The Phase Behavior and Crystallization of 2-Chloromandelic Acid

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The Phase Behavior and Crystallization of 2-Chloromandelic Acid: The Crystal Structure of the Pure Enantiomer and the Behavior of Its Metastable Conglomerate Published as part of a virtual special issue of selected papers presented at the 2010 Annual Conference of the British Association for Crystal Growth (BACG), Manchester, UK, September 5
7, 2010. Heike Lorenz,† Jan von Langermann,† Ghazala Sadiq,‡ Colin C. Seaton,‡ Roger J. Davey,*,‡ and Andreas Seidel-Morgenstern†,§ †

Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstrasse 1, 39106 Magdeburg, Germany Colloids, Crystals and Interfaces Group, School of Chemical Engineering and Analytical Science, University of Manchester, Sackville Street, P.O. Box 88, Manchester, M60 1QD, United Kingdom § Otto von Guericke University Magdeburg, Universit€atsplatz 2, 39106 Magdeburg, Germany ‡

ABSTRACT: Crystallization of racemic 2-chloromandelic acid yields a metastable conglomerate in addition to a more stable racemic compound. The crystal structure of the pure enantiomer is reported and the relative stability of the racemic compound and conglomerate was determined at both room temperature and the melting point. Crystallizations from melt and solution are shown to offer potential crystallization pathways to the conglomerate, provided crystallization of the racemic compound can be avoided.

1. INTRODUCTION Enantiomers are molecules related by mirror image symmetry which possess identical physical and chemical properties, excluding both the direction of rotation of plane-polarized light and the interaction with chiral (biological) substrates. Enantioseparation has become an important task in the development of safe medicines and, it is noted that the application of racemic mixtures of enantiomers has been banned since the end of the last century. Because of their identical properties, such separations are complex tasks compared with classical isomer separation procedures. Well-established techniques include chiral chromatography, enantioselective membrane separation, and crystallization.1
3 Each of these processes has specific advantages with respect to selectivity, productivity, and production costs with crystallization techniques being the most important on an industrial scale. Classically the use of crystallization requires the identification of suitable diastereomeric salts or the direct enantioselective crystallization from a racemic solution (so-called preferential crystallization). For the application of the latter, knowledge of the corresponding binary and ternary phase diagrams is essential since three quite different possibilities exist for chiral systems: the conglomerate, the racemic compound, and the formation of a solid solution at racemic composition (sometimes called pseudoracemate).4 Only in a conglomerate-forming system crystallization from a racemate facilitates spontaneous resolution of enantiomers. The probability of occurrence of these three types of phase behaviors is strongly weighted to racemic compounds (90
95%) with conglomerates occurring far less frequently (5
10%) and only r 2011 American Chemical Society

Scheme 1. Chemical Structures of (a) 2-Chloromandelic Acid and (b) (S)-Clopidogrel

the very rare occurrence of pseudoracemates. As pointed out by Collet, the preponderance of compounds over conglomerates is due to the additional entropy of demixing required to separate enantiomers within a racemic liquid.5 At room temperature, this amounts to a stabilization of 2.1 kJ/mol in favor of racemic compounds. While this is typical of the expected difference between polymorphic forms, where the occurrence of metastable polymorphs and their interconversion is commonplace,6 equivalent reports of metastable conglomerates in racemic systems are rather exceptional. Serendipitously, we discovered that 2-chloromandelic acid is one such system, and we record here some aspects of our study. 2-Chloromandelic acid is used as an intermediate for the synthesis of Received: November 11, 2010 Revised: February 24, 2011 Published: April 08, 2011 1549

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Crystal Growth & Design (S)-Clopidogrel, an antiplatelet agent to treat coronary artery and vascular diseases (Scheme 1). The phase behavior in the chiral 2-chloromandelic acid system was first studied in 1973 by Collet and Jacques7 who reported it to be a conglomerate-forming system, and it was subsequently recorded as such in the book Enantiomers, Racemates and Resolutions.4 Interestingly, in 2009 He et al.8 observed a clear racemic compound behavior with an eutectic position near to the racemic composition. In 2010, we clarified this contradiction describing the system as racemic compound-forming with the occurrence of a metastable conglomerate.9 It appears that the racemic compound has a very small stability regime (and hence was not seen

