Published on Web 11/09/2005
`
`The Predictably Elusive Form II of Aspirin
`Peddy Vishweshwar,† Jennifer A. McMahon,† Mark Oliveira,‡ Matthew L. Peterson,‡ and
`Michael J. Zaworotko*,†
`Department of Chemistry, UniVersity of South Florida, CHE205, 4202 East Fowler AVenue, Tampa, Florida 33620,
`and TransForm Pharmaceuticals, Inc., 29 Hartwell AVenue, Lexington, Massachusetts 02421
`
`Received September 20, 2005; E-mail: xtal@usf.edu
`
`Polymorphism, the existence of more than one crystalline form
`of a compound, is an intensely studied phenomenon, yet it remains
`poorly understood and controlled.1 Polymorphism in active phar-
`maceutical ingredients, API’s, is critical from both regulatory and
`intellectual property perspectives1a since polymorphs can exhibit
`different physical and/or chemical properties. However, the very
`nature of API’s, which typically exhibit exterior hydrogen bonding
`sites and/or conformational flexibility, makes them ideal candidates
`for polymorphism control using additives or templates.2 Further-
`more, whereas API’s have traditionally been limited to polymorphs,
`solvates, and salts,3 in recent years, an alternative form, pharma-
`ceutical co-crystals, has been targeted.4 In this context, aspirin is
`somewhat of an enigma. Aspirin was first synthesized in 18535
`and had by the turn of the 19th century become the world’s best-
`selling drug.6 In the 1960s and 1970s, aspirin was subjected to a
`series of studies7 to determine whether it exhibits polymorphism,
`and there were indications that there could be a metastable form.7d
`However, these studies were inconclusive. In the end, differences
`in physical properties were attributed to salicylic acid impurities.8
`Most recently, computational studies have addressed polymorphism
`in aspirin.9
`In this contribution, we report the results of a series of studies
`concerning pharmaceutical co-crystals of aspirin, resulting in
`isolation and structural characterization of the elusive form II of
`aspirin as well as a pharmaceutical co-crystal involving aspirin and
`another API, carbamazepine.
`
`The crystal structure of aspirin form I has been studied by both
`X-ray10 and neutron diffraction.11 Herein we shall use as a reference
`point Wilson’s 100 K structure11 (CSD refcode: ACSALA02) to
`compare with form II since our data were also collected at 100 K.
`Form I consists of centrosymmetric carboxylic acid dimer moieties
`(O(cid:226)(cid:226)(cid:226)O: 2.635 Å, 177.7(cid:176) ) that are, in turn, linked via centro-
`symmetric methyl C-H(cid:226)(cid:226)(cid:226)O (C(cid:226)(cid:226)(cid:226)O: 3.553 Å, 164.0(cid:176)) 12 contacts
`of acetyl groups, thereby forming 1D chains (Figure 1a).
`Aspirin form II was repeatedly obtained during attempted 1:1
`co-crystallization of aspirin and levetiracetam from hot acetonitrile
`and was subsequently also observed in the presence of a molar
`equivalent of acetamide. Small plate-like crystals form in ap-
`proximately 3 days, and one was mounted on a diffractometer
`directly from the viscous mother liquor to avoid conversion into
`form I. In addition to single crystal structure determination, form
`II was also characterized by melting point, IR, DSC, and HPLC
`
`† University of South Florida.
`‡ TransForm Pharmaceuticals, Inc.
`16802 9 J. AM. CHEM. SOC. 2005, 127, 16802-16803
`
`Figure1. Crystal packing of aspirin forms I, II, and S. L. Price predicted
`form II. (a) Form I: 1D chains sustained by alternating carboxylic acid
`and acetyl group centrosymmetric dimers. (b) Form II: acid dimers are
`connected via catemeric methyl C-H(cid:226)(cid:226)(cid:226)O and phenyl C-H(cid:226)(cid:226)(cid:226)O (not shown)
`hydrogen bonds. (c) Acetyl group C-H(cid:226)(cid:226)(cid:226)O dimers in form I and catemers
`in form II. (d) S. L. Price predicted form II. Note the similarity with the
`crystal packing of form II (b).
