CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 2 363–368
PerspectiVes Growth of an Organic Co-Crystal upon a Component Subphase Colin C. Seaton,† Andrew Parkin,‡ Chick C. Wilson,‡ and Nicholas Blagden*,† Institute of Pharmaceutical InnoVation, School of Pharmacy, UniVersity of Bradford, Bradford, BD7 1DP, U.K., and WestCHEM Research School, Department of Chemistry, UniVersity of Glasgow, UniVersity AVenue, Glasgow G12 8QQ, U.K. ReceiVed NoVember 9, 2006; ReVised Manuscript ReceiVed October 17, 2007
ABSTRACT: We report on the templated growth of 2:1 benzoic acid/isonicotinamide co-crystal on a benzoic acid subphase. The molecular basis for the template, registry between the phases, is presented. The template growth of behavior of the title compound was contrasted with that from melt and solution. This approach may be applicable as a precursor for the synthesis of bulk composite crystals. Introduction A central principle of crystal engineering is the systematic design and synthesis of functional materials through the selective manipulation of intermolecular interactions. Within this context, a possible route for adjusting a molecular material’s properties is through combination with another component. This may result in either forming a composite, where the components exist as separate phases bound through a common epitaxial boundary, or a molecular compound or co-crystal,1 consisting of a single phase with the two separate components intimately bound. Co-Crystal and Multifunctional Materials. The co-crystallization of two or more components to create a new functional material is of interest to both academia and industry. For example, it is seen as a potential alternative to salts for modifying the physicochemical properties of an active pharmaceutical ingredient.2 This application is of interest since it may have fewer problems with polymorphism compared with single component systems.3 Composite Materials and Epitaxy. Forming a composite material is widely employed for creating functional materials with unique physical properties. It is also important in biomaterials4 where organic and inorganic phases are bound together. Traditionally, epitaxy research has focused on inorganic and mineral systems, and while many examples exist that typify the directed growth of crystalline materials on an ordered substrate (such as a crystal surface, self-assembled monolayer, or polymer) fewer examples exist for the growth of organic crystals on organic crystals. Lattice Registry and Directing Crystal Growth. It has been shown the sublimation of one material onto a crystal of another * Corresponding author. Telephone: +44 (0)1274 234765. Fax: +44 (0)1274 23. E-mail:
[email protected]. † University of Bradford. ‡ University of Glasgow.
Figure 1. Hot-stage microscopy of new co-crystal phase transformation (a) initial at 30 ºC and (b) transformed at 120 ºC.
may be a route to the selective nucleation and growth of polymorphic phases.5 The creation of composite coordination crystals6 through seeding or a nucleation template with isostructural crystals also highlights the potential for creating new molecular composites by solution crystal growth. In all these cases, complementary crystal lattices and intermolecular interac-
10.1021/cg060793m CCC: $40.75 2008 American Chemical Society Published on Web 12/20/2007
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component subphase and then to compare the resulting crystal growth behavior with the outcomes from conventional solution based crystallizations for a 1:1 ratio of starting components. Model System
Figure 2. Growth on benzoic acid template by new phase; inset shows schematic representation of finned growth with interaction angle indicated, bar 1 mm.
