Molecular Packing, Morphological Modeling, and Image Analysis of Cyanazine Crystals Precipitated from Aqueous Ethanol Solutions Liam A. Hurley and Alan G. Jones*
CRYSTAL GROWTH & DESIGN 2004 VOL. 4, NO. 4 711-715
Department of Chemical Engineering, UCL (University College London), Torrington Place, London WC1E 7JE, England
Robert B. Hammond Department of Chemical Engineering, University of Leeds, Clarendon Road, Leeds LS2 9JT, England Received March 27, 2003;
Revised Manuscript Received March 31, 2004
ABSTRACT: The phase behavior and morphology of cyanazine crystallized from aqueous ethanol solutions are reported. Two distinct crystalline phases were observed. A single crystal X-ray structure determination revealed a monohydrate phase, having plate morphology and containing ordered sheets of water, in addition to a previously determined anhydrous phase having needle morphology. Molecular modeling studies were used to predict the different growth morphologies of the two crystal phases using both geometric and attachment energy models. In the presence of aqueous ethanol, a slow conversion of plate crystals to needle crystals was observed at all temperatures. Particle morphology was taken as a diagnostic for the relative amounts of the monohydrate and anhydrous phases present in the crystallizing mixture; consequently, the anhydrous phase was concluded to be the thermodynamically stable phase at all temperatures studied (above 10 °C). Image analysis of cyanazine crystals grown from agitated supersaturated solutions showed that the initial predominant crystal morphology was highly dependent upon solution supersaturation and water weight fraction, and to a lesser extent the temperature of the precipitating solution. 1. Introduction Previous investigations into the precipitation of the herbicide chemical cyanazine, Figure 1, (Bladex; Shell Chemicals Ltd.; systematic IUPAC name 2-(4-chloro-6(ethylamino)-1,3,5-triazin-2-ylamino)-2-methyl propionitrile) from aqueous ethanol solutions revealed that two distinct crystal morphologies, needles and platelets, were produced1 and that these have different crystal structures. The needles are anhydrous, while the platelets are monohydrates containing ordered sheets of water1,2 indicative of pseudopolymorphic behavior. In this paper, the molecular packing and morphology of the two crystal phases are modeled and compared and the conditions under which they form in bulk agitated suspensions are examined. Figure 1. Molecular structure of cyanazine.
2. Experimental Methods 2.1 Crystal Structure Determination. Table 1 summarizes crystallographic details for the anhydrous and monohydrate phases of cyanazine. 2.2 Crystal Melting Points. Melting points of both anhydrous and monohydrate crystal phases were determined by differential scanning calorimetry (Perkin-Elmer DSC7). 2.3 Image Analysis. Having observed that cyanazine crystals precipitated from aqueous ethanol solutions exist in two distinct morphologies, image analysis was employed to study the influence of water weight fraction, temperature, and supersaturation upon the relative number populations of crystals designated by morphology. The experimental procedure for preparing cyanazine crystals in bulk has been described previously.3 Briefly, cyanazine was precipitated from aqueous ethanol solution via antisolvent addition in a 1-L * Corresponding author. E-mail:
[email protected].
Table 1. Summary of Crystallographic Data for the Anhydrous and Monohydrate Phases of Cyanazine parameter a/Å b/Å c/Å β/° space group Z Volume/Å3 Density/g cm-3
anhydrous phase 13.984(5) 10.449(5) 17.146(6) 98.89(3) P21/n 8 2474.8 1.292
monohydrate phase 27.223(6) 10.663(2) 9.282(3) 93.05(2) C2/c 8 2690.6 1.277
agitated round-bottomed vessel. Once precipitation occurred samples from unseeded solutions were added to 50-mL sample cells. A dispersant (Morwet D425) was immediately added to the solution to prevent agglomeration from taking place. Samples were then pipetted onto a microscope slide with a cover slide placed on top. The sample was then wax sealed. An image analyzer (Contextvision GOP-302) was used to
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determine the percentage number and area of cyanazine needles and plates produced under different experimental conditions. Crystal shapes were immediately recorded on separate picture frames. The magnification of the optical lens was also recorded, while a graticule was used to measure the size of the crystals. A number count for the percentage number needles and plates in each batch as well as the measurement of each crystal dimension was then carried out.