`
`(see Supporting Information). Crystals of form II convert to form
`I under ambient conditions; however, they are relatively stable at
`100 K. DSC thermograms reveal an endothermic peak at 135.5 (cid:176)C
`for form II versus a melting transition at 143.9 (cid:176)C for form I. The
`chemical composition of bulk samples of form II aspirin was
`determined by HPLC to be consistent with those of form I, salicylic
`acid content of 0.5-3.0% in form I versus 1.7% in a form II sample.
`There are clear differences between the unit cell parameters:
`form I (P21/c): a ) 11.233(3) Å, b ) 6.544(1) Å, c ) 11.231(3)
`Å, (cid:226) ) 95.89(2)(cid:176) , V ) 821.218 Å3; form II (P21/c):13 a ) 12.095(7)
`Å, b ) 6.491(4) Å, c ) 11.323(6) Å, (cid:226) ) 111.509(9)(cid:176) , V ) 827.1(8)
`Å3. The molecular geometry of aspirin molecules in form II is
`slightly different in terms of the torsion angle defined by the
`carboxylic acid and acetyl groups, although the centrosymmetric
`carboxylic acid dimer remains intact [O(cid:226)(cid:226)(cid:226)O: 2.632(14) Å, 173.1(cid:176) ].
`
`10.1021/ja056455b CCC: $30.25 © 2005 American Chemical Society
`
`Merck Exhibit 2166, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`C O M M U N I C A T I O N S
`
`torsional angle, and hydrogen
`1:1 co-crystal packing diagram,
`bond tables. This material is available free of charge via the Internet
`at http://pubs.acs.org.
`
`References
`
`(1) (a) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon: Oxford,
`2002. (b) Davey, R. J. Chem. Commun. 2003, 1463. (c) Dunitz, J. D.;
`Bernstein, J. Acc. Chem. Res. 1995, 28, 193.
`(2) (a) Kuhnert-Brandsta¨tter, M.; Aepkers, M. Mikroskopie 1961, 16, 189.
`(b) Davey, R. J.; Blagden, N.; Potts, G. D.; Docherty, R. J. Am. Chem.
`Soc. 1997, 119, 1767. (c) 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.
`(d) Weissbuch, I.; Lahav, M.; Leiserowitz, L. Cryst. Growth Des. 2003,
`3, 125. (e) Rubin-Preminger, J. M.; Bernstein, J. Cryst. Growth Des. 2005,
`5, 1343.
`(3) Haleblian, J. K. J. Pharm. Sci. 1975, 64, 1269.
`(4) (a) Almarsson, O‹ .; Zaworotko, M. J. Chem. Commun. 2004, 1889. (b)
`Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Walsh,
`R. D. B.; Rodriguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des.
`2003, 3, 909. (c) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya,
`V. N.; Stahly, B. C.; Stahly, G. P. J. Am. Chem. Soc. 2004, 126, 13335.
`(d) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des.
`2005, 5, 1013.
`(5) LaFont, O. ReV. d¢histoire de la pharmacie 1996, 43, 269.
`(6) (a) Aspirin and Other Salicylates; Vane, J. R., Bottling, R. M., Eds.;
`Chapman and Hall: London, 1992. (b) Moore, N.; Van Ganse, E.; Le
`Parc, J. M.; Wall, R.; Schneid, H.; Farhan, M.; Verrie`re, F.; Pelen, F.
`The PAIN Study: Paracetamol, Aspirin and Ibuprofen. Clin. Drug InVest.
`1999, 18, 89. (c) Mehta, A. Chem. Eng. News 2005, June, 46-47. (d)
`More information on aspirin can be found in Bayer’s aspirin web site at
`URL http://www.aspirin.de.
`(7) (a) Mitchell, A. G.; Saville, D. J. J. Pharm. Pharmacol. 1967, 19, 729.
`(b) Tawashi, R. Science 1968, 160, 76. (c) Tawashi, R. J. Pharm.