tions are required for the successful formation of the desired product.7 Similar geometric and molecular matches are also required for creating twinned crystals8 and directed habit modification.9 Lattice Registry and Cocrystallization. The work reported herein is a logical extension of these ideas and focuses on examining the possibility of a composite molecular co-crystal by a solution template nucleation route. A subphase which itself was a component of the co-crystal overlayer phase was chosen to encourage the selectivity of the process, since it should maximize the complementarities between the intermolecular interactions between the subphase and the overlayer. This is motivated by the need to have a design strategy that promotes a specific chemical and lattice similarity between the crystallizing phases on a pair of faces. This heightens the potential for template nucleation and enhances the possibility of epitaxial growth through surface chemistry molecular registry. To examine the proposed strategy for composite crystal design the benzoic acid/isonicotinamide co-crystal was employed as the model system. The overall approach adopted was to undertake the growth of a molecular co-crystal on a single
Isonicotinamide (INA) is a commonly selected compound for forming co-crystals,10 and the majority are with carboxylic acids. The structure of the 1:1 benzoic acid/isonicotinamide co-crystal (BZ-INA) was previously reported11 and was selected as the test case for these studies because of the significant differences in solubility12 of the two components in water (per 100 g of water at 40 °C, ∼0.5 g of benzoic acid, and ∼32 g of isonicotinamide). The differentiation in solubility is a specific requirement for the template studies. We have also previously shown that solvent choice will affect which phase is obtained.13 The thermodynamically stable 1:1 form was obtained from organic solvents, while from aqueous solution the metastable 2:1 phase was obtained. The specific details of the growth studies on BZ-INA co-crystal system and full details of the crystal structure of 2:1 benzoic acid:isonicotinamide co-crystal (2BZ-INA) have been previously reported.14 Experimental Section Template crystals of benzoic acid (BZ-template) were grown by slow evaporation of an aqueous solution; these were then used as the subphase, due to the difference in solubility with isonicotinamide. The overall composition of the growth solution for the epitaxy studies was based on the solubility of benzoic acid in water to ensure a saturated solution at 40 °C. For the template studies, an equimolar solution of benzoic acid (0.355 g, 0.003 mol) and isonicotinamide (0.334 g, 0.003 mol) in water (50 mL) was heated to 70 °C to ensure complete dissolution of the components. This solution was then cooled to 45 °C over 3 h, and the BZ-template was suspended in the solution. During the growth cycle, the solution was further cooled to 30 °C over a 15-h period. After this time, the BZ-template crystal was removed, washed, and examined
Figure 3. Comparison of simulated powder patterns for (a) benzoic acid, (b) form I isonicotinamide, (c) form II isonicotinamide, (d) 1:1 benzoic acid/isonicotinamide co-crystal, BZ-INA (e) 2:1 benzoic acid/isonicotinamide, and (f) the experimental pattern templated phase.
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Figure 4. Plot of the V/V0 against azimuth angle for selected faces of (a) BZ-INA and (b) 2BZ-INA against the (010) face of benzoic acid. using optical micrographs and previously reported characterization profiles of the 2BZ-INA and BZ-INA co-crystals.15
Results and Discussion Phase Formation. The experimental protocol adopted for our template studies are a consequence of the phase formation profile of BZ with INA from a solvent screen. The key points from the literature screens with regards phase formation of BZ with INA are as follows. For most of solvents13 the previously published co-crystal, BZ-INA, was obtained. However, cocrystallization of BZ with INA from water resulted in a crystal phase with a 2:1 ratio of BZ-INA as the persistent phase. This new phase 2BZ-INA was further characterized for component ratio, and the phase was identified.13 This characterization work showed that the material was a 2:1 benzoic acid/isonicotinamide co-crystal. The DSC data shows that 2BZ-INA is metastable relative to BZ-INA, and transformation between the forms was achieved at 143 °C; a mixture of BZ-INA + BZ was obtained as the 2:1 co-crystal transformed to the 1:1 co-crystal, and then the sample melted at 166 °C. This was confirmed by the hotstage microscopy (Figure 1) and with powder X-ray diffraction (XRD) of samples taken before and after transformation, which clearly showed that a solid-state phase transformation began at
∼120 °C. This transformation occurs within the limits of the melting point of benzoic acid, which is at 122 °C. Solid-State Method. Thermal microscopy (used to determine the binary phase diagram), which can be complemented by the Kofler contact method,16 reports the two co-crystal phases from melt crystallization.17 Also specific thermal microscopy studies and diffraction on 2BZ-INA14 have been undertaken and shows the 2BZ-INA will convert to the BZ-INA phase though a meltmediated solid-state process. This is accompanied by the concomitant sublimation of excess BZ as the stoichiometric composition of the co-crystal changes. A portion of the benzoic acid crystals are observed to form on the faces of the transforming co-crystal, and this suggests that a nucleated template growth of benzoic acid occurs during the conversion of the 2:1 to 1:1 phase. However, because of the kinetic aspects of this thermal growth process, studies on solution crystallization were undertaken to examine in greater detail the molecular basis for nucleation and growth of a co-crystal on a component subphase. The focus on a solution route in our work stems from the fact that it offers the possibility of avoiding a solid-state transformation during the template growth stage. To this end, the crystallization from water was examined for the template work, as this system has two desirable features. The first relates to
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Figure 5. Comparison of packing motifs for (a) 1:1 co-crystal and (b) 2:1 co-crystal.
