CRYSTAL GROWTH & DESIGN
Formation of New Polymorphs of Acridine Using Dicarboxylic Acids as Crystallization Templates in Solution
2004 VOL. 4, NO. 6 1099-1103
Xuefeng Mei and Christian Wolf* Department of Chemistry, Georgetown University, Washington, D.C. 20057 Received April 9, 2004
ABSTRACT: Two new polymorphic structures of acridine have been prepared using terephthalic and cis,trans-muconic acid as templates in a supersaturated phase to affect the nucleation process and crystal growth of acridine by hydrogen-bonding and π-π interactions. Isothermal evaporation of a solution of acridine in ethanol afforded a single crystal structure consisting of V-shaped arrangements of dimeric acridine π-stacks (acridine II), whereas the template-assisted crystallization approach resulted in the formation of the new polymorphs acridine VI and VII exhibiting less regular packing motifs. Crystal polymorphism is a widespread phenomenon that plays a major role in the development of pharmaceuticals, organic pigments, or explosives.1 The ability of organic molecules to crystallize in several packing arrangements or in various conformations can result in the formation of different crystal morphologies, which is often accompanied by significant changes of the physical properties such as color, solubility, bioavailability, and thermodynamic stability.2 A common strategy for the optimization of the physical properties of crystalline organic materials is to alter the supramolecular arrangement through structural modifications at the molecular level. The careful selection and modification of a supramolecular synthon’s directional and nondirectional forces, such as hydrogen bonding, electrostatic forces, and π-π or CH/π interactions, has become an important tool in crystal engineering.3 For example, drug development efforts often include extensive screening of chemically derivatized prodrugs to identify crystals with superior shelf life and bioavailability.4 However, the manipulation of the packing arrangement of a crystal through derivatization of the molecular structure of a drug is limited since this may ultimately affect the drug’s pharmacological and toxicological properties. The development of new tools to induce or, if possible, to control polymorphism of organic compounds without the need for structural modification is therefore of high importance. Efforts to grow single crystals of organic compounds commonly include temperature lowering, isothermal evaporation, and isothermal diffusion crystallization techniques.5 The use of structurally similar additives that direct the nucleation process of a synthon through habit modification in the supersaturated solution has been recognized as a new entry toward manipulating crystal formation and growth.6 Acridines have found extensive use as antimalarials binding to protoporphyrin IX,7 anti-prions,8 and antimicrobial and anticancer DNA intercalating drugs.9 The control of the polymorphism of potential drug candidates derived from acridine is therefore crucial for future drug development efforts. Herein, we report the preparation of two new polymorphs of acridine using complimentary dicarboxylic acid crystallization templates in solution. Five polymorphic modifications of acridine including form I, which is a hydrate, have been reported to date (Table 1).10 The four anhydrous crystal forms of acridine * To whom correspondence should be addressed. Tel: +1 202 687 3468. Fax: +1 202 687 6209. E-mail:
[email protected].
Figure 1. Crystal structure of acridine II. Table 1. Crystallographic Data of the Polymorphic Forms of Acridine crystal structure
form II
form III
form IV
form V
crystal system space group a (Å) b (Å) c (Å) β V
monoclinic P21/n 11.375 5.988 13.647 98.97 818.2
monoclinic P21/a 16.292 18.831 6.072 95.07 1855.5
orthorhombic P212121 15.61 29.34 6.22 90 2848.7
monoclinic Aa 20.04 5.95 16.37 110.63 1826.8
exhibit different packing motifs and physical properties.11 Acridine II is monoclinic and belongs to the P21/n space group,12 whereas acridine III exhibits a monoclinic system belonging to the P21/a space group.13 Acridines IV and V have been characterized as orthorhombic (P212121) and monoclinic (Aa) crystals.14 Form II has been reported to be the most stable polymorph of acridine.11b We were able to grow a single crystal of acridine II from ethanol through isothermal solvent evaporation (Figure 1). The crystal structure shows π-stacked antiparallel acridine dimers arranged in a Vshaped packing pattern. However, single crystals of acridine and derivatives thereof exhibiting a less regular packing motif and a less stable crystal lattice than acridine
10.1021/cg0498655 CCC: $27.50 © 2004 American Chemical Society Published on Web 09/03/2004
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Figure 2. Structures of cis,trans-muconic and terephthalic acid.
