration by IR spectroscopy is however not simple, although the applications are increasing in number.5 The solvent-solute interactions have a strong impact on IR spectra and can be observed as absorption peak broadening and peak shifts. These effects are especially strong in systems with hydrogen bonding, and they are highly temperature dependent.6,7 The difficulties can often be overcome by the use of multivariate calibration methods, such as PLS that use absorbance at several wavelengths for the calibration and do not depend on selective measurements.8-10 When using the ATR technique, the IR radiation is totally internally reflected within an element that is in contact with the sample. During the reflection at the interface, the radiation interacts with the medium and absorption corresponding to an optical path of a few micrometers is obtained.11,12 Several examples of reaction monitoring by in situ ATR-IR have recently been presented.13-15 In situ ATR-IR has been used with univariate calibration methods in batch cooling crystallizations,16,17 and in combination with multivariate calibration in a pH swing crystallization.18 In case of crystallization processes, the crystals do not usually influence the measurements.13 Experimental Section The experimental work is focused on the determination of solubility relationships, nucleation of different solid phases, and phase transformation. ATR-IR is applied to record the concentration in solution, to record events of nucleation, and to identify the structure of the nucleated phase. It is further applied to record the dissolution of each respective solid phase and hence provide information on solid-phase stability. Detailed attention is devoted to calibration and to accuracy in concentration determination. Chemicals and Apparatus. Pure, distilled, and deionized water was used as solvent in all experiments and (()-, (+)-, and (-)-mandelic acid (Scheme 1) were purchased from SigmaAldrich with a purity of 99% for the racemate and 99% ee for the pure enantiomers. The solid-state IR spectra of the enantiomerically pure and racemic mandelic acid are recorded by pressing tablets of small amounts of substance in a bulk of KBr powder and subjecting these tablets to an IR measurement with a Mattson FTIR. The solubility experiments performed using gravimetric analysis are performed in 100-mL closed Erlemeyer flasks, agitated by magnetic stirrer, and kept in a thermostatic bath with an accuracy of ( 0.1 °C. All other experiments are performed in a 100-mL glass jacketed crystallizer equipped with a probe for IR measurements. In the first series of experiments, a magnetic stirrer is used as an impeller. A pitched blade turbine type impeller with a diameter of 35 mm
Profir et al. is used in all other experiments. The temperature in the crystallizer is controlled by a Pt100 sensor connected to a programmable Julabo FP50-HP thermostatic bath, with an accuracy of ( 0.01 °C and is also recorded by a Pt100 sensor connected to the spectroscopic instrument described below. Both Pt100 sensors and the bath are calibrated using calibrated mercury precision thermometers from Thermo-Schneider, Wertheim, Germany (( 0.01 °C at 0-30 °C). In situ spectroscopic measurements in the range 650-4000 cm-1 are performed using a ReactIR 1000 Fourier TransformIR instrument (Applied Systems, Millersville, MD) equipped with a DiComp ATR probe for in situ measurements. Spectral resolution is approximately 4 cm-1, giving a total of 1737 data points per spectrum. All spectra are averages of 64 scans. With these settings, a spectrum is collected approximately every 40 s. Air background is used. All calculations are performed on PC running Matlab 5.3 (Mathworks, Natick, MA) and the PLS Toolbox for Matlab (Eigenvector Research, Manson, WA). Experimental Procedures. The solubility of enantiomerically pure and racemic mandelic acid in water is measured between 1 and 40 °C. Two methods are used: gravimetry and in situ ATR-IR spectroscopy. In the gravimetric analysis, all solutions were equilibrated for at least 48 h at constant temperature and under agitation. Three independent aliquots were taken from each flask and filtered through a 0.2 µm membrane filter into vials. Each sample was weighed before and after drying under vacuum at room temperature. The solubility measurements using IR spectroscopy were performed by evaluating the mother liquor concentration of slurries subjected to slow-temperature ramps.19 For this purpose, racemic and enantiomerically pure mandelic acid slurries were equilibrated for at least 22 h and then heated at +1 or +3 °C/h until a selected high temperature was reached without dissolving all crystals in the slurry. After the slurries were kept at the high temperature for 1 h or overnight, they were subjected to a slow cooling rate (-1 or -3 °C/h) until a selected low temperature was reached. For practical reasons, the temperature ramps have been measured in five independent segments: two segments for racemic mandelic