Spectroscopic Characterization of Intermolecular Interactions in Solution and Their Influence on Crystallization Outcome Christopher S. Towler and Lynne S. Taylor* Department of Industrial and Physical Pharmacy, Purdue UniVersity, 575 Stadium Mall DriVe, West Lafayette, Indiana 47907
CRYSTAL GROWTH & DESIGN 2007 VOL. 7, NO. 4 633-638
ReceiVed April 20, 2006; ReVised Manuscript ReceiVed NoVember 9, 2006
ABSTRACT: Crystallization from solutions is an important technique for a wide range of industries. One of the prime requirements for crystallization is that molecular aggregation or clustering occurs prior to the formation of stable nuclei. Despite this, very little work has been carried out to investigate the nature of supersaturated solutions and the structure of prenucleation clusters. In this study, we have probed molecular assemblies in solution, using spectroscopic techniques, to search for structural features common to both solutions and solids. For the systems studied, it was found that, although solute-solute interactions could be detected in solution, there was generally a limited relationship with the solid forms, and therefore, these assemblies were not predictive of the polymorph initially crystallized. Introduction Crystallization from solution is a commonly used separation, extraction, and purification technique industrially employed to produce a wide variety of materials. Despite this, knowledge of the properties of supersaturated solutions and in particular the mechanisms of assembly by which molecules form viable nuclei are still limited. One of the issues associated with crystalline materials is polymorphism, which is defined as the ability of a molecule to crystallize into more than one crystal structure.1 If the structure of prenucleation aggregates could be identified and related to structure in the final solid form, then a greater amount of control over the outcome of the crystallization, and polymorphic form, might be achieved. As described by Khamskii,2 the nature of a supersaturated solution is complex, and a number of attempts have been made to distinguish between stable and labile solutions by measurement of concentration-dependent properties. Some investigations have revealed changes in these properties with increasing solute concentration, which can be linked to the formation of molecular clusters. Work by Mullin and Leci,3 Garside,4,5 and Myerson6-9 provides indirect evidence as to the existence of molecular clusters in supersaturated solutions and to the number of molecules present in these clusters. However, an investigation by Narayanan showed no difference in solution properties as one moves to supersaturation.10 Despite the body of work providing evidence for the presence of molecular clusters, there are few reported attempts to investigate their structure. Raman spectroscopy has been used to investigate the nature of supersaturated solutions in inorganic systems,11-15 but it seems little work has subsequently been carried out to apply similar techniques to organic systems. To our knowledge, only once has vibrational spectroscopy been utilized successfully to show common structural motifs in solution and the final solid form,16 linking dimers in some supersaturated solutions of tetrolic acid to dimers in the polymorph subsequently crystallized. For a different molecule, changes in the chemical shift of 1H NMR with concentration, so-called complexation-induced shifts, have been shown as evidence for molecular aggregation in solution. Some attempt * To whom correspondence should be addressed.
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was made to describe the structure of the aggregates, with it being suggested that they were similar to the dimer motifs in the solid structure.17 There are several views of how solute molecules might arrange themselves within critically sized nuclei.18 Supersaturated solutions may be thought of as homogeneous, in which molecular clusters are found, but have significant amounts of solvent within them and with structures that have no long range order. In polymorphic systems, there might also be clusters with some short range order and with a range of structures resembling each of the possible polymorphs.19 Recent work suggests that phase separation may occur via a two-step process, with the solute forming a dense liquid-like phase prior to a further organizational step.20-22 Simulations on the crystallization of acetic acid by Gavezzoti suggested that it might not be expected that the precursor liquid-phase would contain anything related to the final crystal structure.23 Clearly, in a supersaturated solution, there are solute-solvent interactions along with those between solute molecules themselves. It has been shown that the interaction of solvent with solute clusters can be utilized to engineer the crystallization of new crystal forms.16,24-26 Crystallization solvents are selected for their ability to disrupt or promote particular hydrogenbonding networks observed in some of the predicted crystal forms, hence directing the crystallization toward desired solid forms. The interplay between solvent and growing crystal faces is further illustrated by Lahav and Leiserowitz in their recent examination of the growth of polar crystals.27 In the present study, we have investigated the solution behavior of two polymorphic systems, indomethacin and anthranilic acid, using IR and Raman spectroscopy to identify if any of the interactions observed in the solutions are characteristic of those in the crystalline polymorphs. More specifically, it was of interest to see if the presence of specific solute-solute interactions resulted in a polymorph containing the same interactions. The first molecule studied, indomethacin, has numerous reported polymorphs,28 but the R and γ forms are the most commonly observed. The γ form is the more stable of the two with the R form readily transforming to γ under slurry conditions. The R form crystallizes from solutions of high concentration, while the γ form is prevalent from solutions of somewhat lower concentration.29 For example, in ethanol, R has
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Towler and Taylor
Figure 3. Hydrogen-bonded molecules in (left to right) form I, II and form III of anthranilic acid. Note the zwitterion and neutral molecule in form I and the carboxylic acid dimer in forms II and III. Table 1. Vibrational Spectroscopic Assignments for the r, γ and Amorphous Forms of Indomethacin30 peak position (cm-1) solid form
Figure 1. Hydrogen bonding in the R (left) and γ (right) forms of indomethacin. R Indomethacin contains chains of molecules linked by carboxylic acid dimers and an amide, carboxylic acid interaction. γ Indomethacin consists of discrete carboxylic acid dimers.