Scheme 1. Packing Motif of the Ionic Supramolecular Structure Consisting of Antiparallel Acridine Rings and Isophthalic Acid Anions
II are likely to have superior pharmacological properties such as enhanced solubility and bioavailability. Shameri and co-workers reported the formation of a supramolecular salt from acridine and isophthalic acid consisting of antiparallel acridinium molecules that undergo π-stacking stabilized by infinite anionic chains of dicarboxylic acids along the a-axis of the crystal.15 The chains of dicarboxylic acid synthons are stabilized by strong OH‚‚‚O bonds and through hydrogen bonding between the carboxylate groups and the acridinium moieties. The packing motif is illustrated in Scheme 1. Because of the well-known polymorphism of acridine and the significance of its derivatives in drug development, we have become interested in using carboxylic acids as solution templates to manipulate the nucleation and crystallization process. We assumed that dicarboxylic acids with different geometries are likely to afford distinct aggregates with acridine stabilized by hydrogen-bonding and π-π interactions. Accordingly, dicarboxylic acids exhibiting a welldefined geometry and strong directional forces could prearrange acridine molecules in solution prior to crystallization and thus induce new polymorphic forms of the latter. We therefore attempted to grow single crystals of acridine in the presence of cis,trans-muconic and terephthalic acids exhibiting different geometries and intramolecular distances between the acid functions (Figure 2). Cocrystallization experiments employing acridine and equimolar amounts of cis,trans-muconic and terephthalic acid revealed the formation of a distinctive packing arrangement (Figure 3).16 A closer look at the cocrystal structures reveals that acridine and cis,trans-muconic acid undergo proton transfer to form an organic salt consisting of antiparallel acridinium π-stacks stabilized by alternating hydrogen bonding with two polymeric carboxylate chains that also undergo headto-tail hydrogen bonding. By contrast, acridine and terephthalic acid form neutral cocrystals exhibiting antiparallel acridine dimers but not infinite π-stacks as the distance between neighboring acridine molecule alternates. The acridine dimers are stabilized through OH‚‚‚N and
Communications CH‚‚‚O hydrogen bonds with terephthalic acid molecules. The solid state structures of the two cocrystals are significantly different as a consequence of the different molecular geometry of the dicarboxylic acids used and the constituent supramolecular synthons, i.e., neutral O -H‚‚‚N hydrogen bonds and charge-assisted O-‚‚‚H-N+ hydrogen bonding.16 We therefore assumed that the presence of either cis,trans-muconic or terephthalic acid templates in solution would favor the formation of structurally different acridine aggregates. However, it should be noted that proton transfer between aromatic heterocycles and carboxylic acids has been reported to occur independently in solution and during crystallization indicating that crystallographic analysis of an organic salt does not provide unequivocal evidence for in solution proton transfer.17 Nevertheless, we rationalized that crystallization of acridine in the presence of substoichiometric amounts of the acid template could be achieved by screening a variety of solvents. The employment of 50 mol % of the template would favor the formation of small aggregates, impede cocrystallization, and ultimately result in template-assisted crystallization of new polymorphic forms of acridine. Although the various aspects of crystallization (nucleation, crystal growth, and dissolution) are generally not understood, it seems reasonable that the presence of a dicarboxylic acid template can inhibit the formation of a regular packing motif such as form II and thus induce the formation of other polymorphs. After we screened various solvents including ethyl alcohol, methyl alcohol, acetonitrile, and dimethylformamide to prevent cocrystallization, we were able to grow single crystals of acridine suitable for crystallographic analysis from solutions containing 50 mol % of terephthalic acid and cis,trans-muconic acid, respectively. We were pleased to find that the presence of the dicarboxylic acids results in the reproducible formation of distinct acridine packing arrangements. Our templateassisted crystallization approach afforded two new polymorphic structures of acridine. Polymorph VI was obtained by slow solvent evaporation from EtOH:MeOH (1:1) in the presence of 0.5 equiv of terephthalic acid (Figure 4).18 Form VII was prepared by slow crystallization from dimethyl formamide (DMF) in the presence of 0.5 equiv of cis,transmuconic acid (Figure 5).19 Both polymorphs are monoclinic and belong to the Cc and P21/n space group, respectively (Table 2). By contrast, crystallization of acridine using DMF or a 1:1 mixture of methanol and ethanol as the solvent in the absence of acid templates was found to result in the formation of polymorph II. Although the nucleation and crystallization process of acridine and the role of the solvents used are not fully understood, we believe that thepresence of 50 mol % of terephthalic acid or cis,transmuconic acid results in the formation of distinct aggregates in solution prior to crystallization and thus in the induction of polymorphism. The crystal structure of form VI shows the presence of two independent acridines in the asymmetric unit forming a V-shaped arrangement of chains of acridines exhibiting a parallel orientation (Figures 6 and 7). The net parallel acridine orientation
Figure 3. Packing arrangements of the supramolecular structures obtained with acridine and equimolar amounts of cis,trans-muconic acid (top) or terephthalic acid (bottom).