Figure 6. A schematic representation of the envisaged pair motif registry between 2BZ-INA and BZ.
the difference in solubility of the components, and the second to the fact that this solvent system mediates the formation of the metastable 2:1 over the 1:1 phase, with the caveat that no short-term transformation to the more stable 1:1 phase was noted during our solution screen studies. Template Growth Studies. Visual inspection of a BZtemplate crystal, extracted from an incubated BZ-INA solution, confirmed that the formation of small, clear needle crystals had grown on specific faces of the BZ-template subphase crystal. A common binding angle of 37-38° was noted for the alignment between the subphase and these overlayer crystals. The overall visual morphology of these crystals suggests a composite crystal had been produced, as these small needle crystals had selectively nucleated and grown on the side (010) face of the BZ-template (Figure 2). The face selective nature of the process indicates that a registry exists between the two phases. BZ-template crystals that were left longer in the solution (up to 2 days) all displayed aligned crystal growth on {010} faces with limited growth on other faces; these crystals were easily distinguished as they were nonaligned and easily removed by washing or ultrasound. Repetition of the experiment pointed to the extent of nontemplated growth of the overlayer being
dependent on the time the BZ-template crystals were left in the solution and on the initial concentration of the parent solution. Powder X-ray Analysis of Overlayer Crystals. The X-ray powder diffraction pattern was collected for harvested aligned crystals on the BZ-template. Comparison with the predicted patterns of both starting materials (BZ-template and INA polymorphs, Figure 3a-c) and the co-crystals (BZ-INA and 2BZ-INA, Figure 3d-f) was undertaken, which indicated that the new phase was 2BZ-INA. Lattice Registry. The lattice registry between the BZtemplate (010) face and selected faces of both BZ-INA and 2BZINA co-crystals was investigated using the Epicalc methodology.18 In the case of BZ-INA, no face results in a commensurate interaction, (V/V0 > 0, Figure 4a), while 2BZ-INA has a commensurate match between the {100} and {001} faces with the (010) face of the BZ-template, (V/V0 ) 0, Figure 4b). The (010) face of the BZ-template is dominated by carboxylic acid functionalities. The angle of these groups to the surface is approximately 40°, and the similarity to the measured angle between the two crystals suggests a molecular registry between these groups and the growing co-crystal. Crystal Packing of BZ-INA Phase. One critical step for rationalizing the molecular basis for any interaction between the two BZ-INA phases and BZ subphase, is defining the similarities and differences in packing between BZ-INA and 2BZ-INA. The packing motifs of both phases are shown in Figure 5. Both forms feature the common CO2H · · · Nring hydrogen bond, which appears in the majority of isonicotinamide and carboxylic acid co-crystals.10 This interaction forms a heterodimer between the isonicotinamide and benzoic acid. These dimers then pair together in BZ-INA, (i.e., for 1:1 ratio the sequence BZ::INA::INA::BZ occurs) but are capped by the second benzoic acid molecule in 2BZ-INA, (i.e., for 2:1 ratio the sequence BZ::INA::BZ occurs), to form a -CO2H · · · -CONH2 ring. Molecular Registry. Considering the required molecular registry on the (010) face of benzoic acid with the 2BZ-INA overlayer would suggest the formation of such a ring motif is required for stability. A successful template at the molecular level requires the creation of an interaction between an INA molecule and the BZ-template, since the alternative would just increase the benzoic acid surface. From the existing co-crystal structures, this would occur through either CO2H · · · Nring or CO2H · · · CONH2 interactions. Subsequent addition of benzoic acid would then form the packing motifs of 2BZ-INA (Figure
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Figure 7. Experimental crystal face determination of 2BZ-INA.
6). The {100} and {001} faces of 2BZ-INA both offer the required functionality to bind through such motifs, and lattice agreement suggests that these faces are the most likely binding sites to support a nucleation template process. However, a single crystal study of 2BZ-INA identifies the {001} face as potential binding face (Figure 7). Additionally, the angle between this face and the growing dimer is 34°, which complements the existing angle of the substrate (Figure 8). However, to fully quantify this proposed model, a molecular level examination of the registry between these faces is currently under investigation. This uses the differential evolution optimizer to locate low energy packings between crystal blocks.7 Conclusion The nucleation and resulting stabilization of the metastable 2BZ-INA occurs during co-crystallization in water, using a 1:1 ratio of the components, and this differs from the solvent conditions previously reported for obtaining the BZ-INA phase, which is obtained from crystallization in organic solvents using a 1:1 ratio of the components. In the case of crystallization from aqueous solution, a significant difference in solubility exists between benzoic acid and isonicotinamide in water. For the organic solvents, BZ and INA have comparable solubilities, and this correlates with BZ-INA always being obtained from an equimolar composition in these types of solvents. The presence of BZ-template in an equimolar aqueous solution of the components was shown to be capable of supporting an epitaxially templated growth to create a composite material consisting of the 2:1 co-crystal on a BZ-template subphase. During template studies, sufficient supersaturation excess of benzoic acid was ensured to preserve the integrity of the BZ-template. This phase formation is in preference to the growth of isonicotinamide or BZ-INA on the subphase from aqueous solution. These conditions for templated growth in aqueous solution suggest that wherever the stabilization of the metastable 2BZ-INA is observed for a 1:1 ratio of the components a template growth mechanism is also possible. Our findings to date indicate that unless the solution chemistry is available the process does not occur; in the organic solvents with equimolar loading, where a greater similarity in solubility of the components exists, only BZ-INA is obtained and a template process is not supported. The 2:1 co-crystal, 2BZ-INA is a metastable phase to the previously published BZ-INA phase.