acid (from 1 to 15 °C at 1 °C/h and from 15 to 33 °C at 3 °C/h) and three segments for L-(+)-mandelic acid (from 1 to 15 °C at 1 °C/h, from 15 to 30 °C at 1 °C/h and from 30 to 40 °C at 3 °C/h). To test the applicability of the ATR-IR technique for in situ monitoring of the mother liquor concentration in crystallization processes, seeded batch cooling crystallizations were performed for both the enantiomerically pure and the racemic mandelic acid. The crystallization of the racemate was performed at 312 rpm, by cooling a filtered 300 g/kg of water solution to 28.5 °C, achieving a supersaturation ratio of 1.11. Seeds of the commercially available racemate (1.0 g of 0.45-0.20 mm size) were added and after 30 min, a cooling profile of -3 °C/h was applied until the temperature reached 20 °C. In the seeded batch cooling crystallization of the enantiomerically pure mandelic acid, a filtered 300 g/kg of water solution of L-(+)mandelic acid was cooled to 40 °C, achieving a supersaturation ratio of 1.06. A total of 1.0 g of L-(+)-mandelic acid seeds of 0.224-0.16 mm size was added, and a cooling profile of -6 °C/h was applied directly after seeding until the temperature reached 10 °C. During both crystallizations, IR spectra were continuously recorded, and from these, the mother liquor concentration was evaluated. Three series of unseeded crystallization experiments were performed investigating the nucleation and the transformation behavior of the crystallized mandelic acid racemate. In the first series, in addition to recording the nucleation and dissolution temperature of racemic mandelic acid, IR spectra necessary for building the calibration model were collected. Thirteen racemic solutions with known concentrations between 25 and 700 g/kg of water at different temperatures between 1 and 70 °C were used. Each solution was heated to 60 or 70 °C, temperatures that are higher than the highest sample temperature at which the calibration is applied. At such high temperatures, the mandelic acid was completely dissolved in all samples. Each sample was then subjected to a constant
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Table 1. Operating Conditions for the Study of Nucleation and Transformation of Racemic Mandelic Acid cooling rate [°C/min]
heating rate [°C/min]
stirring rate [rpm]
run
-0.1 (low) -0.5 (high) -0.5 (high) -0.5 (high) -0.5 (high)
+0.5 (low) +0.5 (low) +0.5 (low) ca. 2 (high) ca. 2 (high)
150 (high) 150 (high) stop, then 150 (low) 150 (high) stop, then 150 (low)
1 2 3 4 5
cooling rate of -0.5 °C/min, while IR spectra of the mixture were acquired once every minute. The cooling was stopped upon nucleation, and, instead, heating at a rate of +0.5 °C/ min was applied until the formed crystals dissolved completely. For the 200 and 400 g/kg of water solutions, the applied heating rate was +2 °C/min. The IR spectra collected prior to nucleation and after the redissolution are used in the calibration set. In the second series of unseeded experiments, the influence of the cooling, heating, and stirring rates on the nucleation and dissolution of racemic mandelic acid was investigated. Solutions of initial concentration of 400 g/kg of water were used in all runs with operating parameters as shown in Table 1. All solutions were filtered by a 1.2 µm membrane filter at 60 °C before being introduced into the crystallizer. The solutions were held at 60 °C for at least 30 min and then cooled to 45 °C, well above the saturation temperature. After the given cooling rate was applied, the temperature at which nucleation occurs was recorded. For the high stirring rate, the heating was applied immediately after nucleation, while for the low rate, the stirring and cooling were interrupted for approximately 10 min allowing ripening of the crystals formed in a stationary solution at the nucleation temperature. A fraction of the crystals formed were sampled off-line after nucleation, then filtered and dried under vacuum at room temperature. The temperature at which the whole crystalline mass dissolves at the given heating rate was also recorded. The runs 2 and 4 in Table 1 are repeated for a higher (600 g/kg of water), and a lower (200 g/kg of water), initial solution concentration. In the third series of unseeded experiments, several attempts to study the dissolution behavior of mandelic acid conglomerate crystals were performed at different temperatures. In a total of five runs, conglomerate crystals were either added as equal amounts of (-)- and (+)-mandelic acid to, with respect to the racemic compound, slightly super- or undersaturated solutions or were formed directly in solutions by primary nucleation according to the procedures used in the previous experiments. The crystals were dissolved either by heating or by adding pure solvent while IR spectra were continuously recorded. Calibration. Partial least squares (PLS) regression was used for estimating concentrations from IR spectra. Algorithms can be found in the literature.8-10 The