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by Collet and Jacques) lying in the composition range 45
55 mol % of the pure enantiomer.8 In a more recent publication, He et al. have revisited this system very intensively and clarified a number of issues.10 For example, they confirmed the low metastability of the racemic compound described in ref 10 (form β) and found a stable crystal form grown from toluene (form R) (physical-chemical properties are given in Table 2 and will be discussed below). In addition, they report that freezedrying an aqueous solution, recrystallization from polar solvents, or melt crystallization can yield a conglomerate either as a single phase or mixed with the stable compound.11 In our present work, we report some extensions to the latest study of He et al. including results of using 2-chloromandelic acid synthesized by a combination of chemical and biochemical routes, the determination of the single crystal structure of the pure enantiomer, extended measurements providing the binary melt phase diagram of the system, and first measurements of solubilities using ethylacetate as a solvent. Furthermore, some general points addressing similarities and differences between polymorphism and conglomerate/racemic compound behavior are discussed.

2. EXPERIMENTAL SECTION Figure 1. H-bonded chain taken from the crystal structure of the (R)enantiomer of 2-chloromandelic acid.

2.1. Materials. Two sources of both pure enantiomer and racemic 2-chloromandelic acid have been used. One purchased from SigmaAldrich, who sell both pure enantiomers ((R), 99% and (S), 97% purity)

Figure 2. Calculated and measured XRPD patterns of chloromandelic acid crystal forms. a - pure enantiomer, calculated from crystal structure; b - pure enantiomer, experimental; c - conglomerate, experimental; d - racemic compound form R, calculated from crystal structure; e - racemic compound form R, experimental; f - racemic compound β, calculated from crystal structure. 1550

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Figure 3. Calculated BFDH morphology for (R)-2-chloromandelic acid (a) and microscopy image of crystal morphology of (R)-2-chloromandelic acid onto the (001) face (b).

Table 1. Final Refined Cell Parameters and Agreement Factors for LeBail and Rietveld Refinements (Enantiopure 2-Chloromandelic Acid) unit cell (a, b, c, (Å); β (°))

single crystal

LeBail refinement

Rietveld refinement

8.0612(4), 7.4986(3),

8.2148(13), 7.6734(10),

8.2106(35), 7.6596(29),

13.8910(6), 105.997(5)

13.9791(12), 105.608(1)

13.9623(24), 105.355(1)

Rwp/Rp (%)

N/A

10.38, 7.62

16.18, 11.55

Rwp/Rp (background subtracted,%) χ2, RF2

N/A N/A, 4.32

16.79, 11.57 3.457, N/A

21.04, 17.60 8.712, 11.30

Figure 4. Final observed (black circles), calculated (solid line), and difference (below) X-ray powder diffraction profile for the final Rietveld refinement of (R)-2-chloromandelic acid. Reflection positions are also marked. The inset displays an enlarged view of the high angle region of the plot. and a racemate (98% purity) (substances used in Manchester and Magdeburg without further purification), and a second, used in Magdeburg where racemic 2-chloromandelic acid and (S)-2-chloromandelic acid were prepared via the synthetic route described below. For this sodium cyanide and diisopropylether were obtained from Sigma-Aldrich, USA; toluene and concentrated hydrochloric acid were purchased from Merck, Germany; the immobilization reagent Sylgard 184 was a product sample from Dow Corning, USA; and polyvinylalcohol was received from Fluka, USA, as Mowiol 18-88. The hydroxynitrile lyase was a gift from J€ulich Chiral Solutions, a Codexis company formally based in J€ulich, Germany. Toluene and ethyl acetate for solubility/solution studies were supplied by Sigma-Aldrich (99.8% HPLC grade and 99.5%þ biotech grade, respectively) and methanol (analytical reagent grade) by Fisher Scientific. Deionized water was used throughout the study.