γ amorphous
IR
Raman
assignment
1734 1692 1680
1735
free COOH carbonyl asymmetric COOH of cyclic dimer free amide carbonyl symmetric COOH hydrogen bonded amide carbonyl asymmetric COOH of cyclic dimer free amide carbonyl free COOH carbonyl asymmetric COOH of cyclic dimer free amide carbonyl
1648 1718 1691 1735 1710 1684
1689 1679 1649 1698 1681
form I produces very different IR and Raman spectra from forms II and III. Form II crystallizes from most solvents below 50 °C and will subsequently undergo transformation to form I. Form III is obtained from the melt or from solutions at temperatures above 50 °C.33 Hence, as form II crystallizes first, we expect that an investigation of the crystallization of anthranilic acid from a range of solvents should show common spectral features attributable to form II. Experimental Section Figure 2. Carbonyl region in the IR spectra of R (upper, dashed line) and γ (lower, solid line) indomethacin. The extra peaks seen in the spectrum of the R form reflect the increased number of carbonyl interactions that occur in this polymorph.
been crystallized from a solution with a degree of supersaturation above 4, and at a degree of supersaturation below about 3.5 the γ form was produced. The crystal structures of the two forms differ by interactions of the carboxylic acid group (Figure 1) as well as molecular conformation. γ Indomethacin consists entirely of cyclic dimers, whereas the R form has three molecules in the asymmetric unit. Two molecules form a carboxylic acid dimer and the third forms a carboxylic acid, amide interaction. In R indomethacin, each molecule has a different conformation, whereas the γ form has one conformation. Subsequently, the IR and Raman spectra of the two forms in the carbonyl region30 (Figure 2) are markedly different, and a study of the indomethacin solutions over a range of concentrations might be expected to display differences in this region that may be connected to the final solid form. Anthranilic acid has three known polymorphs,31 a lowtemperature stable form I, metastable form II, and a hightemperature stable form III.32 The crystal structure of the stable form I has two molecules in its asymmetric unit, a zwitterion and a neutral molecule, whereas forms II and III have one neutral molecule in the asymmetric unit cell (Figure 3). Consequently
Indomethacin (99%) and anthranilic acid (g98%) were purchased from Sigma-Aldrich (St Louis, MO) and used as received. A range of indomethacin solutions were prepared in ethanol (solubility at 25 °C of 25 mg/mL) and nitromethane (11 mg/mL) up to a supersaturation of 5.5 (defined as c/c* where c* is the equilibrium solubility and c is the concentration used) and measurements taken. Ethanol and nitromethane were chosen as the solvents as neither has been observed to form solvates in our experience. Ethanol is a hydrogen bond donor and acceptor, while nitromethane does not have a hydrogen bond donor but can act as an acceptor. Indomethacin contains two carbonyl functions that can be used to investigate the hydrogen-bonding motifs in solution as a function of concentration. Vibrational spectroscopic assignments for the R, γ and amorphous forms of indomethacin (shown in Table 1) have been made previously, and these can be used to aid in interpretation of the present data.30 Anthranilic acid solutions were prepared in acetonitrile (150 mg/ mL), DMSO (175 mg/mL), ethanol (200 mg/mL), toluene (25 mg/ mL), and methanol (25 mg/mL), at concentrations levels that would usually lead to the formation of form II, and IR and Raman spectra were collected. Solutions in water were also examined to see if form I type characteristics could be observed, but due to the low solubility of anthranilic acid in water no signals attributable to the solute were recorded. For anthranilic acid, only limited solubility data are available, and hence supersaturations could not be accurately calculated. Supersaturations were maximized by use of a simple method. Solvent was heated to the required crystallization temperature, and anthranilic acid was added in small amounts, with stirring, until no more would dissolve and there was an excess of solid. The temperature of the solutions was then raised to dissolve any excess solid. In this way, it was known that
Intermolecular Interactions in Solution
Figure 4. NH2 region of the IR spectra of the three known anthranilic acid polymorphs.
