CRYSTAL GROWTH & DESIGN
Polymorph Control of Felodipine Form II in an Attempted Cocrystallization
2009 VOL. 9, NO. 3 1254–1257
Benyong Lou,† Dan Bostro¨m,‡ and Sitaram P. Velaga*,† Department of Health Science, Luleå UniVersity of Technology, Luleå S-971 87, Sweden, and Energy Technology and Thermal Process Chemistry, Umeå UniVersity, Umeå S-901 87, Sweden ReceiVed September 2, 2008; ReVised Manuscript ReceiVed January 26, 2009
ABSTRACT: The metastable form II of racemic felodipine was obtained in an attempted cocrystallization with isonicotinamide. Its low temperature crystal structure was characterized by a 1D hydrogen-bonded chain consisting of four independent felodipine molecules. Polymorphism of active pharmaceutical ingredient (API), i.e., its ability to exist as two or more crystalline forms with different arrangement and/or conformations in the unit cell, is often a critical issue in pharmaceutical development programs.1 The polymorphic forms of a compound may exhibit different physicochemical properties (such as solubility, dissolution rate, bioavailability) and mechanical properties. The particular crystal form that occurs during crystallization is a result of competitive, thermodynamic, and kinetic molecular recognition processes.2 Consequently, the selective crystallization of polymorphs remains challenging, as can be evidenced by the sudden appearance of an unexpected new polymorph of ritonavir after the marketed form had been manufactured for several years.3 Polymorph control and/or generation of new polymorphs is currently attempted by various approaches including altering the solvent of crystallization,4 templating with surface,5 polymer heteronuclei,6 tailor-made additives,7 etc. Recently, polymorphic forms of APIs were obtained in the attemped cocrystallization of APIs and guest molecules, suggesting a role of supramolecular heterosynthons in the control of polymorphism.8 Interestingly, for benzidine, four polymorphs containing more than one molecule in the asymmetric unit (Z′ ) 1.5, 3, and 4.5) were isolated through the attempted cocrystallization.8c Felodipine, ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6dimethyl-3,5- pyridinedicarboxylate, a calcium channel blocker, is an effective and widely prescribed medication in the treatment of hypertension.9 Its crystal structure, determined in 1986, comprises space group P2(1)/c and unit-cell dimensions a ) 12.086 Å, b ) 12.077 Å, c ) 13.425 Å, and β ) 116.13°.10 This form, referred to as felodipine form I, is easily obtained by recrystallization from methanol or ethanol. In contrast, felodipine form II is crystallized from hexane/methanol mixture and is associated with considerable kinetic stability and improved physical properties.11 However, the lack of reproducibility of form II because of poor crystallization control has limited its potential in the product development.11 In this contribution, we present details of the attempted cocrystallization of felodipine with isonicotinamide, which consistently generated felodipine form II. Further, the low-temperature crystal structure of this metastable form is presented for the first time and the structural diversities between form I and II are discussed. Felodipine form II can be isolated through an attempted cocrystallization of form I with isonicotinamide (1:1 molar ratio) in methanol. The cocrystallization experiments were also carried out in other solvents such as ethanol, propanol, ethyl acetate, acetone, and acetonitrile and no cocrystals were obtained. However, in the presence of nonstoichiometric amounts of isonicotinamide (i.e., below 1:1 molar ratio), the mixture of form I and form II was * Corresponding author. E-mail:
[email protected]. † Luleå University of Technology. ‡ Umeå University.