3. Computational Methods Molecular modeling offers a sophisticated method for predicting steady state crystal shapes under various conditions. The relationship between the external structure of a crystal and its internal molecular arrangement was initially investigated by Bravais,4 Friedel,5 and Donnay and Harker,6 the studies of whom are collectively known as the BFDH theory. Application of the BFDH theory represents a quick approach for identifying the crystallographic forms {hkl} most likely to constitute a crystal habit. Later, the periodic bond chain (PBC) theory due to Hartman and Perdok7 quantified crystal morphology in terms of the interaction energy between crystallizing units. Calculations of the relative attachment energies of the most likely crystal faces, initially selected on the basis of decreasing interplanar spacing, have been used to predict the relative growth rates of crystal faces and hence crystal morphology.8 Both BFDH and attachment energy approaches were employed to calculate crystal morphologies in this work. The single crystal structure determinations provided the necessary atomic fractional coordinates of the asymmetric unit for use in the attachment energy calculations. The computer program used in the calculations reported here employed the methodology fully elucidated in the description of the program HABIT.9 Hydrogen atom positions were optimized, and atomic charges were calculated for the cyanazine molecule using the semiempirical AM1 method in MOPAC.10 The force-field parameters used were the nonbonded atomatom potential parameters from the Tripos force field.11 Predicted morphologies are generally less sensitive to force field than other approximations in the attachment energy model, and so use of the Tripos force field is suitable.12 Hydrogen bonds were treated by scaling the equilibrium van der Waals radii of the hydrogen and hydrogen-bond acceptor atoms. The suitability of the force-field parameters was assessed by comparing calculated lattice energies, for similar molecules, with experimentally determined sublimation enthalpies. In the case of cyanazine, no experimental sublimation enthalpy was available, but the force-field parameters were found to perform satisfactorily for similar molecules. A cut-off radius of 30 Å from the central test molecule was used in the calculations, such was found to be sufficient for convergence of the calculated lattice energy. Because of concerns regarding the efficacy of the force field, specifically, to treat hydrogen-bonding interactions involving water molecules and problems with the accurate location of the hydrogen atoms belonging to the water molecules, it was only possible to treat the anhydrous phase of cyanazine with the attachment energy model. 4. Results and Discussion 4.1 Crystal Structure of the Anhydrous Phase. The structural data are summarized in Table 1. The
Figure 2. Molecular packing arrangement in the anhydrous phase of cyanazine, view down the b-axis (hydrogen bonds indicated as broken lines).
Figure 3. Experimentally observed morphology for the anhydrous phase of cyanazine.
molecular packing arrangement in the anhydrous phase is illustrated in Figure 2. This figure gives an indication of the intermolecular hydrogen bonding between the cyanazine molecules. The average hydrogen-bonding ring nitrogen to amine hydrogen separation is 2.11 Å, and the corresponding separation between the nitrogen atoms is 3.09 Å. The crystal faces of the typical needle crystal used for structure determination were identified on the diffractometer and are illustrated in Figure 3. 4.2 Crystal Structure of the Monohydrate Phase. The structural data are summarized in Table 1. The structure determination ruled out the possibility that the plates and needles are polymorphs. By way of confirmation that a monohydrate phase was present, an analysis of the anisotropic temperature factors showed no anomalies in the case of the oxygen atom of the water molecule in comparison with the other atoms. The unit cell dimensions, given one long cell edge, are consistent with plate-shaped crystals. The molecular packing arrangement in the monohydrate phase is illustrated in Figure 4. The water molecules form chains along [010] which lie in planes perpendicular to [100]. The crystal faces of the typical plate crystal used for structure determination were identified on the diffractometer and are illustrated in Figure 5. 4.3 Crystal Melting Points. Differential calorimetry scans for the two crystal phases are overlaid in Figure
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Figure 4. Molecular packing arrangement in the monohydrate phase of cyanazine, view down the b-axis.
Figure 5. Experimentally observed morphology for the monohydrate phase of cyanazine.
Figure 7. Photomicrographs of cyanazine needles and plates (a) X ) 0.65, S ) 3.0; (b) X ) 0.65, S ) 3.0; (c) X ) 0.85, S ) 7.0; (d) X ) 0.80, S ) 5.0.
Figure 6. Differential scanning calorimetry results for both phases of cyanazine.
6. Crystals of the anhydrous phase give a single dominant peak, indicating a melting transition at 165.1 °C, while cyanazine plates show one sharp peak, indicating a melting transition at 163.2 °C and a broad peak above 60 °C. The latter is evidence of the gradual evaporation of water molecules from the crystal lattice, and the simultaneous rearrangement of cyanazine molecules to form the more stable anhydrous phase. This is verified by the closeness of the melting points at around 165 °C. Results from the DSC analysis, suggesting the relative stability ordering of the anhydrous and monohydrate phases, concur with observations made by optical microscopic analysis which showed that, with time, cyanazine platelets in solution fragmented, dissolved, and recrystallized as needles. Similar observations were found for cyanazine platelets filtered from solution and subjected to quick high-temperature oven drying. This experimental evidence suggests that the monohydrate phase is metastable above 10 °C, while the anhydrous phase is thermodynamically stable.
