Stable Polymorph of Venlafaxine Hydrochloride by Solid-to-Solid Phase Transition at High Temperature Saikat Roy,† Prashant M. Bhatt,† Ashwini Nangia,*,† and Gert J. Kruger*,‡ School of Chemistry, UniVersity of Hyderabad, Hyderabad 500 046, India, and Department of Chemistry, UniVersity of Johannesburg, P.O. Box 524, Auckland Park, Johannesburg 2006, South Africa
CRYSTAL GROWTH & DESIGN 2007 VOL. 7, NO. 3 476-480
ReceiVed October 31, 2006
ABSTRACT: A novel polymorph of the antidepressant drug venlafaxine hydrochloride (VenHCl) was visualized in thermal microscopy and identified by variable-temperature powder X-ray diffraction at 180-190 °C. Its single-crystal X-ray structure was solved and refined satisfactorily in P21/n space group (form 6, Z′ ) 2, T ) 100 K, R1 ) 0.1073). The powder X-ray diffraction pattern and melting point of form 6 are significantly different from the known polymorphs 1-5. Form 6 has a higher melting point and is more stable than marketed drug forms 1 and 2. Polymorphism is the existence of the same chemical compound in more than one crystalline modification in the solid state.1 Literature values on the occurrence of polymorphism range from 5% in small organic molecules to 30-50% in drug substances of 1 is very difficult at the present time. (2) Neither could it have been obtained in high-throughput polymorph screens,22 as these automated methods of sampling the crystallization landscape mostly deal with modifying the solution crystallization conditions.5e (3) Rolf Hilfiker2 emphasizes in his authoritative book on pharmaceutical polymorphism that, “Although in hindsight everything may appear to be easy and straightforward, crystalline molecular solid-state forms are non-obvious, novel and require inventiveness.” (4) Finally, discovering the most stable polymorph of a commercial drug has assumed great significance for the pharmaceutical industry in the post-Ritonavir (Abbott)23 era. In conclusion, a new, more stable, higher melting polymorph of venlafaxine hydrochloride is characterized by single crystal and powder XRD. The methodology and techniques used to search for the thermodynamic polymorph outlined herein are of general applicability to the area of polymorphism and phase transitions and offer the prospect of discovering new polymorphs and establishing phase relationships in other polymorphic systems, even in cases in which a stable modification may have been known for quite some time. Acknowledgment. A.N. thanks the DST for research funding (SR/S5/OC-02/2002) and the X-ray CCD diffractometer (IRPHA). UGC is thanked for the UPE program. S.R. and P.M.B. thank the UGC and CSIR for fellowship. G.J.K. thanks the DST/INT/SAFR/ COP/2001 project. Supporting Information Available: PXRD plots, HSM frames, packing diagrams, and crystallographic data (.cif) of form 6 are available free of charge via the Internet at http://pubs.acs.org.
Figure 6. DSC of form 1 (black), form 2 (red), and form 6 (blue) at a heating rate of 2 °C min-1. Form 6 has the highest melting point of 219220 °C compared to form 1 and 2 of 208-210 °C. In both forms 1 and 2, the lower T endotherm is due to melting and the higher T peak is a phase transition. See ref 8 for details.