Figure 1. Asymmetrical unit of form II with 30% thermal ellipsoids. Table 1. Hydrogen-Bonding Parameters of Form II D-H · · · A
H· · ·A (Å)
D· · ·A (Å)
D-H · · · A (deg)
symmetry codes
N1-H · · · O6 N2-H · · · O9 N3-H · · · O13 N4-H · · · O1
2.02 2.11 2.03 2.08
2.887(5) 2.951(5) 2.899(5) 2.931(5)
169.0 160.7 167.4 161.6
x - 1/2, y - 1/2, z
obtained. Cocrystallization with other cocrystal formers (such as benzoic acid, glutaric acid, glycine, saccharin, glucose) always generated form I. Considering that isonicotinamide contains pyridinyl and amide group in the structure, we attempted to obtain form II by using some compounds containing pyridinyl or amide group such as nicotinamide, benzamide, urea, pyrazine, pyrazinecarboxamide. However, form I and corresponding guest molecules were always crystallized separately. Interestingly, formamide forms a solvate with felodipine, the structure of which comprises hydrogen-bonding interactions between amide group and felodipne. The powder X-ray diffraction pattern of the bulk samples of form II was similar to that reported previously11 and matches with the pattern calculated from the single crystal structure. Form II showed one sharp melting peak at 136 °C (∆H ) 70.84 ( 0.68 J/g), whereas form I melted at 144 °C (∆H ) 76.02 ( 0.72 J/g). Further, form II transformed to form I upon slurring for 24 h in methanol-water (1:1) at room temperature. This suggests that form II is thermodynamically metastable at room temperature and reveals enantiotropic relationship between the two forms.12 Single crystals of form II suitable for single-crystal X-ray diffraction were obtained in methanol-water (1:1) solution.13 Form II crystallizes in the space group C2/c with four independent
10.1021/cg8009749 CCC: $40.75 2009 American Chemical Society Published on Web 02/05/2009
Communications
Crystal Growth & Design, Vol. 9, No. 3, 2009 1255
Figure 2. 1D hydrogen-bonded chains along [110] and [1j10].
Figure 3. Packing structure of form II viewed along [110].
molecules of felodipine in the asymmetric unit (Figure 1). Each molecule is involved in hydrogen-bonding interactions with two adjacent felodipine molecules via the dihydropyridine N atom and the carbonyl O atom of methyl ester (Table 1). Consequently, a 1D infinite hydrogen-bonded chain is formed along the direction [110]. The ethyl ester of felodipine is free from hydrogen bonding with dihydropyridine N atom. The methyl ester and ethyl ester groups of felodipine molecules in the chain extend themselves outside in different directions. It is interesting to note that the 1D hydrogen-bonded chain occurs also along the direction [1j10] (Figure 2). Moreover, the 1D chain stacks orderly via weak C-H · · · O interactions contributed by methyl ester and ethyl ester, respectively. The chains with the same directionality stack together in parallel with each other via weak C-H · · · O interactions occurring between methyl ester groups of felodipine. The chains with opposite directionality stack perpendicularly via weak C-H · · · O interactions between ethyl ester groups of felodipine and this gives rise to a complicated packing structure (Figure 3).
Figure 4. (Top) Packing structure of form I viewed along the b axis; (bottom) 1D hydrogen-bonded chain along the b axis in form I.
The Fourier transform infrared spectrum of form II showed a stretching vibration peak for N-H at 3336 cm-1 and for carbonyl
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Figure 5. Hydrogen-bonded structure of felodipine formamide solvate.