Racemic 2-chloromandelic acid was synthesized via the reaction of 2-chlorobenzaldehyde with HCN to yield a cyanohydrin intermediate which was then hydrolyzed to give the desired product.12 The crude 2-chloromandelic acid was recrystallized twice from toluene to give a final chemical purity as determined via HPLC, NMR, X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC) of >99.5%.9 The pure (S)-enantiomer was prepared by using the (S)-selective hydroxynitrile lyase from Manihot esculenta (MeHNL), which was immobilized in polydimethylsiloxane (PDMS) to facilitate a very low water content. The immobilized MeHNL was combined with the HCNsolution in diisopropylether and 50 g (0.36 mol) of 2-chlorobenzaldehyde and vigorously stirred overnight. The purity (including enantiopurity) was determined via HPLC, NMR, XRPD, and DSC, which was >99.5%.9 1551

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Figure 5. Raman spectra of 2-chloromandelic acid species; 1 - pure enantiomer, 2 - metastable conglomerate, 3 - stable racemic compound form R.

2.2. Techniques. DSC experiments were performed using a DSC131 from Setaram (France) with a start temperature of 30 °C and heating at 2 K/min up to 130 or 140 °C. Calculated amounts of racemate and/or enantiomer were coground and dissolved in acetone. After evaporation of the solvent, the solid was crushed into fine powder and 10
15 mg thereof were used for DSC experiments. Solid samples were analyzed throughout by XRPD to identify the solid phases present. In Magdeburg an X’Pert Pro diffractometer (PANalytical GmbH, Kassel, Germany) with CuKR radiation was used. Measurements covered a 2Theta range from 3 to 40° with a step size of 0.0167°. In Manchester a Rigaku Miniflex was used, operating over an angular range of 2
45°, and a step size of 0.03°. Single crystal diffraction was performed at 100 K on an Oxford Xcaliber2 diffractometer with MoKR radiation with a graphite monochromator using an Oxford Cryosystems Cryostream 700 to maintain the temperature. The data were collected and processed using CryAlisPro software. Structure solution was carried out using Shelxs97 and refined against F2 for all reflections by full matrix methods in Shelxl97.13 All non-hydrogen atoms were refined anisotropically, and the hydrogen atoms were placed in geometric positions and refined as riding atoms except for those bound to oxygen, which were freely refined. Raman spectra were collected using an FT-Raman spectrometer ‘MultiRAM’ from Bruker, Germany, within a range of 300
3500 cm
1 and a laser light wavelength of 1064 nm at 100 mW. The samples were scanned for a period of 10 s; the resolution was at 4 cm
1. Optical microscopy was performed using a Zeiss Axioplan 2 polarizing microscope, Linksys image capture software, and a Linkam hot stage.

3. RESULTS AND DISCUSSION 3.1. Solid Phases. The crystal structures of the as-supplied pure enantiomer crystals and racemic compound crystals grown from toluene were solved successfully. For the racemic compound, we found the same structure as the form R reported by He et al.,8 while the pure enantiomer structure is reported herein (P21, a = 8.0959 Å; b = 7.5319 Å; c = 13.8991 Å; β = 105.901°, R = 4.7%; T = 293 K; Flack parameter 0.99). This structure has two molecules in the asymmetric unit, their conformation differing only in the orientation of the hydroxyl -O
H bond. The conformation of the molecule is similar to the conformation observed in the racemic compound. These two conformationally distinct molecules form a hydrogen-bonded chain along the a-axis, as seen in Figure 1, which utilizes a combination of hydroxyl-carboxylic acid and carboxylic acid to hydroxyl carbonyl

Figure 6. Hot stage microscopy images showing the recrystallization of a racemic supercooled melt between 48 and 83 °C. The conglomerate grows between (a) 48 °C and (b) 64 °C and converts to the racemic compound above (c) 76 °C and (d) 83 °C. (Scale: the longest dimension of the rhombs in (a) is approximately 30 μm.)