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Figure 5. Raman spectra of anthranilic acid in selected solutions. Despite each solution leading to the crystallization for form II, the spectra are all different. Reading from top down, solvents are acetonitrile, benzyl alcohol, DMSO, ethanol, and toluene.
the solutions were at least saturated at the temperatures at which crystallization was carried out. Solution Raman spectra were collected using a RamanRxn1 Systems from Kaiser Optical System, which employs a 150 mW external cavity stabilized diode laser at 785 nm. All the Raman spectra, unless otherwise stated, were collected using an integration time of 5 s and summing 10 scans for each spectrum. IR spectra were measured using a Nicolet Nexus 670 FTIR and a multi-bounce HATR ZnSe accessory. Spectra were collected using 64 scans per spectrum at a resolution of 4 cm-1.
Results Anthranilic Acid. For a small molecule, the vibrational spectra of the various polymorphs of anthranilic acid are complicated, particularly in the carbonyl region where intra along with intermolecular hydrogen bonds add to the complexity. This complexity apparent in the solid-state spectra is mirrored in the spectra of many of the anthranilic acid solutions. Thus, the NH2 symmetric and asymmetric stretching at around 3300 cm-1 (Figure 4) proved most useful for identification of the different polymorphs. The change in these peaks reflects how the environment of the NH2 differs in the structures of the three forms. The first point of interest is that no common features were observed in Raman spectra from the different solutions (Figure 5). Hence, although form II is obtained in all the solvent systems investigated, there are no shared structural features between the solute in solution and final solid form, and solute-solvent interactions appear to dominate. Despite the clearly different solute-solvent interactions observed, no solvent directed polymorphism is observed. We note similarities between this work, in which spectroscopy indicates extensive solvent-solute interaction, and other studies which indicate that solvent has a noticeable affect on the morphology of form II. Form II of anthranilic acid has been shown to crystallize in a number of different morphologies depending on solvent; for instance, from ethanol a flat, plate morphology has been observed, although needles and prisms have also been reported.32,34 So for anthranilic acid, while solvent seems to have a marked effect on crystal growth, it seems to have little effect on nucleation. Despite the differing interactions observed in each solvent, form II is crystallized first.
Figure 6. Solution IR spectra of anthranilic acid in toluene (25 mg/ mL) and the solid-state IR of forms II and III.