at 1698 and 1683 cm-1. However, in form I, the N-H and carbonyl stretching vibration peaks were at 3373 and 1697 cm-1, respectively. The occurrence of red shift in form II indicates enhancement of hydrogen bonding interactions between dihydropyridine N and carbonyl O atoms of felodipine and this can be confirmed by the weak hydrogen bonds in the crystal structure of form I. Form I consists of only one molecule of felodipine in the asymmetric unit. There exist very weak hydrogen-bonding interactions between dihydropyridine N and carbonyl O atoms of both methyl and ethyl esters (distance 3.155 and 3.237 Å, respectively). There also exists relatively weak hydrogen bonding in the other dihydropyridine derivatives.10 This is partly due to the shielding effect of the methyl groups in the dihydropyridine ring. The weak hydrogen bonds link felodipine molecules into a 2D structure that stacks into a completely different packing structure with that of form II and in the structure there also exist 1D chains based on hydrogen-bonding interactions between dihydropyridine N and carbonyl O atoms of methyl ester (Figure 4). An indirect way of observing the pathway of crystallization is offered by the study of crystal structures which contain multiple molecules in the crystallographic asymmetric unit (Z′ > 1).14 The high Z′ polymorph may be a fossil relic of the crystal nucleus of a more stable polymorph.15 In the case of felodipine, polymorph II (Z′ ) 4) corresponds to a kinetically stable form which rearranges in a solvent (solvent mediated transformation) to form the thermodynamically stable form I. Form II seems to be a precursor crystal nucleus to form I and both structures are stabilized by similar synthons. There is 1D hydrogen-bonded chain based on hydrogen bonding between dihydropyridine N and carbonyl O atoms of methyl ester in form II. Also, in the 2D structure of form I, along b axis there exist similar 1D hydrogen-bonded chain based on hydrogen bonding interactions between dihydropyridine N and carbonyl O atoms of methyl ester. The crystal structure of the solvate of felodipine with formamide (1:1)16 shows there exist hydrogen-bonding interactions between amide group and felodipine (Figure 5). Two molecules of formamide are assembled to form a hydrogen-bonded dimer based on homosynthon R22(8). Formamide is simultaneously hydrogen-bonded to the dihydropyridine N atom of felodipine and the carbonyl O atom of methyl ester of another felodipine molecule. Thus, formamide connects felodipine molecules into a 1D double-chain structure. The structure indicates that the amide group can interact with the dihydropyridine N atom and the carbonyl O atom of methyl ester of felodipine. Although isonicotinamide failed to enter the lattice of felodipine, the amide group of isonicotinamide may have played a subtle role in the crystal growth of form II of felodipine. Structurally similar additives can be used to obtain the metastable form of pharmaceutical compounds through inhibiting the growth of stable form17 and even salts show the potential to induce the metastable polymorph.18 The failure of cocrystallization experiments shows the selected cocrystal formers can play a structure-directing
role in the growth of the metastable form.8 In this case, isonicotinamide induces the generation of form II, which is otherwise poorly reproducibile in absence of isonicotinamide. The generation of felodipine form II exemplifies that cocrystallization of host drugs with guest molecules can increase the chances of obtaining metastable polymorphs because guest molecules are not limited to structurally similar compounds to host drugs. In conclusion, we obtained the metastable form II of racemic felodipine in an attempted cocrystallization with isonicotinamide. The crystal structure is characterized by a 1D hydrogen-bonded chain of felodipine molecules. Isonicotinamide plays an important role in the stable growth of felodipine form II.
Acknowledgment. We acknowledge the financial support from a Norbottensforskningsråd (NoFo05-011) grant. Supporting Information Available: X-ray crystallographic file in CIF format for form II; felodipine formamide, PXRD pattern, and DSC for form I and form II (PDF). 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 Press: Oxford, U.K., 2002. (b) Stahly, G. P. Cryst. Growth. Des. 2007, 7, 1007. (2) Rodrıg´uez-Spong, B.; Price, C. P.; Jayasankar, A.; Matzger, A. J.; Rodrıg´uez-Hornedo, N. AdV. Drug DeliVery ReV. 2004, 56, 241. (3) Chemburkar, S. R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.; Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W.; Quick, J.; Bauer, P.; Donaubauer, J.; Narayanan, B. A.; Soldani, M.; Riley, D.; McFarland, K. Org. Process Res. DeV. 2000, 4, 413. (4) (a) Trifkovic, M.; Rohani, S.; Mirmehrabi, M. Org. Process Res. DeV. 2007, 11, 138. (b) Parmar, M. M.; Khan, O.; Seton, L.; Ford, J. L. Cryst. Growth Des. 2007, 7, 1635. (5) (a) Mitchell, C. A.; Yu, L.; Ward, M. D. J. Am. Chem. Soc. 2001, 123, 10830. (b) Hiremath, R.; Varney, S. W.; Swift, J. A. Chem. Commun. 2004, 2676. (6) (a) Price, C. P.; Grzesiak, A. L.; Matzger, A. J. J. Am. Chem. Soc. 2005, 127, 5512. (b) Lang, M. D.; Grzesiak, A. L.; Matzger, A. J. J. Am. Chem. Soc. 2002, 124, 14834. (7) (a) 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, 1149. (b) Lu, J. J.; Ulrich, J. Cryst. Res. Technol. 2003, 38, 63. (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. (8) (a) Day, G. M.; Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem Commun. 2006, 54. (b) Vishweshwar, P.; McMahon, J. A.; Oliveira, M.; Peterson, M. L.; Zaworotko, M. J. J. Am. Chem. Soc. 2005, 127, 16802. (c) Rafilovich, M.; Bernstein, J. J. Am. Chem. Soc. 2006, 128, 12185. (9) Nussinovitch, N.; Carroll, J.; Shamiss, A.; Grossman, E.; Katz, A.; Rachima, C.; Rosenthal, T. J. Hum. Hypertens. 1996, 10, S165. (10) Fossheim, R. J. Med. Chem. 1986, 29, 305.