Figure 8. View of 2BZ-INA along the a-axis with the dimer growth direction and [010] face indicated.
Verification of the extent of this kinetic process will be the focus of future work and will involve determining the phase behavior of this system over a range of compositions and time-resolved diffraction studies. Overall, the new 2:1 phase has been shown to be isolatable from co-crystallization from aqueous solution, from a solution containing a 1:1 ratio of the components by a templated process and directly from solution studies. Overall, these findings are initial tentative steps to the rational design of organic multicomponent composite molecular solids, utilizing both a component phase and a co-crystal phase. This approach may be applicable as a precursor for the synthesis of bulk composite crystals for drug delivery systems and other applications relating to smart materials. Acknowledgment. We acknowledge the EPSRC for funding, Rigaku for the loan of a diffractometer, Oxford Cryosystems for the loan of a low-temperature device, Dr. David Apperley at the EPSRC solid-state NMR service, and Mr. David Berry (Bradford University) for collecting the DSC and solution NMR data. Supporting Information Available: Information on isonicotinamide torsion angles (Figures 1A and Table 1A). This information is available free of charge via the Internet at http://pubs.acs.org.
References (1) Herbstein, F. H. Crystalline Molecular Complexes and Compounds; Oxford University Press: UK, 2005.
368 Crystal Growth & Design, Vol. 8, No. 2, 2008 (2) (a) Morrissette, S. L.; Almarsson, O.; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R. AdV. Drug DeliVery ReV. 2004, 56, 275. (b) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499. (3) (a) Almarrsson, O.; Zaworotko, M. J. Chem Commun. 2004, 1889. (b) Vishweshwar, P.; McMahon, J. A.; Peterson, M. L.; Hickey, M. B.; Shattock, T. R.; Zaworotko, M. J. Chem. Commun. 2005, 4601. (4) (a) Vogelson, C. T. Mod. Drug DiscoVery 2001, 4, 49. (b) Davis, S. A.; Dujardin, E.; Mann, S. Curr. Opin. Solid State Mater. Sci. 2003, 7, 273. (5) (a) Carter, P. W.; Ward, M. D. J. Am. Chem. Soc. 1994, 116, 769. (b) Bouafede, S. J.; Ward, M. D. J. Am. Chem. Soc. 1995, 117, 7853. (c) Mitchell, C. A.; Yu, L; Ward, M. D. J. Am. Chem. Soc. 2001, 123, 10830. (d) Hiremath, R; Varney, S. W.; Swift, J. A. Chem. Commun. 2004, 2676. (e) Price, C. P.; Grzesiak, A. L.; Matzyer, A. J. J. Am. Chem. Soc. 2005, 127, 5512. (f) Hiremath, R.; Basile, J. A.; Varney, S. W.; Swift, J. A. J. Am. Chem. Soc. 2005, 127, 18321. (6) (a) Luo, T. J. M.; McDonald, J. C.; Palmore, G. T. R. Chem. Mater. 2004, 16, 4916. (b) Dechambenoit, P.; Ferlay, S.; Hosseini, M. W. Cryst. Growth Des. 2005, 5, 2310. (7) Seaton, C. C.; Blagden, N. ACA Trans. 2004, 39, 90. (8) (a) Lieberman, H. F.; Williams, L.; Davey, R. J.; Pritchard, R. G. J. Am. Chem. Soc. 1998, 120, 686. (b) Davey, R. J.; Williams-Seton, L.; Lieberman, H. F.; Blagden, N. Nature 1999, 402, 797. (c) Edgar, R.; Schultz, T. M.; Rasmussen, F. B.; Feidenhans’l, R.; Leiserowitz, L. J. Am. Chem. Soc. 1999, 121, 632. (d) Cashell, C.; Sutton, D.; Corcoran, D.; Hodnett, B. K. Cryst. Growth Des. 2003, 3, 869. (e) Blagden, N.; Song, M.; Davey, R. J.; Seton, L.; Seaton, C. C. Cryst. Growth Des. 2005, 5, 467. (9) (a) Weissbuch, I.; Addadi, L.; Lavah, V.; Leiserowitz, L. Nature 