calibration set consists of 374 spectra collected from racemic solutions with the concentration-temperature distribution show in Figure 1. The first derivative of spectra in the 1880-1010 cm-1 region is used. The interval includes the prominent absorption of mandelic acid such as the carbonyl stretching at approximately 1730 cm-1. Exclusion of the O-H stretching region at 30003600 cm-1, where the water absorption is very strong and displays large frequency shifts with temperature, enhances the predictive ability. Because the water absorption is mostly broader than the mandelic acid absorption, the use of derivative spectra enhances the signals from mandelic acid as compared to those from water. It should be noted, however, that it is unlikely that the regression only reflects the absorption of mandelic acid; refractive index effects or interactions with the solvent might also be correlated with the mandelic acid concentration and thus useful for calibration. All concentrations given in this paper are in grams of mandelic acid per kilogram of water. However, if used in the calibration, a clear nonlinear relationship between spectra and
Figure 1. The concentration-temperature distribution of the 374 spectra used in the calibration set. There are two independent samples each for the concentration levels of 50 and 100 g/kg of water. concentration appears, since Beer’s law states that absorbance is proportional to concentration expressed in mass (or moles)/ volume unit. Therefore in the calibration, the mass units, cm M, are recalculated into volume unit concentrations, cvM, by the approximate formula:
cvM )
cm M m 100 cM + FW FM
After this transformation, there are no signs of nonlinearity, indicating that the approximation is adequate for our purposes. After prediction, all concentrations are transformed to g/kg of water. The calibration set used in this work does not contain independent sample spectra because of the way they were collected, and, therefore, a segmented cross validation scheme is used to optimize the model and to obtain a realistic estimate of the prediction error. All spectra measured on each particular mixture are used in one validation segment, giving 13 segments of approximately 30 spectra each (see Figure 1), reducing the risk for overfit caused by effects that are common for each sample, such as mistakes in sample preparation or spectral background artifacts. This approach yields a PLS calibration model with five components and an estimated prediction error, measured as the root-mean-squared error of prediction (RMSEP)9 of 3.8 g/kg of water, corresponding to approximately 1% relative error at the mean concentration. It is our belief that this can be further reduced by the use of more calibration samples if required. Figure 2 shows predicted (by segmented cross-validation) versus experimental concentrations for the calibration set. Full (leave one spectrum out) cross-validation yields a lower and over-optimistic estimate of prediction error. We have used two methods to automatically detect outliers such as spectra influenced by crystals, in predicting the concentration of the samples: Hooteling’s20 T2 and the magnitude of the spectral residuals.9 If either or both of these are higher than what can be expected from the calibration samples, the predictions are considered to be less accurate (see Figures 5 and 9). Interferences in spectra due to temperature effects are accounted for by having the calibration set span the temperature interval used (see Figure 1) and allowing an increased model complexity (i.e., number of PLS components) as illustrated in Figure 3. From this figure, it is clear that the temperature effect on predictions is large if too few PLS components are used. The use of five components in the calibration model almost completely removes the temperature dependence.
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Figure 2. Predicted vs prepared concentrations of mandelic acid for the five-component PLS calibration model. All predictions are from segmented cross validation as discussed in the text. The diagonal line corresponds to perfect prediction.
Figure 3. Cross-validatory predictions using one (×), two (+), three (b), four (0), and five (O) PLS components versus the temperature at which the spectrum was measured. The true concentration is 700 g/kg of water.
Figure 4. The solubility of racemic and enantiomerically pure mandelic acid in water: from gravimetric analysis for racemic (b) and L-(+)-mandelic acid (O) with error bars given as 95% confidence intervals and from IR measurements from heating (s) and cooling (- - -) ramps, respectively.
Results and Discussion Solubility. The solubility of mandelic acid measured in this work is presented in Figure 4. The concentrations of the mother liquor measured by IR spectroscopy at slow heating or cooling show good correspondence with the solubility data obtained by the gravimetric method and with similar literature data available in the Beil-
Profir et al.