Figure 8. Effects of supersaturation and water weight fraction on the distribution of cyanazine crystal needles and plates.
4.4 Image Analysis. Photomicrographs of cyanazine exhibiting needles and plates are displayed in Figure 7. The effects of parameter changes on crystal habit are illustrated in Figures 8-10. All supersaturations reported in the following discussion were calculated on the basis of solubility data for the anhydrous phase of cyanazine in aqueous ethanol solutions.13 Given that the monohydrate phase, when in suspension, was observed to transform to the anhydrous phase over a long time scale (many days), it has been concluded that the monohydrate phase is thermodynamically less stable
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Figure 9. Effect of temperature on cyanazine crystal shape distribution at S ) 5.
Figure 11. Predicted Donnay-Harker morphological model for cyanazine monohydrate phase.
Figure 10. Effect of water weight fraction on cyanazine crystal shape distribution at S ) 5 and 10 °C.
Figure 12. Predicted Donnay-Harker morphological model of cyanazine anhydrous phase.
and therefore more soluble, at a given temperature and solvent composition, than the anhydrous phase. At low initial supersaturations (S < 3, where S is defined as the ratio of mass concentration of anhydrous solute to the mass of solvent) very few plate-shaped cyanazine crystals were produced at all three temperatures, irrespective of the water weight fraction. This observation is consistent with the monohydrate phase having a higher solubility and therefore exhibiting a lower level of supersaturation, although it was not possible to make solubility measurements specifically on the monohydrate phase. For water weight fractions X > 0.65 an increase in initial supersaturation decreased the percentage of needles in solution, and increased the percentage of plates. Eventually, at high enough initial supersaturations, platelets were the only form of cyanazine crystals present. Clearly, at higher supersaturations (with respect to the anhydrous phase), there is competition between formation of critical nuclei of the two phases. The thermodynamic driving force (supersaturation) to precipitation of the monohydrate phase at a given temperature and solvent composition is always smaller than for the anhydrous phase; nevertheless, with increasing supersaturation, a predominance of the monohydrate phase was observed. This implies that the free energy barrier to formation of a critical nucleus is smaller for the monohydrate phase and therefore the rate of nucleation is greater. An increase in supersaturation at water weight fractions X < 0.65 failed to produce any cyanazine platelets. It is interesting to note that a weight fraction of 0.65 of
water in the solvent mixture represents roughly a 4:1 molar ratio of water to ethanol. It seems unlikely that the absence of the monohydrate phase over a wide range of supersaturations for water weight fractions less than 0.65 can be due solely to the effects of solubility. Given that the solubility of anhydrous cyanazine is 300 times less in pure water than pure ethanol, interactions between solute and ethanol molecules are clearly favored over solute water interactions, but the latter are nevertheless feasible. Within the monohydrate crystal lattice the water molecules form into hydrogen-bonded chains along the [010] crystallographic direction. It is suggested therefore that clusters of water molecules may be necessary in solution during the nucleation process as a precursor to the hydrogen-bonded chains of water molecules finally manifest in the monohydrate crystalline phase. 4.5 Comparison of Experimentally Observed and Theoretically Calculated Crystal Morphology. Predicted morphological models for cyanazine platelets and needles based on BFDH and an attachment energy model prediction for the anhydrous phase are shown in Figures 11-13, respectively. The results from the application of the BFDH and attachment energy approaches are summarized in Table 2. Given are attachment and slice energies for the anhydrous phase, together with the relative growth rates of the individual faces of the crystalline phases. The calculated lattice energy for the anhydrous phase was -41.79 kcal/mol. In comparison the calculated and observed morphologies for both the monohydrate and anhydrous phases