interactions. Such chains are translated along the b-axis and joined by hydroxyl
hydroxyl H-bonds. The crystal structures of the compounds R and β have been discussed in detail by He et al.8 It is noted here only that these polymorphs both utilize the R22(8) centrosymmetric carboxylic acid dimer. In the stable form R, both molecules in the asymmetric unit are involved in such dimers which are linked via hydroxyl
hydroxyl interactions to give racemic chains. In the metastable form β, only one of the molecules in the asymmetric unit forms such dimers. Thus, the unstable polymorph has fewer hydrogen bonds in comparison with the pure enantiomer and stable racemic compound which have the same number and type 1552

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Table 2. Summary of Thermal Properties for 2-Chloromandelic Acid

solid phase metastable conglomerate

source

this work Collet, Jacques7 He et al.10 stable racemic compound form R this work Collet, Jacques7 He et al.10 enantiomer this work Collet, Jacques7 He et al.10

a

melting melting enthalpy/ temperature/ °C kJ 3 mol
1 83.0 85.5 85.0 90.2 n.m.a 89.9 119.2 119.5 118.7

21.1 20.1 21.4 23. 2 n.m. 23.1 24.3 24.7 24.9

n.m.
not mentioned.

Figure 7. DSC curve of an equimolar mixture of racemic conglomerate and racemic compound form R; 1 - melting of the metastable conglomerate, 2 - recrystallization to racemic compound form R, 3 - melting of racemic compound form R.

of hydrogen bonding. Interestingly, these packing motifs contrast markedly with those seen in the racemic compounds and pure enantiomers of mandelic and 4- and 3-fluoromandelic acids which are all based on homochiral hydroxylhydroxyl C11(5) chains. Of the available structures of other halogenated mandelic acids, only the racemic compound of 2-fluoromandelic acid exhibits the R22(8) dimer. The calculated XRPD patterns corresponding to the three 2-chloromandelic acid structures (pure enantiomer, racemic compound R and β) are included in Figure 2 and were used in this present study to characterize both the materials appearing during measurement of phase diagrams and the products of crystallization experiments. Figure 2 also shows the experimental powder patterns of the pure enantiomer (b), and two materials crystallized from racemic solutions, one of which (c) has an XRPD pattern identical to the pure enantiomer and is certainly the conglomerate reported by He et al.,10,11 while the second (e) has a pattern identical to that of the stable racemic compound, form R. We failed to observe the structure of form β in any of our experiments. Samples of the racemic compound crystallized from toluene (form R) remained unchanged during suspension and grinding experiments, confirming it as the stable racemate, at least at room temperature and suggesting that the observed conglomerate is metastable, a feature discussed later in more detail in competitive slurry studies. One issue arising from these powder data (Figure 2) was the apparent discrepancy between the calculated powder pattern for the pure enantiomer (Figure 2a) and its measured pattern (Figure 2b), which appears to have many high intensity reflections missing. XRPD samples were prepared using both ground and unground material, but no change in the XRPD pattern was observed. Using the pure enantiomer single crystal structure of (R)-2-chloromandelic acid as a starting point, a Rietveld refinement of the measured powder pattern was performed. The temperature difference in measurement temperatures for the single crystal (100 K) and the powder data (298 K) was accounted for using a LeBail method (in the program GSAS)14 to improve the fit of lattice, zero-point and profile parameters. A Rietveld

Figure 8. Binary melt phase diagram of 2-chloromandelic acid containing measurement data both from the metastable conglomerate and the racemic compound form R (left: racemic composition, right: pure enantiomer). The liquidus curve of the 2-chloromandelic acid enantiomer was calculated using an average melting enthalpy of 21.5 kJ 3 mol
1 as obtained for all mixtures on the enantiomer side to account for the temperature dependence of the melting enthalpy.