Figure 5. In situ monitoring of the mother liquor concentration during seeded, batch cooling crystallization of racemic (O) and L-(+)-mandelic acid (]). The respective solubilities are shown by (s) and (×) illustrates measurements less accurate according to the calibration model.
stein Database.21 The difference between the cooling curve and the heating curve illustrates that equilibrium is not fully established in every point. True equilibrium should be in the range between the curves. The rate of dissolution is generally believed to be faster than the rate of growth, since the latter is suffering also from surface integration resistance. Hence, the cooling curve is above the heating curve and the concentrations obtained upon heating are believed to be a more accurate representation of the solubility and will be used as such throughout this paper. The ratio of the mole fraction solubility of the racemate to that of the pure enantiomer increases from 2 at 27.4 °C to 2.84 at the highest measured temperature of 33.2 °C. According to the literature,3 if the racemate is a conglomerate, this ratio varies from x2 for highly dissociated ionic compounds to 2 for nondissociated, ideal solutions of organic compounds. If the racemate is a racemic compound, this ratio can vary within wider limits, but the solubility of a racemic compound in equilibrium with a saturated solution cannot exceed the solubility of the corresponding conglomerate.3 The present results show that a racemate solubility that is twice the solubility of the pure enantiomer or higher, does not allow for the conclusion that the racemate is a conglomerate. Because of solution nonidealities, there are exceptions to the double solubility rule. Batch Crystallization Monitoring. Figure 5 shows the concentration measured every 5 min during the seeded batch cooling crystallization of enantiomerically pure and racemic mandelic acid, respectively. All measurements performed in the L-(+)-mandelic acid crystallization batch are measurements of solution spectra and accurate according to the calibration model. In the racemic batch, a secondary nucleation occurs after some time and the measurements become less accurate indicated by a higher magnitude of the spectra residuals measured as compared to the calibration spectra residuals. This suggests that, as long as no small crystals exist in the slurry, for instance, generated by a nucleation event, the mother liquor concentration can be quite accurately monitored in situ during a seeded crystallization.
Crystallization of Mandelic Acid
Figure 6. Superposed in situ IR spectra of the solid phases formed in the calibration experiments for the solutions with initial concentration of 450 g/kg of water ([) and 500 g/kg of water (]) and of the separately measured solid state IR spectra of enantiomerically pure (s) and (- - -) racemic mandelic acid. All spectra are baseline corrected and normalized.
Nucleation and Transformation. Upon nucleation in the first series of unseeded experiments, the crystal mass disabled the magnetic stirring. Furthermore, the spectra collected after nucleation were detected as outliers by the calibration model and showed large differences when compared to the solution IR spectra. This indicates that these spectra are not solution spectra. After comparison with separately measured solid-state IR spectra of the commercially available racemic and L-(+)-mandelic acid, it is concluded that, upon primary nucleation, the ATR element is covered by crystals and the IR spectra of this solid phase is recorded in situ. Figure 6 shows as an example, the spectra of the crystals formed in the solutions with initial concentrations of 450 and 500 g/kg of water, respectively, superposed on the separately measured mandelic acid solid-state spectra. After baseline correction and normalization, the IR spectrum of the crystals formed in the 450 g/kg of water solution is practically identical to the solid-state spectrum of the commercially available racemic mandelic acid, meaning that a racemic compound was formed in this case. For the crystals formed in the 500 g/kg of water solution, the IR spectrum of the formed crystals is identical to the solid-state spectrum of the commercially available L-(+)-mandelic acid, indicating that the crystals formed upon nucleation in this case are of a conglomerate type. The crystals that formed upon nucleation in the rest of the samples were identified in a similar manner. Figure 7 shows the nucleation and dissolution temperatures recorded for all samples. The figure shows that there are two metastable zone limits, one for each solid-phase crystallized. Similarly, the phases dissolve at different temperature, implying the existence of a conglomerate solubility curve above the measured solubility, the solubility of the racemic compound. In the second series of primary nucleation experiments, the influence of the filtration and of the cooling, heating, and stirring rates is investigated. The observed nucleation and dissolution temperatures are shown in Figure 8.
Crystal Growth & Design, Vol. 2, No. 4, 2002 277
Figure 7. The temperature of nucleation (diamond) and of dissolution (triangle) of the conglomerate (filled) and the racemic compound (transparent). The figure shows also the solubility of the racemic compound (s).
Figure 8. The nucleation ([) and dissolution (]) temperature for racemic mandelic acid as compared to the solubility of the racemic compound (s). The numbers given are operating conditions according to Table 1.