Communications (11) Rollinger, J. M.; Burger, A. J. Pharm. Sci. 2001, 90, 949. (12) Burger, A.; Ramberger, R. Mikrochim. Acta II 1979, 259. (13) Crystal data for form II: C72H76Cl8N4O16, M ) 1536.97, colorless, 0.25 × 0.20 × 0.20 mm3, monoclinic, space group C2/c (No. 15), a ) 32.392(7) Å, b ) 18.717(4) Å, c ) 23.711(5) Å, β ) 91.00(3)°, V ) 14373(5) Å3, Z ) 8, Dc ) 1.421 g/cm3, F000 ) 6400, KappaCCD, Mo KR radiation, λ ) 0.71073 Å, T ) 150(2) K, 2θmax ) 50.0°, 24170 reflections collected, 12339 unique (Rint ) 0.0315). Final GOF ) 1.107, R1 ) 0.0999, wR2 ) 0.2433, R indices based on 9516 reflections with I > 2σ(I) (refinement on F2) 927 parameters, 14 restraints. There are spurious peaks (1.54-2.04 e/A3) around Cl and ester O atoms for every independent felodipine molecule. The reported crystal structure data is the best one we could obtain from multiple experiments. CCDC 668477. (14) Desiraju, G. R. CrystEngComm. 2007, 91. (15) (a) Steed, J. W. CrystEngComm. 2003, 169. (b) Das, D.; Banerjee, R.; Mondal, R.; Howard, J. A. K.; Boese, R.; Desiraju, G. R. Chem.
Crystal Growth & Design, Vol. 9, No. 3, 2009 1257 Commun. 2006, 555. (c) Kumar, V. S. S.; Addlagatta, A.; Nangia, A.; Robinson, W. T.; Broder, C. K.; Mondal, R.; Evans, I. R.; Howard, J. A. K.; Allen, F. H. Angew. Chem., Int. Ed. 2002, 41, 3848. (16) Crystal data for felodipine formamide: C19H22Cl2N2O5, M ) 429.29, colorless block, 0.43 × 0.24 × 0.14 mm3, triclinic, space group P1j (No. 2), a ) 9.6360(19) Å, b ) 11.335(2) Å, c ) 11.685(2) Å, R ) 100.99(3)°, β ) 112.09(3)°, γ ) 107.52(3)°, V ) 1058.9(4) Å3, Z ) 2, Dc ) 1.346 g/cm3, F000 ) 448, KappaCCD, Mo KR radiation, λ ) 0.71073 Å, T ) 295(2)K, 2θmax ) 54.0°, 8620 reflections collected, 4547 unique (Rint ) 0.0157). Final GOF ) 1.078, R1 ) 0.0627, wR2 ) 0.1872, R indices based on 3944 reflections with I > 2σ(I) (refinement on F2), 252 parameters, 1 restraint. CCDC 675336. (17) Lee, E. H.; Byrn, S. R.; Carvajal, M. T. Pharm. Res. 2006, 23, 2375. (18) Lee, E. H.; Boerrigter, S. X. M.; Rumondor, A. C. F.; Chamarthy, S. P.; Byrn, S. R. Cryst. Growth Des. 2008, 8, 91.
CG8009749