refinement was then performed with the structural model maintained by the inclusion of bond and angle constraints to the expected values for simple organic molecules, while preferred orientation was included using the March Dollase function15 in the (001) direction. This is certainly consistent with the Bravais, Friedel, Donnay and Harker (BFDH) morphology prediction which shows the morphology as (001) plates and the crystal morphology in Figure 3. Isotropic temperature factors were unrefined and fixed to a single value for all atoms (0.025). Initially, the hydrogen atoms were included in the model but due to instabilities during the refinement were removed. A high level of preferred orientation was displayed by the sample given by the low value of 0.3364, which was obtained for the refined preferred orientation parameter in the March Dollase function.15 A value less than 1 would be expected for platy crystals in flat plate diffraction geometry. The final refined parameters are given in Table 1. The similarity of values between the two refinements and successful fit of the experimental data (Figure 4) confirm the identity of the sample as the pure (R)-enantiomer. The results of the XRPD patterns in characterizing the two racemic phases (conglomerate and racemic compound form R, 1553

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Crystal Growth & Design Figure 2c,e) were confirmed by the measured Raman spectra (Figure 5) which show identical spectra for the enantiomer and the conglomerate while that of the racemic compound, form R, shows clear differences in both the hydroxyl and carbonyl stretching regions. Overall these studies confirm the conclusions of He et al.10 and show conclusively the existence of the metastable conglomerate. 3.2. Crystallization from Melts and Solutions. In this section, we report on preliminary crystallization experiments, which reproducibly led to the appearance of the conglomerate. Melting and rapid solidification of (Sigma-Aldrich) racemic 2-chloromandelic acid on a Petri dish yielded a solid having the XRPD of the pure enantiomer. This appears to be consistent with observations made both by hot stage microscopy and DSC. Figure 6, for example, shows hot stage microscopy images of the recrystallization of a racemic melt prepared by heating form R of the racemic compound to 120 °C. Cooling to 25 °C and reheating yielded first the growth of the conglomerate, seen in Figure 6a,b at 48 and 64 °C followed by the transformation to the racemic compound illustrated in Figure 6c,d at 76 and 83 °C. Figure 7 shows an associated DSC heating experiment using an equimolar mixture of conglomerate and racemic compound form R. Here the melting of the metastable conglomerate starts at 83 °C, and the racemic compound recrystallizes almost instantly from the melt and finally melts at 90 °C (peak onsets). This metastable conglomerate was also accessible by solution crystallization using material prepared by the synthetic route described above in which the crude synthetic racemate was recrystallized from toluene to yield a material melting at 83 °C and again having the XRPD pattern of the pure enantiomer. On the other hand, a cooling crystallization from water produced the stable racemic compound on stirring for one week at 5 °C. Finally, suspension experiments confirmed the metastability of the conglomerate versus the racemic compound. A 50:50 mixture of conglomerate and racemic compound form R slurried in water, toluene, or ethylacetate, always yielded the racemic compound form R after approximately two days. The conglomerate was fully transformed into the racemic compound. 3.3. Phase Diagram Studies. Table 2 summarizes the thermophysical properties of the metastable conglomerate, the stable racemic compound, and the pure enantiomer. The melting point of the conglomerate is 83.0 °C, only slightly lower than for the racemic compound at 90.2 °C. The pure enantiomer melts at 119.2 °C. The melting enthalpy of the pure enantiomer is 24.3 kJ 3 mol
1, slightly higher than 23.2 kJ 3 mol
1 for the racemic compound. The 29 K difference in melting point between the pure enantiomer and the racemic compound together with the heat of melting of the pure enantiomer can be used, following the methodology of Jacques & Collet,4 to calculate the Gibbs free energy (ΔG°) for the conversion of conglomerate to compound. This calculation assumes the formation of the racemic compound by a “reaction” of the enantiomers (in a mixture, i.e., a conglomerate); thus ΔG°-values are positive for conglomerates and negative for the formation of racemic compounds. For a system where the racemic compound has a lower melting point than the enantiomers then eq 1 is used to calculate ΔG°, where ΔHfE is the enthalpy of fusion for the enantiomer, TfR is the melting temperature of the racemic compound and TfE is the melting temperature of the enantiomer. This gives ΔG° at TfR