However, a few interesting features were seen in the IR spectra of some of the solutions, in particular, toluene and acetonitrile. Nonpolar solvents, such as toluene, are expected to favor the presence of neutral molecules in solution,35 and this is confirmed by the solution spectroscopy, which showed no evidence of zwitterionic molecules as found in polymorph I. However, the solution IR spectra of anthranilic acid in toluene show interesting behavior in the NH2 region. Measurements of the solution spectra at different concentrations and temperatures that would lead initially to form II, all displayed the NH2 doublet at the higher wavenumber location, corresponding to peaks seen in the solid-state spectrum of form III (Figure 6). So, for anthranilic acid, we see a situation where IR spectroscopy indicates a predominance of clusters in solution that do not correspond to the polymorph initially crystallized. Anthranilic acid in toluene has form III-like characteristics, yet form II is crystallized. In contrast, in acetonitrile, a peak attributed to the carboxylic acid dimer, can be seen at 1670 cm-1, which increases with increasing anthranilic acid concentration (Figure 7). This peak corresponds to a peak observed in the solid-state spectrum of form II. Indomethacin. Assignments for IR spectra of indomethacin solutions are given in Table 2. In both the IR and Raman spectra
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Figure 7. IR spectra of anthranilic acid (52 and 150 mg/mL) in acetonitrile. Note the presence of the carboxylic acid dimer of form II, present as a shoulder in the less concentrated solution, developing to a distinct peak at higher concentration. Table 2. Assignments for IR Spectra of Indomethacin Solutions solvent
peak position (cm-1)
EtOH
1712 1680 (high concentrations indomethacin) 1656 (low concentrations indomethacin) 1741 1714 1684
MeNO2
assignment asymmetric COOH of cyclic dimer amide carbonyl carbonyl hydrogen bonded to solvent free carboxylic acid carbonyl asymmetric COOH of cyclic dimer free amide carbonyl
of indomethacin in ethanol, a broad peak at around 1660 cm-1 is seen at lower concentrations. This peak occurs at the same position for both techniques and can be assigned as arising from both of the carbonyl functions which are hydrogen bonded with the solvent molecules. The breadth of the peak is similar to that observed in the solid-state spectrum of the amorphous material. As the concentration of indomethacin in ethanol increases, the IR spectra undergo two changes in the carbonyl region; the development of a shoulder at 1711 cm-1 and a shift of the peak at 1660 to 1680 cm-1 (Figure 8). The shoulder at 1711 cm-1 can be assigned to the asymmetric stretch of a carboxylic acid dimer.30 The corresponding symmetric stretch is not seen in the Raman spectrum (this is also true of the gamma
Figure 8. IR spectra of increasing concentration of indomethacin in ethanol.
Towler and Taylor
Figure 9. IR spectra of increasing concentration of indomethacin in nitromethane.
polymorph in which the hydrogen-bonding motif is dimers). The peak shift from 1660 cm-1 is due to carbonyl groups, which were previously hydrogen bonded to solvent, becoming unbonded. We can link this to the indomethacin molecules becoming more closely associated in solution, forming soluterich clusters. Hence, the amount of space available for solvent molecules to hydrogen bond is reduced, and the solvent is removed from the clusters. In general terms, it can be said that the solution spectra and therefore the indomethacin clusters appear to be changing to more γ-like in nature. Despite this, it is the R polymorph that is initially crystallized. In MeNO2, a very different spectroscopic signature is obtained due to MeNO2 being able to act only as a hydrogen bond acceptor and not as a donor. Therefore, interaction of the solute with the solvent will result in different hydrogen bonding arrangements than for an ethanolic solution. Two carbonyl peaks are evident at low concentrations, at 1685 and 1740 cm-1, which can be assigned to benzoyl carbonyl and acid carbonyl, respectively, neither of which is hydrogen bonded. As the concentration increases, a peak appears in the IR spectrum at 1713 cm-1 (Figure 9). This is assigned to the formation of carboxylic acid dimers. In addition to the bands in the 1600 to 1700 cm-1 region, a band around 920 cm-1 increases in intensity in both systems as the concentration of indomethacin is increased. This peak, attributed to the OH deformation vibration of the carboxyl group,36 is typical of carboxylic acid dimers. Thus, in both EtOH and MeNO2, the solute molecules appear to predominantly interact with the solvent below a certain concentration, and as the concentration of indomethacin increases the number of solute-solute interactions increases and there is evidence for dimer formation. Evidence for dimer formation can be seen in undersaturated solutions as well as those that are supersaturated. This is as might be expected as it has been demonstrated that the dimer is the stable configuration for carboxylic acids with bulky substituents37 and has previously been shown to exist even in dilute solutions.36 Hence, in these systems we are able to observe a carboxylic dimer, the structural motif present in the crystal structures of both the R and γ polymorphs and believed to be present in other forms.30 Solution spectroscopy also indicates that in MeNO2 there are still many free amide carbonyl groups present that might facilitate the nucleation of the R polymorph. However, this is not true in EtOH, in which any remaining carbonyl groups appear to be hydrogen bonded to the solvent. In EtOH, with
Intermolecular Interactions in Solution
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is present in the crystal structure of R-indomethacin, even at concentrations from which the R form is crystallized. Vibrational spectroscopy has been shown to be potentially useful for the identification of molecular aggregates in solution. However, it is apparent that solvent-solute interactions may dominate the solution spectra complicating efforts to characterize intermolecular interactions in solute clusters. Furthermore, in cases where solute-solute interactions can be identified, the structural motifs present in solution are not necessarily indicative of the polymorphic form initially crystallized, in agreement with some of the results of other recently published work.38 These results highlight the complex nature of the molecular recognition events and times scales that are involved during nucleation.