6 and the enantiotropic relation (Table 1) mean that VenHCl polymorph 6 is the most stable modification. It was possible to crystallize form 6 only by solid-state heating of form 1 or 2 in our hands. Attempted crystallization of form 6 from several solvents, such as ethylene glycol, DMSO, DMF, i-PrOH, MeOH, EtOHEtOAc, MeOH-EtOAc, MeCN-DMF, at temperatures varying from 25 to 100 °C afforded only form 1 or 2 crystals by unit cell checking or gave ill-defined powders. There is an ongoing discussion in the recent literature about the occurrence and reasons for high Z′ in crystal structures5e,12b,13b,18 and whether high Z′ polymorphs are metastable relative to their low Z′ crystal structures.3b,19 The above data show that form 6 (Z′ ) 2) is more stable than polymorphs 1 and 2 (Z′ ) 1). Why does form 6 crystallize at high temperature using multiple molecules? The two conformers of VenHCl separated by ∼0.2 kcal mol-1 (and perhaps many other conformers as well) are in dynamic equilibrium at >170 °C because the thermal energy of atoms (RT ∼ 0.6, 0.8, 1.0 kcal mol-1 at 300, 400, 500 K) is comparable to the rotation barrier of methyl group and torsions about C-C single bonds in the molecule (0.5-3.0 kcal mol-1).20 With several low-lying conformers in equilibrium, crystal nucleation occurs with multiple molecules in the unit cell (Z′ ) 2), similar to the situation described for conformational isomorphs of 4,4-diphenyl-2,5-cyclohexadien1-one.13b Even though there are strong H bonds in these ionic
References (1) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon, Oxford, 2002. (2) Hilfiker, R.; Blatter, F.; von Raumer, M. in Polymorphism in the Pharmaceutical Industry; Hilfiker, R., Ed.; Wiley-VCH: Weinheim, 2006; pp 1-19. (3) (a) Davey, R. J.; Dent, G.; Mughal, R. K.; Praveen, S. Cryst. Growth Des. 2006, 6, 1788. (b) Das, D.; Banerjee, R.; Mondal, R.; Howard, J. A. K.; Boese, R.; Desiraju, G. R. Chem. Commun. 2006, 555. (4) Gardner, C. R.; Walsh, C. T.; Almarsson, O ¨ . Nat. ReV. 2004, 3, 926. (5) (a) Hulme, A. T.; Price, S. L.; Tocher, D. A. J. Am. Chem. Soc. 2005, 127, 1116. (b) Day, G. M.; Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2006, 54. (c) 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. (d) Vishweshwar, P.; McMahon, J. A.; Oliveira, M.; Peterson, M. L.; Zaworotko, M. J. J. Am. Chem. Soc. 2005, 127, 16802. (e) Rafilovich, M.; Bernstein, J. J. Am. Chem. Soc. 2006, 128, 12189. (f) Chen, S.; Xi, H.; Yu, L. J. Am. Chem. Soc. 2005, 127, 17439. (g) Price, C. P.; Grzesiak, A. L.; Matzger, A. J. J. Am. Chem. Soc. 2005, 127, 5512. (h) David, W. I. F.; Shankland, K.; Pulham, C. R.; Bladgen, N.; Davey, R. J.; Song, M. Angew. Chem., Int. Ed. 2005, 44, 7032. (i) Rodrı´guez-Spong, B.; Price, C. P.; Jayashankar, A.; Matzger, A. J.; Rodrı´guez-Hornendo, N. AdV. Drug. Del. ReV. 2004, 56, 241. (j) Bernstein, J. Chem. Commun. 2005, 5007. (6) (a) Yardley, J. P.; Husbands, G. E. M.; Stack, G.; Butch, J.; Bicksler, J.; Moyer, J. A.; Muth, E. A.; Andree, T.; Fletcher, III, H.; James, M. N. G.; Sieleck, A. R. J. Med. Chem. 1990, 33, 2899. (b) Husbands, G. E. M.; Yardley, J. P.; Muth, E. A. U.S. Patent 4,535,186, 1985. (7) (a) Vega, D.; Ferna´ndez, D.; Echeverria, G. Acta Crystallogr. 2000, C56, 1009. (b) Sivalakshmidevi, A.; Vyas, K.; Rao, S. M.; Reddy, G. O. Acta Crystallogr. 2002, E58, o1072.