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Figure 4. Asymmetric unit of acridine VI.
Figure 8. Projection of antiparallel acridines in polymorph VII. Figure 5. Asymmetric unit of acridine VII.
Figure 6. Projection of offset parallel acridines in polymorph VI. Figure 9. Crystal structure of acridine VII.
interactions. The parallel acridine arrangement may be a consequence of interactions with the terephthalic acid in solution; that is, the acid template may impede the formation of a thermodynamically more stable packing motif such as form II.
Figure 7. Crystal structure of acridine VI. Table 2. Crystallographic Data of Acridine VI and VII crystal structure
form VI
form VII
crystal system space group a (Å) b (Å) c (Å) β V
monoclinic Cc 6.174 23.498 12.868 96.48 1854.8
monoclinic P21/n 6.057 22.813 13.204 95.94 1814.6
results in the noncentrosymmetric space group Cc and a new polar polymorph. It is noteworthy that the acridine molecules do not undergo face-to-face or face-to-edge
Employing cis,trans-muconic acid as an additive in the crystallization of acridine was also found to impede the formation of the most stable polymorph II. Crystallographic analysis of form VII revealed a new crystal structure consisting of distinct acridine tetramers exhibiting a packing arrangement similar to polymorph II (Figures 8 and 9). We assume that the diffusion of cis,trans-muconic acidstabilized acridine aggregates onto the crystal surface precludes the formation of the regular crystal structure of form II and favors the formation of polymorph VII. The presence of two independent molecules in the asymmetric unit results in two packing patterns, i.e., antiparallel acridine dimers that undergo π-π interactions and form a V-shaped arrangement with two acridines. As a consequence of the antiparallel acridine packing, form VII affords a centrosymmetric space group P21/n. The distance between the antiparallel acridines was determined as 3.66 Å. The two peripheral acridines of the tetramers are stabilized by face-to-edge interactions with acridine rings from adjacent tetrameric units. In contrast to form VII exhibiting π-stacked acridine rings, the offset arene arrangement in polymorph VI precludes stabilization of the crystal lattice by π-π interactions. Accordingly, we assume that acridine VII is the more
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Figure 10. Packing motif in acridine polymorphs II, III, and VII (from left to right).
stable polymorph, which is supported by a higher melting point and density. The melting point and density have been determined as 99 °C (1.283 g/cm3) for acridine VI and 101 °C (1.312 g/cm3) for acridine VII. Polymorphs VI and VII do not afford the regular herringbone packing motif of form II but a perpendicular arrangement of dimeric or tetrameric units (Figures 1, 7, and 9). It should be noted that thermodynamically favored acridine II has a melting point of 107 °C and a calculated density of 1.325 g/cm3. Although polymorphic forms II, III, and VII are in the same space group, they clearly afford different packing motifs (Figure 10). Form II shows a regular herringbone packing, whereas forms III and VII have a less regular packing motif exhibiting a zigzag or perpendicular arrangement of tetrameric units. In summary, we have studied the molecular arrangements and directional forces between dicarboxylic acids and acridine by crystallographic analysis of their cocrystals and utilized a solid state-deduced molecular recognition model to prepare two new polymorphs of acridine. Acridines VI and VII have been prepared using 50 mol % of terephthalic and cis,trans-muconic acid in solution to demonstrate the feasibility of polymorphism induction by using acid templates that preorganize acridine synthons in a supersaturated phase prior to crystallization. Although a systematic strategy toward template-engineered polymorphs is still elusive, we expect that this concept will become a useful tool to induce polymorphism of basic compounds. Acridine VI was obtained by slow solvent evaporation of EtOH:MeOH (1:1) in the presence of 0.5 equiv of terephthalic acid. Form VII was prepared by slow crystallization from DMF in the presence of 0.5 equiv of cis,transmuconic acid. Acridine II was obtained by isothermal evaporation of solutions in ethanol or DMF or by using a 1:1 mixture of methanol and ethanol. Single crystal X-ray diffractions were performed at -86 (acridine VI) and -88 °C (acridine VII) using a Siemens P4 Single Crystal platform diffractometer with graphite monochromated Mo KR radiation (λ ) 0.71073 Å). The structures were solved by direct methods and refined with full-matrix least-squares difference Fourier analysis using SHELX-97-2 software. Nonhydrogen atoms were refined with anisotropic displacement parameters, and all hydrogen atoms were placed in calculated positions and refined with a riding model. Data were corrected for the affects of absorption using SADABS. Supporting Information Available: Crystallographic data of acridine VI and VII. This material is available free of charge via the Internet at http://pubs.acs.org.