1991, 253, 637. (b) Weissbuch, I.; Popovitzbiro, R.; Lahav, M.; Leiserowitz, L. Acta Crystallogr. Sect. B 1995, 51, 115. (10) 34 co-crystal structures in the CSD (November 2006 release). (11) Åakröy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem., Int. Ed. 2001, 40, 3240. (12) Mullin J. W. Crystallization, 4th ed.; Elsevier: UK, 2001. (13) Re-examination of the solution crystallization of BZ-INA co crystals: A limited screen of the co-crystallization of a 1:1 mixture of benzoic acid and isonicotinamide in a range of solvents was also undertaken for comparison (the solvents were water, methanol, ethanol, nitromethane, propan-2-ol, and THF, solution loadings typically up to
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(14) (15)
(16)
(17)
(18)
(19)
40 mg/mL). In all cases, crystals were obtained through slow evaporation of a saturated solution. The saturated solution was obtained by heating 20 mL of the chosen solvent to 5 °C below boiling point and then loading with an equimolar amount of the components BZ and INA to achieve saturation. All chemicals and solvents were obtained from Aldrich and of 99.9% purity for the chemicals and HPLC grade for the solvents. All the resulting materials were first identified by X-ray powder diffraction.15 Any new phase was further characterized15 by DSC, hot stage microscopy, solution (1H and 13C), and solid-state NMR (13C), and single crystal studies were attempted. Seaton C. C.; Parkin A.; Wilson C. C., Blagden N. Cryst. Growth Des., submitted. Data Collection: All X-ray powder diffraction data (5° e 2θ e 40° in 0.02 steps over 1 h) were collected on a Bruker-AXS D8 FOCUS using Cu KR radiation in θ-θ reflection geometry and a scintillation counter. With phase specific peaks at 6.5°, 14.5°, and 19.0° 2-θ for 2BZ-INA, compared to BZ (9.0°, 33.0°), INA-I (18.1°, 26.5°), INAII (15.0°, 22.0°), BZ-INA (13.0°, with common peak with 2BZ-INA at 26.0°). The DSC data were collected on a Perkins-Elmer DSC7 with a heating rate of 10 °C/min. The 2BZ-INA crystals were faceindexed using the program RAXSHAPE within the CrystalClear suite of programs.19 Solution NMR was collected on a JEOL GX at 270MHz. δH (ppm): 7.45 (t, CHCHCCO2H), 7.59 (t, CHCHC), 7.74 (br s, CONH2), 7.77 (d, CH-CCONH2), 7.96 (d, CHCCO2H), 8.26 (br s, CONH2), 8.71 (d, NCHCHring). δC (ppm): 122.0 (NCHCHring), 129-133 (Phbenzoic), 141.8 (Chetero-CONH2), 150.8 (NCHCHring), 166.9 (CONH2), 167.9 (CO2H). The solid-state NMR data for 2BZ-INA was collected by the EPSRC service at University of Durham, δC (ppm): 123.3 (NCHCHring), 129-133 (Phbenzoic), 142.9 (Chetero-CONH2), 149.1 (NCHCHring), 169.8 (CONH2/CO2H{overlap}). Kofler, L.; Kofler, A. Thermal Micromethods for the Study of Organic Compounds and Their Mixtures, Wagner, Innsbruck (1952), translated by McCrone, W. C.; McCrone Research Institute: Chicago, 1980. (a) Sangster, J. J. Phys. Chem. Ref. Data 1999, 28 (4), 889. (b) SekiguchiK.HimuroI.; Horikoshi, I.; Tsukada, T.; Okamoto, T.; Yotsuyanagi, T. Chem. Pharm. Bull. 1969, 17, 191. (a) Hiller, A. C.; Ward, M. D. Phys. ReV. B 1996, 54 (19), 14037. (b) Last, J. A.; Hooks, D. E.; Hillier, A. C.; Ward, M. D. J. Phys. Chem. B. 1999, 103 (32), 6723. CRYSTALCLEAR 1.3.6; Rigaku: The Woodlands, TX, 1998.
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