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assuming that the heat capacity of the materials is temperature independent. ! f T ΔG° ¼ ΔHEf 1
Rf
TRf R ln 2 ð1Þ TE Using our measured values eq 1 gives a ΔG° of
0.30 kJ 3 mol
1. Collet points out5 that the most stable racemic compounds have values for this free energy change over
8.4 kJ 3 mol
1; for the majority of racemic compounds ΔG° is smaller than
4.2 kJ 3 mol
1. A zero value would indicate that the formation of a conglomerate is equally as probable as the formation of a racemic compound. In our case, the Gibbs free energy for the racemic compound is negative but very close to zero indicating a low relative stability of the racemic compound. The evidence of the presence of a conglomerate of 2-chloromandelic acid that is metastable compared to the (stable) racemic compound, together with the diminutive existence region of the racemic compound in the phase diagram (Figure 8) are thus consistent with this very low free energy gain. Practically, this situation leads to the observation that the occurrence of the racemic compound versus the conglomerate can depend on the crystallization (reaction) conditions. The binary phase diagram of the (R,S)-2-chloromandelic acid system is shown in Figure 8. The liquidus lines were calculated according to the Schr€oder-van Laar and Prigogine-Defay equations.4 The phase diagram clearly emphasizes the existence of a racemic compound that melts at a slightly higher temperature than the racemic conglomerate, ca. 90 °C vs 83 °C. The intersection of the liquidus lines of the pure enantiomer and the racemic compound determines the eutectic composition at a mole fraction of 0.56 and the corresponding eutectic temperature at 87.5 °C. The eutectic composition observed in the vicinity of the racemic composition specifies a small existence region for the racemic compound and therefore, a comparatively low or limited stability of this compound as mentioned already above. The part of the liquidus curve that falls below this eutectic line characterizes metastable states matching the melting temperature of the metastable conglomerate at racemic composition of ca. 82 °C. The measured values for the corresponding eutectic temperature vary between 78 and 83.5 °C (mean value 80 °C), a feature that may be attributed to the different sources of the 2-chloromandelic acid containing different amounts and identities of impurities. Attempts to identify the impurities using a range of analytical methods (HPLC, 1H NMR, XRPD) were unsuccessful. Most data for the conglomerate equilibria in the phase diagram have been determined via the conglomerate or mixtures of the pure enantiomer with the conglomerate. However, sometimes mixtures prepared with the racemic compound form R (via dissolution and recrystallization from acetone) provided a conglomerate exemplified with samples of composition 0.833 and 0.85 in Figures 8 and 9. In Figure 9, examples of DSC curves are given to illustrate the melting behavior of the pure enantiomer, the racemic compound, the conglomerate, and the mixtures mentioned above. The sample containing 85 mol % of (S)-2-chloromandelic acid (curve 3) shows eutectic melting at 81 °C, which can clearly be assigned to the conglomerate. This is followed by dissolution of the excess enantiomer in the melt (liquidus temperature obtained from the peak maximum ∼111 °C). On the other hand, a sample of similar composition of 83.3 mol % (S) (curve 4) exhibits an initial melting of a conglomerate in the mixture at 82 °C, followed by 1554

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Figure 9. DSC curves of 2-chloromandelic acid samples of selected composition: 1 - (S)-enantiomer; 2 - stable racemic compound form R; 3 - mixture
mole fraction x = 0.85; 4 - mixture
mole fraction 0.833; 5 - metastable conglomerate.