`Pharmacol. Lett. 1969, 21, 701. (d) Mitchell, A. G.; Saville, D. J. J.
`Pharmacol. 1969, 21, 28. (e) de Bisschop, M. J. Pharm. Belg. 1970, 25,
`330. (f) Summers, M. P.; Carless, J. E.; Enever, R. P. J. Pharm.
`Pharmacol. Lett. 1970, 22, 615. (g) Kildsig, D. O.; Denbo, R.; Peck, G.
`E. J. Pharm. Pharmacol. 1971, 23, 374. (h) Bauer, K.; Voege, H. Pharm.
`Ind. 1972, 34, 960. (i) Summers, M. P.; Enever, R. P.; Carless, J. E. In
`Particle Growth in Suspensions; Smith, A. L., Ed.; Academic Press:
`London, 1973. (j) Bettinetti, G. P.; Giordano, F.; Giuseppetti, G. Farmaco,
`Ed. Pratica 1975, 30, 244. (k) Agafonov, V. N.; Leonidov, N. B. Khimiko-
`Farmat. Zhurnal 1978, 12, 127. (l) Jerslev, B.; Lund, U. R. Dan. Sch.
`Pharm. 1981, 9, 61. (m) Chang, C. J.; Diaz, L. E.; Morin, F.; Grant, D.
`M. R. Dan. Sch. Pharm. 1986, 24, 768.
`(8) (a) Pfeiffer, R. R. J. Pharm. Pharmacol. Lett. 1971, 23, 75. (b) Mitchell,
`A. G.; Milaire, B. L.; Saville, D. J.; Griffiths, R. V. J. Pharm. Pharmacol
`1971, 23, 534. (c) Mulley, B. A.; Rye, R. M.; Shaw, P. J. Pharm.
`Pharmacol. 1971, 23, 902. (d) Schwartzman, G. J. Pharm. Pharmacol.
`Lett. 1972, 24, 169.
`(9) (a) Ouvrard, C.; Price, S. L. Cryst. Growth Des. 2004, 4, 1119. (b) Glaser,
`R. J. Org. Chem. 2001, 66, 771. (c) Payne, R. S.; Rowe, R. C.; Roberts,
`R. J.; Charlton, M. H.; Docherty, R. J. Comput. Chem. 1999, 20, 262.
`(10) (a) Wheatley, P. J. J. Chem. Soc. 1964, 6036. (b) Kim, Y.; Machida, K.;
`Taga, T.; Osaki, K. Chem. Pharm. Bull. 1985, 33, 2641.
`(11) Wilson, C. C. New J. Chem. 2002, 26, 1733.
`(12) Desiraju G. R.; Steiner, T. The Weak Hydrogen Bond in Structural
`Chemistry and Biology; Oxford University Press: Oxford, 1999.
`(13) Crystal data of form II: chemical formula C9H8O4, formula weight 180.15,
`monoclinic, space group P21/c, a ) 12.095(7) Å, b ) 6.491(4) Å, c )
`11.323(6) Å, (cid:226) ) 111.509(9)(cid:176), V ) 827.1(8) Å3, Z ) 4, Fcalc ) 1.447 Mg
`m-3, T ) 100 K, (cid:237) ) 0.115 mm-1, 1780 reflections measured, 748 unique
`reflections, 648 observed reflections [I > 2(cid:243)(I)], R1obs ) 0.162, wR2obs
`) 0.308. Crystal size: 0.25 (cid:2) 0.15 (cid:2) 0.005 mm. All atoms were refined
`isotropically because of the relatively weak data.
`(14) (a) Moulton, B.; Zaworotko, M. J. Chem. ReV. 2001, 101, 1629. (b)
`Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311. (c)
`Frankenbach, G. M.; Etter, M. C. Chem. Mater. 1992, 4, 272.
`(15) Leiserowitz, L.; Nader, F. Acta Crystallogr. 1977, B33, 2719.