References (1) (a) Desiraju, G. R. Crystal Engineering: The Design of Organic Solids; Elsevier: New York, 1989. (b) Moulton, B.; Zaworotko, M. J. Chem. Rev. 2001, 101, 1629-1658. (c) McMahon, J. A.; Zaworotko, M. J.; Remenar, J. F. Chem. Commun. 2004, 278-279. (2) (a) Timofeeva, T. V.; Kuhn, G. H.; Nesterov, V. V.; Nesterov, V. N.; Frazier, D. O.; Penn, B. G.; Antipin, M. Y. Cryst. Growth Des. 2003, 3, 383-391. (b) Price, C. P.; Grzesiak, A. L.; Kampf, J. W.; Matzger, A. J. Cryst. Growth Des. 2003, 3, 1021-1025. (c) Vrcelj, R. M.; Sherwood, J. N.; Kennedy, A. R.; Gallagher, H. G.; Gelbrich, T. Cryst. Growth Des. 2003, 3, 1027-1032. (3) (a) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311-2327. (b) Braga, D. Chem. Commun. 2003, 27512754. (4) Reutzel-Edens, S. M.; Bush, J. K.; Magee, P. A.; Stephenson, G. A.; Byrn, S. R. Cryst. Growth Des. 2003, 3, 897-907. (5) Hulliger, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 143162. (6) (a) Weissbuch, I.; Leiserowitz, L.; Lahav, M. Adv. Mater. 1990, 2, 40-43. (b) Weissbuch, I.; Leiserowitz, L.; Lahav, M. Adv. Mater. 1994, 6, 952-956. (c) Davey, R. J.; Bladgen, N.; Potts, G. D.; Docherty, R. J. Am. Chem. Soc. 1997, 119, 1767-1772. (d) Caira, M. R. Top. Curr. Chem. 1998, 198, 163-208. (e) He, X.; Stowell, J. G.; Morris, K. R.; Pfeiffer, R. R.; Li, H.; Stahly, G. P.; Byrn, S. R. Cryst. Growth Des. 2001, 1, 305-312. (f) Davey, R. J.; Bladgen, N.; Righini, S.; Alison, H.; Ferrari, E. S. J. Phys. Chem. B 2002, 106, 19541959. (g) Blagden, N.; Davey, R. J. Cryst. Growth Des. 2003, 3, 873-885. (h) Thallapally, P. K.; Jetti, R. K. R.; Katz, A. K.; Carrell, H. L.; Singh, K.; Lahiri, K.; Kotha, S.; Boese, R.; Desiraju, G. R. Angew. Chem., Int. Ed. 2004, 43, 11491155. (7) (a) Peters, W.; Robinson, B. L. Ann. Trop. Med. Parasitol. 1992, 86, 455-457. (b) Dominguez, J. N. Curr. Top. Med. Chem. 2002, 2, 1173-1185. (c) Ridley, R. G. Nature 2002, 415, 686-693. (d) Di Giorgio, C.; Delmas, F.; Filloux, N.; Robin, M.; Seferian, L.; Azas, N.; Gasquet, M. Costa, M.; Timon-David, P.; Galy, J.-P. Antimicrob. Agents Chemother. 2003, 47, 174-180. (8) Korth, C.; May, B. C. H.; Cohen, F. E.; Prusiner, S. B. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 9836-9841. (9) (a) Yang, X.; Robinson, H.; Gao, Y.-G.; Wang, A. H.-J. Biochemistry 2000, 39, 10950-10957. (b) Baguley, B. C.; Wakelin, L. P. G.; Jacintho, J. D.; Kovacic, P. Curr. Med. Chem. 2003, 10, 2643-2649. (c) Teulade-Fichou, M.