recrystallization of the stable racemic compound from this melt and afterward the eutectic melting of the racemic compound at 88.4 °C before complete liquefaction. The identity of the solid phases present was confirmed by XRPD measurements. For the sample curve 3 only the XRPD pattern of the enantiomer was observed since it was a mixture of conglomerate and excess enantiomer. Sample 4 showed both the pattern of the enantiomer and the racemic compound. The construction of the Tammann-plot4 using all available experimental data for both the conglomerate and the racemic compound, indicates partial miscibility in the solid state very close to the pure enantiomer at about 0.95
0.96 mol fraction (Figure 10). The significantly deviating “eutectic” temperatures measured at the mole fraction of 0.95 (Figure 8) might also be an indication of partial miscibility in the system. More work would be necessary to clarify this point if the pure enantiomer were to be separated by crystallization. 3.4. Separation Strategies for 2-Chloromandelic Acid from Solution. The appearance of the metastable conglomerate from both melts and solutions raises the prospect that a preferential crystallization process might be designed to facilitate enantiomer separation, provided conditions could be defined that minimize the chance of nucleating the racemic compound. To design such a process, the ternary phase diagram would be an essential requirement in order to define the extent of metastability of the conglomerate. In choosing solvents for ternary phase diagram determination approximate solubility screens were performed using the commercial racemate. In water its solubility was >3 M and in methanol >10 M suggesting that on purely cost grounds these polar solvents would not be appropriate for further work. In the less polar solvent ethylacetate at 25 °C, the solubility of the compound was 0.24 mol fraction and of the pure enantiomer 0.15 mol fraction, respectively. If this system followed ideal behavior,4 then the conglomerate would be expected to have a solubility of approximately twice that of the pure enantiomer, 0.3 mol fraction in ethyl acetate, that is, higher than the racemic compound. This implies that a solution saturated with conglomerate would be supersaturated with respect to the compound to the extent of 25%. In order to crystallize the conglomerate this supersaturation would have to be accessible without the risk of

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Figure 10. Tammann-plot for 2-chloromandelic acid indicating partial miscibility in solid state.

nucleating the compound and it is thus apparent why techniques which generate supersaturation rapidly, such as evaporative crystallization, spray drying method or application of an antisolvent, would be successful. Further, it has not escaped our notice that a process may be stabilized if a suitable additive can be selected for preferential inhibition of the crystallization of the compound,16 and work is currently underway to explore this aspect of a potential crystallization process for the metastable conglomerate. Otherwise, due to the low eutectic composition in the racemic compound-forming system, just small enantiomeric enrichments provided by a previous (e.g., chromatographic) step might allow for enantioselective crystallization.

4. CONCLUSIONS: SIMILARITIES AND DIFFERENCES BETWEEN POLYMORPHISM AND THE CONGLOMERATE/RACEMIC COMPOUND BEHAVIOR In agreement with the recently published work,9,10 2-chloromandelic acid was found to be a racemic compound-forming substance, which in addition exhibits a metastable conglomerate. The formation of (metastable or stable) conglomerates seems to be reasonably common for 2-substituted phenyl derivatives, in particular for halogen atoms in 2-position. Examples are known from a recently published paper by Bredikhin et al. on 2-halogen substituted phenyl glycerol ethers.17 Within this work, the corresponding physicochemical properties for both possible solid phases were given and discussed. The appearance of the metastable conglomerate from both melts and solutions raises the prospect that a preferential crystallization process can be designed for racemate resolution. Also selective crystallization from enantiomerically enriched solutions offers a way to the desired enantiomer. However, the final purity achievable might be impaired by miscibility in solid state which could not completely be ruled out in this study. Since the racemic compound of 2-chloromandelic acid can also occur in two polymorphic forms (as found so far), some general points about the similarities and differences between polymorphism and the conglomerate/racemic compound behavior of a system should be added here. First, the terms should not be mixed or the occurrence of a conglomerate and a racemic compound in a certain chiral system must not be confused with polymorphism. 1555