`(16) Single crystals of the 1:1 co-crystal of aspirin and carbamazepine were
`obtained by dissolving equimolar amounts of aspirin and carbamazepine
`in ethyl acetate and standing for 3 days. Crystal data: chemical formula
`C24H20N2O5, formula weight 416.42, triclinic, space group P1h, a )
`9.0317(18) Å, b ) 11.364(2) Å, c ) 11.424(2) Å, R )60.350(4)(cid:176), (cid:226) )
`85.599(4)(cid:176), (cid:231) ) 84.724(4)(cid:176), V ) 1014.0(3) Å3, Z ) 2, Fcalc ) 1.364 Mg
`m-3, T ) 100 K, (cid:237) ) 0.097 mm-1, 5971 reflections measured, 4052 unique
`reflections, 2931 observed reflections [I > 2(cid:243)(I)], R1obs ) 0.057, wR2obs
`) 0.119. The co-crystal can also be obtained by solvent-drop grinding of
`equimolar amounts of aspirin and carbamazepine (20 (cid:237)L of ethyl acetate
`per 100 mg of solid, 2-4 min of grinding).
`JA056455B
`
`J. AM. CHEM. SOC. 9 VOL. 127, NO. 48, 2005 16803
`
`Figure2. Simulated powder X-ray diffraction (PXRD) patterns of aspirin
`form I, II, and S. L. Price predicted form II crystal structures. See the
`noticeable additional peaks in form II and S. L. Price predicted form II
`compared to form I near 2ı: 20 and 26(cid:176).
`
`However, the crystal packing of adjacent dimers is different; methyl
`groups form catemeric C-H(cid:226)(cid:226)(cid:226)O [C(cid:226)(cid:226)(cid:226)O: 3.85(2) Å, 164.0(cid:176)]
`hydrogen bonds with the carbonyl oxygen (graph set C(4)) of the
`acetyl group versus centrosymmetric dimers (graph set R2
`2(8)) in
`form I (Figure 1). The existence of competing catemer/dimer motifs
`is well documented in polymorphs of carboxylic acids and primary
`amides.1a,4,14 Simulated powder X-ray diffraction patterns also
`exhibit significant differences (Figure 2). It is interesting to note
`that a computational study concerning polymorphism in aspirin
`predicted a low energy polymorph with a low shear elastic constant,
`implying a low barrier to transformation. This calculated structure
`is consistent with that of form II.9a
`The discovery of a new form of aspirin through attempted co-
`crystallization of amides and acids is perhaps unexpected when one
`considers that acids and amides are known to form reliable
`supramolecular heterosynthons.15 Indeed, attempted co-crystalliza-
`tion of carbamazepine and aspirin resulted in the expected4b 1:1
`co-crystal,
`the structure of which is illustrated in Supporting
`Information (Figure S3). This crystal structure16 reveals that aspirin
`molecules form acid-amide supramolecular heterosynthons to
`carbamazepine molecules through O-H(cid:226)(cid:226)(cid:226)O [O(cid:226)(cid:226)(cid:226)O: 2.564(2) Å,
`167.5(cid:176)] and N-H s(cid:226)(cid:226)(cid:226)O [N(cid:226)(cid:226)(cid:226)O: 2.914(3) Å, 168.4(cid:176)] hydrogen
`bonds.
`The salient feature of this study is not just the identification of
`aspirin form II, it is also the manner in which it was prepared.
`That crystallization of aspirin form II can occur in the presence of
`certain amides, whereas a co-crystal with carbamazepine can also
`occur and might appear to be counterintuitive. However, these
`observations are consistent with studies that have demonstrated how
`tailor-made additives can disrupt nucleation and induce polymor-
`phism.2 Supramolecular heterosynthons, therefore, seem to have
`implications for control of polymorphism.
`To summarize, we have obtained and characterized a new
`polymorph and a new co-crystal of aspirin. In our opinion, the most
`salient features of the results reported herein are the method by
`which the once elusive form II of aspirin was isolated and the fact
`that it had been hitherto predicted.
`
`Supporting Information Available: X-ray crystallographic in-
`formation in CIF format, IR, DSC, HPLC, aspirin and carbamazepine
`
`Merck Exhibit 2166, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`