Figure 10. Raman spectra of indomethacin in EtOH and MeNO2, at supersaturations where the R polymorph is crystallized. Note the absence in both of the solutions of the R polymorph peak at 1650 cm-1.
increasing indomethacin concentration, we see the formation of solute-rich clusters based predominantly around dimer formation. These clusters are formed at the exclusion of solvent, and hence some carbonyl groups become free from solvent. The R polymorph also contains a dimer interaction, and it seems then that in EtOH the few free carbonyl groups in the soluterich clusters are sufficient to provide a pathway to crystallize the R polymorph. The carbonyl region in the Raman spectra of indomethacin in EtOH and MeNO2, at supersaturations where the R polymorph is crystallized, are shown in Figure 10. Also presented is the solid-state Raman spectrum of R indomethacin. It is immediately apparent that the peak present in the spectrum of the R form at 1650 cm-1, caused by the amide carbonyl to carboxylic acid hydrogen bond, is absent from both the solution spectra. The inference is, therefore, that an interaction present in the solid form crystallized at these supersaturations is not present in the solution prior to crystallization. For indomethacin, the hydrogen-bonding possibilities with each of the solvents are very different, yet the polymorphic outcome is not influenced by the type of interaction that is possible with the solvent. We note the similarity here with work by Slavin et al.29 who observed that the morphology of γ-indomethacin was independent of crystallization solvent. The lack of solvent direction observed and the information that the system exhibits minimum interaction between solvent and growing nuclei is mirrored in this work, in which polymorphic outcome is independent of solvent. Conclusions Anthranilic acid gave rise to complex spectra in most solvents. In acetonitrile, a carboxylic acid dimer is observed in solution that reflects a dimer present in form II, the form that is subsequently crystallized. However, in toluene, a spectrum most closely resembling that of form III is obtained despite form II being crystallized from these solutions. For indomethacin, a carboxylic acid dimer is observed in solution, a structural building block present in both the R and γ forms. The dimer is present even in weakly concentrated solutions and at supersaturations that lead to the formation of the metastable R form. No evidence was observed for the presence of a carboxylic acid, amide carbonyl interaction, which
Acknowledgment. We thank The Particle Technology and Crystallization Centre (PTCC) for funding, Dr. L. J. Mauer of the Department of Food Sciences, Purdue University, for use of the FTIR system, and Dr. D. T. Smith of the Department of Industrial and Physical Pharmacy, Purdue University, for helpful discussions. References (1) McCrone, W. C. In Fox, D., Labes, M. M., Weissberger, A., Eds.; Interscience, New York, 1965; p 725. (2) Khamshii, E. V. Crystallization From Solutions; Consultants Bureau: New York, 1969. (3) Mullin, J. W.; Leci, C. L. Philos. Mag. 1969, 19, 1075. (4) Larson, M. A.; Garside, J. J. Cryst. Growth 1986, 76, 88. (5) Larson, M. A.; Garside, J. Chem. Eng. Sci. 1986, 41, 1285. (6) Ginde, R. M.; Myerson, A. S. J. Cryst. Growth 