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Crystal Growth & Design Polymorphs are different crystalline forms of the same chemical compound having the same chemical formula. The racemic compound is a substance chemically different from the enantiomer (thus, also from the conglomerate). It contains molecules of the two enantiomers in equal amounts in a well-defined arrangement within its lattice (“racemic crystals”). A conglomerate is just a mechanical mixture of equal amounts of homochiral (i.e., enantiopure) crystals, that is, the individual crystals contain only molecules of one of the two enantiomers. Therefore, a conglomerate and a racemic compound of a chiral system show different XRPD patterns, which also applies to different polymorphs of a substance accounting in both cases for differences in solid-state properties. Yet, the crystallographic relation between (enantiopure) crystals of a conglomerate and racemic crystals is not polymorphic, since the two solids are not in equilibrium with the same liquid and vapor phases. However, in the liquid state (melt or solution) often partial dissociation of the racemic compound is observed, meaning that the solid
liquid equilibria are overlaid by a dissociation reaction. Hence, a conglomerate cannot possess polymorphs, but the single enantiomers in their mixture can. Further, somehow analogous to reversible polymorphic phase transitions (enantiotropy), reversible conglomerate
racemic compound transformations (or vice versa) may occur at a certain temperature. However, these phase transitions refer to threephase invariants in the chiral system caused by reversible formation or decomposition of the racemic compound at solid state. While above the transition temperature the racemic compound may be the more stable phase, below the conglomerate is more stable, which is referred to as an eutectoid phase transition (the opposite case is of peritectoid type). The discussed relationships are basically elaborated in an excellent article by G. Coquerel.18 In contrast, the conglomerate described in this contribution is always metastable with regard to the racemic compound (form R), whatever the temperature. Thus, a transition of the conglomerate to the racemic compound is irreversible and in this respect comparable to a monotropic polymorphic phase transition.

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(7) Collet, A.; Jacques, J. Bull. Soc. Chim. France 1973, 12, 3330–3334. (8) He, Q.; Zhu, J.; Gomaa, H.; Jennings, M.; Rohani, S. J. Pharm. Sci. 2009, 98, 1835–1844. (9) von Langermann, J.; Minh Tam, L.; Lorenz, H.; Seidel-Morgenstern, A. Chem. Ing. Tech. 2010, 82, 93. (10) He, Q.; Rohani, S.; Zhu, J.; Gomaa, H. Cryst. Growth Des. 2010, 10, 5136–5145. (11) He et al. refer to this conglomerate as form γ, a designation which we do not favor since it is not a new crystal form but rather a mixture of pure enantiomers. (12) Andexer, J. N.; von Langermann, J.; Kragl, U.; Pohl, M. Trends Biotechnol. 2009, 27, 599–607. (13) Sheldrick, G. M. Acta Crystallogr., Sect. E: Struct. Rep. Online 2008, 64, 112–122. (14) Larson, A. C.; Von Dreele, R. B. GSAS - Generalized Structure Analysis System; Los Alamos National Laboratory Report No. LAUR 86748, 2004; Los Alamos National Laboratory: Los Alamos, New Mexico, USA. (15) Dollase, W. A. J. Appl. Crystallogr. 1986, 19, 267–272. March, A. Z. Kristallogr. 1932, 81, 285–297. (16) Mughal, R. K.; Davey, R. J.; Black, S. N. Cryst. Growth Des. 2007, 7, 225–228. (17) Bredikhin, A.; Gubaidullin, A. T.; Bredikhina, Z. A. J. Mol. Struct. 2010, 975, 323–329. (18) Coquerel, G. Enantiomer 2000, 5, 481–498.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT The authors want to thank Jacqueline Kaufmann, Luise Borchert and Nora Doering for their help in the experimental work. This work was funded by the European Union (EU-project “IntEnant, Integrated Synthesis and Purification of Enantiomers”; NMP2-SL-2008-214129). ’ REFERENCES (1) Subramanian, G. Chiral Separation Techniques, 2nd ed.; WileyVCH: Weinheim, 2001. (2) Collins, A.; Sheldrake, G.; Crosby, J. Chirality in Industry II Developments in the Manufacture and Applications of Optically Active Compounds; John Wiley & Sons: Chichester, 1997. (3) Toda, F. Enantiomer Separation; Kluwer: Dordrecht, 2004. (4) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions; Krieger: Malabar, 1994. (5) Collet, A. in Problem and Wonders of Chiral Molecule; Simonyi, M., Ed.; Akademiai Kiado: Budapest, 1990; pp 91
109. (6) Bernstein, J.; Davey, R. J.; Henck, J.-O. Angew. Chem., Int. Ed. 1999, 38, 3440–3461. 1556

dx.doi.org/10.1021/cg1015077 |Cryst. Growth Des. 2011, 11, 1549–1556