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Figure 13. Predicted attachment energy morphological model for cyanazine anhydrous phase. Table 2. Summary of Morphological Modeling of the Anhydrous and Monohydrate Phases of Cyanazine relative growth rates crystal interplanar attachment slice attachment face spacing energy energy BFDH energy (hkl) dhkl Å kcal/mol kcal/mol model model 1 h 01 101 011 002 110 1 h 11 111 200
11.62 9.98 8.89 8.47 8.33 7.77 7.22 6.91
200 110 310 1 h 11 111 3 h 11 311 020
13.59 9.93 6.91 6.84 6.71 5.65 5.43 5.33
Anhydrous Phase -21.89 -19.90 -19.99 -21.80 -19.37 -22.42 -17.85 -23.94 -21.08 -20.71 -24.82 -16.96 -20.92 -20.87 -32.66 -9.13
1.00 1.16 1.31 1.37 1.39 1.50 1.61 1.68
1.23 1.12 1.09 1.00 1.18 1.39 1.17 1.83
Monohydrate Phase 1.00 1.37 1.97 1.99 2.03 2.41 2.50 2.55
of cyanazine using the BFDH and, in the case of the anhydrous phase, attachment energy models do not show close agreement. The two major underlying assumptions of the morphological models are (a) that any solvent effects are isotropic with respect to all crystal faces, and (b) that the level of supersaturation is sufficiently low that during crystal growth all the faces of the crystal maintain a layer upon layer growth mechanism (i.e., remain below the roughening temperature14). Since the morphological agreement is poor this can be taken as an indication of the operation of significant anisotropic solvent effects, and/or that the requirement for layer growth on all the crystal faces is not fulfilled. Further work could take into account such solvent effects in the modeling.15 5. Conclusions X-ray crystallography reveals that the cyanazine platelets, observed to precipitate from aqueous ethanol
solutions, represent a monohydrate phase while needleshaped cyanazine crystals represent an anhydrous phase. Within the monohydrate crystal lattice water molecules are arranged in hydrogen-bonded chains along [010] which, further, lie in sheets perpendicular to the crystallographic direction [100]. Image analysis results show that the initial predominant phase of cyanazine, produced by precipitation from aqueous ethanol solution, is highly dependent upon supersaturation and water weight fraction, and to a lesser extent the temperature of the precipitating solution. At supersaturations S > 3 and water weight fractions > 0.65 the number distributions of crystals, designated by morphology, are manifestations of the relative rates of the competing nucleation processes for the two phases. The monohydrate phase is not observed at water weight fractions < 0.65 irrespective of temperature or level of supersaturation. This indicates that the presence of clusters of water molecules may be necessary to enable nucleation of the monohydrate phase. Calculated models of the morphologies of the two phases show that the respective crystals have different steady-state crystal habits as expected. The dissimilarity of the calculated and observed morphologies indicates that a combination of nonisotropic solvent effects with crystal growth other than by a layer upon layer mechanism is operating during precipitation of the cyanazine phases. Acknowledgment. L.A.H. was supported by the EPSRC and Shell Research Limited. The authors are indebted to Dr. David Williams (Imperial College, London) for the determination of crystallographic data and to Mr. J. N. Drummond of Shell Research for helpful advice during the course of the project. References (1) Hurley, L. A., Ph.D. Thesis, University of London, 1993. (2) Hurley, L. A.; Jones, A. G.; Drummond, J. N. Precipitation of Cyanazine; In IChemE Research Event, Manchester, January, 1992, (Rugby: IChemE), pp 440-442. (3) Hurley, L. A.; Jones, A. G.; Drummond, J. N. Trans. IChemE 1995, 73 Part B, 52. (4) Bravais, A. Etudes Cristallographiques; Paris: GauthierVillars, 1866. (5) Friedel, G. Bull. Soc. Franc. Mineral 1907, 30, 326. (6) Donnay, J. D. H.; Harker, D. Am. Mineral. 1937, 22, 446. (7) Hartman, P.; Perdok, W. G. Acta Crystallogr. 1955, 8, 49. (8) Docherty, R.; Roberts, K. J. J. Cryst. Growth 1988, 88, 159. (9) Docherty, R.; Roberts, K. J.; Dowty, E. Comput. Phys. Comm. 1988, 51, 423. (10) Stewart, J. P. J. Comput.-Aided Mol. Des. 1990, 4, 1. (11) Clark, M. C.; Cramer, R. D., III; van Opdenbosch, N. J. Comput. Chem. 1989, 10, 982. (12) Brunsteiner, M.; Price, S. L. Cryst. Growth Des. 2001, 1, 447-453. (13) Hurley, L. A.; Jones, A. G.; Drummond, J. N. J. Chem. Eng. Data 1995, 40, 277. (14) Docherty, R.; Clydesdale, G.; Roberts, K. J.; Bennema, P. J. Phys. D., Appl. Phys. 1991, 24, 89. (15) ter Horst, J. H.; Geertman, R. M.; van Rosmalen, G. M. J. Cryst. Growth 2001 230, 277-284.
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