A conglomerate is obtained in all runs upon nucleation, regardless of the cooling rate. Upon heating, a racemic compound crystalline IR spectrum is observed in run 1 and 2 at the 400 g/kg of water concentration level and in run 2 at the 600 g/kg of water concentration level. This indicates that in these cases a transformation of the solid phase occurs in the crystallizer and on the ATR element. The temperature at which these slurries completely dissolved correlates well with the racemic compound solubility, in contrast with the dissolution of the conglomerate slurries, which all dissolve above the racemic compound solubility. The observed conglomerate-racemic compound transformation occurs when a low heating rate is combined with continuous stirring. No transformation is observed if the heating rate is high or, at low heating rates, if the initially formed conglomerate crystals are allowed to grow by ripening in stationary solutions before heating. The transformation is faster in the experiments performed at a high initial concentration/temperature level at otherwise identical operating conditions as exemplified by runs 2 and 4. The filtration applied in all runs, removes micrometer-sized dust particles and improves the reproducibility with respect to the type of solid phase formed, as well as with respect to the nucleation and dissolution temperatures. In all experiments, the crystals were sampled after
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Figure 9. Concentration change of the mother liquor during the isothermal part of the phase transformation experiment: concentration from solution spectra (s) and mixed solutioncrystal spectra with less accurate predictions (sxs).
nucleation and analyzed off-line by solid-state IR spectroscopy. They were all found to be the racemic compound. We believe that, since sampling and drying were performed at room temperature, the less stable conglomerate crystals transform into the racemic compound prior to the solid-state IR analysis. Figure 9 shows the solution concentration change during one experiment in third series of unseeded experiments. Conglomerate crystals were obtained by primary nucleation in a filtered solution of initial concentration of 200 g/kg of water, according to the procedures previously described. The crystals were identified by the in situ solid phase IR spectra collected shortly after the nucleation. After ripening at the nucleation temperature, the slurry was quickly heated to 18.2 °C and kept isothermal without dissolving all crystals. Upon heating, solution IR spectra were collected again, showing that the conglomerate crystals have a solubility of approximately 200 g/kg of water at 18.2 °C, much higher than the racemic compound solubility of 135 g/kg of water at the same temperature. At about 520 min after the initial primary nucleation, the concentration in the solution started to decrease, and soon after, the spectra collected in situ were no longer pure solution spectra. The IR spectra of a solid racemic compound were observed, indicating that the racemic compound had appeared spontaneously. At 1100 min after the primary nucleation, the IR probe was removed from the crystallizer, washed, and reinserted. The spectra then collected show a mother liquor concentration in agreement with the solubility of the racemic compound. The experiment was repeated for a 300 g/kg of water solution at 21 °C, and, this time, the racemic compound was observed to appear after 60 min. When adding 50 g of unfiltered pure water to a conglomerate slurry obtained by primary nucleation of a 400 g/kg of water solution, the racemic compound was observed to appear after 12 min after the water addition. When an artificially made conglomerate of 5.30 g each of (+)- and (-)-mandelic acid was added to a, with respect to the racemic compound, slightly undersaturated solution (100 g/kg
Profir et al.
of water at 15 °C), the racemic compound appeared after 4 min. When added to a, with respect to the racemic compound, slightly supersaturated solution on the other hand (12.0 g each of (+)- and (-)-mandelic acid in a 130 g/kg water solution at 15 °C), the racemic compound appeared already after 1 min. If metastable phases exist and if the supersaturation is sufficiently high, we should according to the Ostvald law of stages22 expect metastable phases to appear prior to the thermodynamically stable phase. Hence, when the supersaturation is sufficiently high, the metastable conglomerate is formed instead of the racemic compound for kinetic reasons. The activation energy barrier for nucleation of the conglomerate is lower than the corresponding barrier for the formation of the racemic compound. In the present experiments, it seems as if dust particles may catalyze the nucleation of the racemic compound to such an extent that the racemic compound occasionally appears in nonfiltered solutions (see Figure 7), but not in the filtered solutions (see Figure 8). Filtration also significantly reduces the spread in data. In the absence of racemic compound nuclei in the solution and if the conditions are suitable, the conglomerate can be retained in a supersaturated solution for a relatively long time. Higher temperature and the presence of dust particles in unfiltered solutions seem to increase the racemic compound nucleation rate. At unfavorable conditions, the transformation to the racemic compound is quite rapid, which explains why it is difficult to perform direct traditional determination of the solubility of the metastable conglomerate. If a solution is seeded with crystals having a particular crystal structure, that structure can crystallize out directly without having to pass a nucleation barrier. The seed crystals grow and promote secondary nucleation of new particles having the same structure. If the solution in the present work is seeded by crystals of the racemic compound, the appearance of the metastable conglomerate is prevented. The commercially available mandelic acid enantiomers used for obtaining an artificial conglomerate are not 100% enantiomerically pure. It is most likely that they are contaminated with small amounts of the racemic compound. When these crystals are introduced as seeds in supersaturated solutions, racemic compound nuclei are thus introduced as well, and the conglomerate transforms rapidly to the racemic compound. Conclusions In the literature, racemic mixtures are claimed to usually form a racemic compound upon crystallization. In less than 10% of the cases, a conglomerate is formed. In this work, it is clearly established that a substance that belongs to the first category can form a metastable conglomerate. It is also shown that this conglomerate can have a reasonable stability that opens for the possibility to perform a separation by direct crystallization. The work also shows that ATR-IR with a multivariate PLS calibration can be used for accurate in situ determination of concentrations in crystallization processes. When properties of the pure enantiomer are to be studied, the calibration can be made with the often much cheaper racemic mixture.