1992, 116, 41. (7) Ginde, R. M.; Myerson, A. S. J. Cryst. Growth 1993, 126, 216. (8) Myerson, A. S.; Lo, P. Y. J. Cryst. Growth 1991, 110, 26. (9) Na, H. S.; Arnold, S.; Myerson, A. S. J. Cryst. Growth 1994, 139, 104. (10) Narayanan, H.; Youngquist, G. R. AIChE Symp. Ser. 1987, 83, 1. (11) Cerreta, M. K.; Berglund, K. A. in 9th Symposium on Industrial Crystallization; Hague, Netherlands, 1984; Jancic, S. J., de Jong, E. J., Eds.; Amsterdam; New York: Elsevier, 1984; p 233. (12) Davis, A. R.; Oliver, B. G. J. Phys. Chem. 1973, 77, 1315. (13) Hussmann, G. A.; Larson, M. A.; Berglund, K. A. in 9th Symposium on Industrial Crystallization; Hague, Netherlands, 1984; Jancic, S. J., de Jong, E. J., Eds.; Amsterdam; New York: Elsevier, 1984; p 21. (14) McMahon, P. M.; Berglund, K. A.; Larson, M. A. in 9th Symposium on Industrial Crystallization; Hague, Netherlands, 1984; Jancic, S. J., de Jong, E. J., Eds.; Amsterdam; New York: Elsevier, 1984; p 229. (15) Rusli, I. T.; Schrader, G. L.; Larson, M. A. J. Cryst. Growth 1989, 97, 345. (16) Parveen, S.; Davey, R. J.; Dent, G.; Pritchard, R. G. Chem. Commun. 2005, 1531. (17) Spitaleri, A.; Hunter, C. A.; McCabe, J. F.; Packer, M. J.; Cockroft, S. L. CrystEngComm 2004, 6, 489. (18) Davey, R. J.; Allen, K.; Blagden, N.; Cross, W. I.; Lieberman, H. F.; Quayle, M. J.; Righini, S.; Seton, L.; Tiddy, G. J. T. CrystEngComm 2002, 257. (19) Etter, M. C. J. Phys. Chem. 1991, 95, 4601. (20) Shore, J. D.; Perchak, D.; Shnidman, Y. J. Chem. Phys. 2000, 113, 6276. (21) Vekilov, P. G. J. Cryst. Growth 2004, 275, 65. (22) Bohenek, M.; Myerson, A. S.; Sun, W. M. J. Cryst. Growth 1997, 179, 213. (23) Gavezzotti, A. in Crystal Engineering: From Molecules and Crystals to Materials; Braga, D., Grepioni, F., Orpen, A. G., Eds.; Kluwer Academic Publishers, Drodrecht, 1999; p 129. (24) Cross, W. I.; Blagden, N.; Davey, R. J.; Pritchard, R. G.; Neumann, M. A.; Roberts, R. J.; Rowe, R. C. Cryst. Growth Des. 2003, 3, 151. (25) Davey, R. J.; Blagden, N.; Righini, S.; Alison, H.; Ferrari, E. S. J. Phys. Chem. B 2002, 106, 1954. (26) Blagden, N.; Davey, R. J.; Lieberman, H. F.; Williams, L.; Payne, R. l Roberts, R.; Rowe, R.; Docherty, R. J. Chem. Soc. Faraday Trans. 1998, 94, 1035. (27) Lahav, M.; Leiserowitz, L. Cryst. Growth Des. 2006, 6, 619. (28) Borka, L. Acta Pharm. Suecica 1974, 11, 295.
638 Crystal Growth & Design, Vol. 7, No. 4, 2007 (29) Slavin, P. A.; Sheen, D. B.; Shepherd, E. E. A.; Sherwood, J. N.; Feeder, N.; Docherty, R.; Milojevic, S. J. Cryst. Growth 2002, 237, 300. (30) Taylor, L. S.; Zografi, G. Pharm. Res. 1997, 14, 1691. (31) Bernstein, J. Polymorphism in Molecular Crystals; Calendon Press, Oxford, 2002. (32) Ojala, W. H.; Etter, M. C. J. Am. Chem. Soc. 1992, 114, 10288. (33) Towler, C. S. Ph.D. Thesis, UMIST (Manchester), 2004. (34) Wells, A. F. Philos. Mag. 1946, 37, 184.
Towler and Taylor (35) Van de Graaf, B.; Hoefnagel, A. J.; Wepster, B. M. J. Org. Chem. 1981, 46, 653. (36) Bellamy, L. S. The Infra-Red Spectra of Complex Molecules, 3rd ed.; Chapman & Hall: London, 1975. (37) Leiserowitz, L. Acta Crystallogr. 1976, B32, 775. (38) Davey, R. J.; Dent, G.; Mughal, R. K.; Parveen, S. Cryst. Growth Des. 2006, 6, 1788.
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