-P.; Perrin, D.; Boutorine, A.; Polverari, D.; Vigneron, J.-P.; Lehn, J.-M.; Sun, J.-S.; Garestier, T.; Helene, C. J. Am. Chem. Soc. 2001, 123, 9283-9292. (10) Lowde, R. D.; Phillips, D. C.; Wood, R. G. Acta Crystallogr. 1953, 6, 553-556. (11) (a) Kofler, A. Ber. Dtsch. Chem. Ges. 1943, 76, 871-873. (b) Clarke, B. P.; Thomas, J. M.; Williams, J. O. Chem. Phys. Lett. 1975, 35, 251-254. (12) Phillips, D. C.; Ahmed, F. R.; Barnes, W. H. Acta Crystallogr. 1960, 13, 365-377. The crystal structure of form II was also prepared by us using slow evaporation of ethanol): Formula, C13H9N; M ) 179; crystal dimensions, 0.5 mm × 0.4 mm × 0.2 mm; monoclinic; space group, P21/n; a ) 11.253 Å; b )
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(13) (14) (15)
(16) (17) (18)
5.951 Å; c ) 13.602 Å; β ) 99.53°; V ) 898.28 Å3; Z ) 2; Fcalcd ) 1.3250 g cm-3; 2θmax ) 54°; T ) -88°; R1 ) 3.81%; wR2 ) 0.1155 with I > 2σ(I); Rσ ) 0.018; GooF ) 1.101; ∆Fmax ) 0.27 e Å-3; ∆Fmin ) -0.16 e Å-3. Phillips, D. C. Acta Crystallogr. 1956, 9, 237-250. Herbstein, F. H.; Schmidt, G. M. J. Acta Crystallogr. 1955, 8, 399-405. (a) Shaameri, Z.; Shan, N.; Jones, W. Acta Crystallogr. Sect. E 2001, 57, O1075-O1077. (b) Shaameri, Z.; Shan, N.; Jones, W. Acta Crystallogr. Sect. E 2001, 57, O945O946. Mei, X.; Wolf, C. Eur. J. Org. Chem., in press. (a) Lee, I. S.; Shin, D. M.; Chung, Y. K. Cryst. Growth Des. 2003, 3, 521-529. (b) Bhogala, B. R.; Nangia, A. Cryst. Growth Des. 2003, 3, 547-554. Crystal structure data of form VI: Formula, C26H18N2; M ) 358; crystal dimensions, 0.5 mm × 0.1 mm × 0.1 mm; monoclinic; space group, Cc; a ) 6.174(2) Å; b ) 23.497(8)
Crystal Growth & Design, Vol. 4, No. 6, 2004 1103 Å; c ) 12.867(4) Å; β ) 96.483(6)°; V ) 1854.84 Å3; Z ) 4; Fcalcd ) 1.2834 g cm-3; 2θmax ) 56°; T ) -86°; 4196 independent reflections (Rint ) 5.38%), of which 1734 were above 4σ(F); R1 ) 0.0403; wR2 ) 0.0808 with I > 2σ(I); Rσ ) 0.136; GooF ) 0.713; ∆Fmax ) 0.11 e Å-3; ∆Fmin ) -0.15 e Å-3. (19) Crystal structure data of form VII: Formula, C26H18N2; M ) 358; crystal dimensions, 0.5 mm × 0.3 mm × 0.3 mm; monoclinic; space group, P21/n; a ) 6.057(1) Å; b ) 22.812(3) Å; c ) 13.204(2) Å; β ) 95.94(4)°; V ) 1814.64 Å3; Z ) 4; Fcalcd ) 1.3118 g cm-3; 2θmax ) 56°; T ) -88°; 4251 independent reflections (Rint ) 4.59%), of which 2562 were above 4σ(F); R1 ) 0.0573; wR2 ) 0.1517 with I > 2σ(I); Rσ ) 0.0545; GooF ) 1.006; ∆Fmax ) 0.22 e Å-3; ∆Fmin ) -0.22 e Å-3.
CG0498655