Crystallization of Mandelic Acid
Acknowledgment. The authors are grateful to Sandra Gracin for performing a part of the mandelic acid solubility measurements at the Royal Institute of Technology, Sweden. The Center for Chemical Process Design and Control (CPDC), supported by the Swedish Foundation for Strategic Research, is acknowledged for financial support that made the spectroscopic equipment available. Notations cvM cm M FW FM
concentration of mandelic acid in volume units, g/cm3 concentration of mandelic acid in mass units, g/100 g of water density of water, 1 g/cm3 density of solid racemic mandelic acid, 1.289 g/cm3
References (1) Collins, A. N.; Sheldrake, G. N.; Crosby, J. Chirality in Industry II; John Wiley & Sons: Chichester, 1997. (2) Collet, A. Enantiomer 1999, 4, 157-172. (3) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolutions; Krieger Publishing Co.: Malabar, FL, 1994. (4) Mitchell, A. G. J. Pharm. Pharm. Sci. 1998, 1(1), 8-12. (5) McKelvy, M. L.; Britt, T. R.; Davis, B. L.; Gillie, J. K.; Graves, F. B.; Lentz, L. A. Anal. Chem. 1998, 70, 119R177R. (6) Colthup, N. B.; Daly, L. H.; Wiberley, S. E. Introduction to Infrared and Raman Spectroscopy, 3rd ed., Academic Press: London, 1990.
Crystal Growth & Design, Vol. 2, No. 4, 2002 279 (7) Wulfert, F.; Kok, W. T.; Smilde, A. K. Anal. Chem. 1998, 70, 1761-1767. (8) Esbensen, K.; Scho¨nkopf, S.; Midtgaard, T. Multivariate Analysis in Practice. Camo: Trondheim, 1994. (9) Martens, H.; Naes, T. Multivariate Calibration; John Wiley & Sons: Chichester, 1989. (10) Geladi P.; Kowalski, B. R. Anal. Chim. Acta 1986, 185, 1-17. (11) Harrick, N. J. Internal Reflection Spectroscopy; John Wiley & Sons: New York, 1967. (12) Mirabella, F. M.; Harrick, N. J. Internal Reflection Spectroscopy: Review and Supplement; Harrick Scientific: Ossining, 1985. (13) Furusjo¨, E.; Danielsson, L.-G.; Ko¨nberg, E.; Rentsch-Jonas, M.; Skagerberg, B. Anal. Chem. 1998, 70, 1726-1734. (14) MacLaurin, P.; Crabb, N. C. Anal. Chem. 1996, 68, 11161123. (15) Bayada, A.; Lawrance, G. A.; Maeder, M.; Molloy, K. J. Appl. Spectrosc. 1995, 49, 1789-1792. (16) Dunuwila, D. D.; Berglund, K. A. J. Cryst. Growth 1997, 179, 185-193. (17) Lewiner, F.; Klein, J. P.; Puel, F.; Fe´votte, G. Chem. Eng. Sci. 2001, 56, 2069-2084. (18) Wang, F.; Berglund, K. A. Ind. Eng. Chem. Res. 2000, 39, 2101-2104. (19) Wood, W. M. L. In Chirality in Industry II; Collins A. N., Sheldrake G. N., Crosby J., Eds.; John Wiley & Sons Ltd.: Chichester, 1997; pp 119-156. (20) De Maesschalck, R.; Jouan-Rimbaud, D.; Massart, D. L. Chemom. Intell. Lab. 2000, 50, 1-18. (21) Beilstein/Crossfire, Version 4.0 1999. Database for properties of organic compounds. Beilstein Institut zur Foerderung der Chemischen Wissenschaften. (22) Mullin, J. W. Crystallization; Butterworth-Heinemann: Oxford, 2001.
CG025519G