480 Crystal Growth & Design, Vol. 7, No. 3, 2007 (8) For an overview of the VenHCl, polymorph literature, their numbering as forms 1-4, the characterization of sublimation form 5, and crystallization of polymorphs 1 and 2 for use in this study, see Roy, S.; Aitipamula, S.; Nangia, A. Cryst. Growth Des. 2005, 5, 2268. (9) Downloaded from the PriorArt Database. http://www.priorartdatabase.com/IPCOM/000029066. (10) Crystal data: Form 6, C17H28NO2+ Cl-, Mr 313.85, monoclinic, P21/ n, T ) 100(2) K, a ) 5.887(10) Å, b ) 19.37(3) Å, c ) 31.41(5) Å, β ) 92.16(3)°, Z′ ) 2, Z ) 8, V ) 3579(10) Å3, µ (Mo-KR) 0.218 mm-1, Fcalc ) 1.165 g cm-3, R1(I > 2σ(I)) ) 0.1073. X-ray reflections were collected on Bruker SMART-APEX CCD diffractometer (Mo-KR radiation, λ ) 0.71073 Å) with 10 s exposure time. Structures were solved and refined on F2 in SHELX-TL. H atoms were refined isotropically. The reported crystal structure data is the best solution we could derive from multiple experiments. Crystal data on polymorphs 1 and 2 are taken from the Cambridge Structural Database, www.ccdc.cam.ac.uk (CSD refcodes WOBMUV, WOBMUV01). Form 1, orthorhombic, Pca21, T ) 293 K, a ) 26.230(5) Å, b ) 5.881(1) Å, c ) 11.448(2) Å, Z′ ) 1, Z ) 4, V ) 1765.95 Å3, Fcalc ) 1.180 g cm-3, R1(I > 2σ(I)) ) 0.0434. Form 2, monoclinic, P21/n, T ) 293 K, a ) 5.797(6) Å, b ) 26.074(7) Å, c ) 11.722(3) Å, β ) 100.72(5)°, Z′ ) 1, Z ) 4, V ) 1740.87 Å3, Fcalc ) 1.197 g cm-3, R1(I >2σ(I)) ) 0. 068. (11) Geometry optimization was carried out using density functional theory (DFT) at the B3LYP/6-31.G (d,p) level in Gaussian 03, Revision B.05. http://www.gaussian.com. (12) (a) Bernstein, J.; Davey, R. J.; Henck, J.-O. Angew. Chem., Int. Ed. 1999, 38, 3440. (b) 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. (13) (a) Reflections were collected on PANlytical X’Pert PRO X-ray powder diffractometer using a parallel beam of monochromated CuKR radiation (λ ) 1.54056 Å) with the generator power set at 40 kV and 40 mA. The sample was heated @ 10° min-1 and intensities were collected at regular T intervals in the 2θ range 5-50°. Full details of the VT-PXRD experiment are described in ref 13b. (b) Roy, S.; Banerjee, R.; Nangia, A.; Kruger, G. J. Chem. Eur. J. 2006, 12, 3777.
Communications (14) (a) Simulation of the powder diffraction from the crystal structure and least-squares refinement of the experimental pattern was done in Powder Cell 2.3 (ref 14b). The unit cell parameters were scaled to correct for the higher temperature of PXRD compared to singlecrystal XRD measurement. The slight differences in peak intensity are due to the preferred orientation of the microcrystalline sample. (b) Krauss, N.; Nolze, G. Federal Institute for Materials Research and Testing, Berlin, Germany, 2000. (15) Ostwald, W. Z. Phys. Chem. 1897, 22, 289. (16) Bond, A. D. Chem. Eur. J. 2004, 10, 1885. (17) Moulton, B.; Zaworotko, M. J. Chem. ReV. 2001, 101, 1629. (18) (a) Anderson, K. M.; Goeta, A. E.; Hancock, K. S. B.; Steed, J. W. Chem. Commun. 2006, 2138. (b) Pidcock, E. Acta Crystallogr. 2006, B62, 268. (c) Babu, N. J.; Nangia, A. Cryst. Growth Des. 2006, 6, 1995. (d) Todd, A. M.; Anderson, K. M.; Byrne, P.; Goeta, A. E.; Steed, J. W. Cryst. Growth Des. 2006, 6, 1750. (e) Hao, X.; Chen, J.; Cammers, A.; Perkin, S.; Brock, C. P. Acta Crystallogr. 2005, B61, 218. (f) Steed, J. W. CrystEngComm 2003, 5, 169. (19) Sarma, B.; Roy, S.; Nangia, A. Chem. Commun. 2006, 4918. (20) Bernstein, J. in Organic Solid State Chemistry; Desiraju, G. R., Ed.; Elsevier: Amsterdam, 1987; pp 471-518. (21) Day, G. M.; Motherwell, W. D. S.; Ammon, H.; Boerrigter, S. X. M.; Della Valle, R. G.; Venuta, E.; Dzyabchenko, A.; Dunitz, J. D.; Schweizer, B.; van Eijck, B. P.; Erk, P.; Facelli, J. C.; Bazterra, V. E.; Ferraro, M. B.; Hofmann, D. W. M.; Leusen, F. J. J.; Liang, C.; Pantelides, C. C.; Karamertzanis, P. G.; Price, S. L.; Lewis, T. C.; Nowell, H.; Torrisi, A.; Scheraga, H. A.; Arnautova, Y. A.; Schmidt, M. U.; Verwer, P. Acta Crystallogr. 2005, B61, 511. (22) Morissette, S. L.; Almarsson, O ¨ .; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. L. AdV. Drug DeliV. ReV. 2004, 56, 275. (23) 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. Proc. Res. DeV. 2000, 4, 413.
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