Pyrazinamide Polymorphs: Relative Stability and Vibrational

Jul 28, 2010 - Synopsis. Four polymorphs of pyrazinamide are characterized by X-ray diffraction, Fourier transform infrared, near-infrared, and Raman ...
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DOI: 10.1021/cg1004424

Pyrazinamide Polymorphs: Relative Stability and Vibrational Spectroscopy

2010, Vol. 10 3931–3941

Suryanarayan Cherukuvada, Ranjit Thakuria, and Ashwini Nangia* School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046, India Received April 2, 2010; Revised Manuscript Received July 6, 2010

ABSTRACT: The stability of four polymorphs of pyrazinamide, R, β, γ, and δ, was studied under solvent-mediated crystallization, neat and liquid-assisted grinding, polymorph seeding, and ambient storage conditions. In contrast to a recent report that the δ polymorph is the most stable modification (Castro et al. Cryst. Growth Des. 2010, 10, 274), we find that the R polymorph is the thermodynamic form. β, γ, and δ transform to the R phase in the above-mentioned conditions as monitored by infrared, near-infrared, and Raman spectroscopy, differential scanning calorimetry, and X-ray powder diffraction. Transformation to the high temperature γ phase is monitored by thermogravimetric analysis-infrared (TG-IR) spectrometry. A semischematic energy-temperature diagram consistent with phase transformation experiments, thermal measurements, and crystal structure data gives the order R < δ < γ < β at 25 C (R is the most stable form), whereas at 160 C γ < R < δ < β (γ stable modification), but at absolute zero δ < R < β < γ (δ stable modification). Even though the δ polymorph has the lowest free energy at absolute zero temperature, the R polymorph is the thermodynamic form under the ambient conditions regime more relevant to crystallization and handling of pharmaceuticals. The intrinsic dissolution rate of the γ form is faster than R and δ polymorphs, but R is the preferred polymorph of pyrazinamide considering both stability and bioavailability criteria. We also report high quality X-ray crystal structures of all the four polymorphs of pyrazinamide (R = 0.0387, 0.0340, 0.0392, and 0.0372 for R, β, γ, and δ).

Introduction Pyrazinamide (pyrazine-2-carboxamide, abbreviated as PZA; Figure 1) is a frontline antituberculosis drug1 and is on the WHO Model List of Essential Medicines.2 It is a rare example of a conformationally rigid molecule with four polymorphs3 (namely, R, β, γ, and δ forms)4 reported in the literature. Even though the carboxamide group can rotate with respect to the aromatic pyrazine ring, the five-member intramolecular N-H 3 3 3 N hydrogen bond renders conformational rigidity to the structure. A study of all polymorphs of a drug is necessary to establish their stability relationships, and this is considered an obligatory step in the manufacture of solid drug forms.5,6 Hence, it is important to gain sufficient knowledge and understanding of the different solid-state forms of a drug (polymorphs, hydrates, solvates, salts, and cocrystals).7 Surprisingly, barring the crystal structures of PZA polymorphs, which date back to the 1960s and 1970s,4 there is a dearth of spectroscopic and phase stability information on PZA. Polymorphism was noted in PZA long before this phenomenon became important to the pharmaceutical industry, which is usually taken as the 1990s decade,8 when litigation took place surrounding forms 1 and 2 of ranitidine hydrochloride (Zantac) and the accidental appearance of a stable, less soluble form II of Ritonavir (Norvir). Spectroscopic studies such as infrared (IR),9 Raman,9b,e,10 and 13C solid-state NMR (SS-NMR)11 are reported on the R polymorph of PZA and bending was studied for its R and δ polymorphs.12 Pyrazinamide is a highly soluble and stable drug,13,14 and as such there is little scope for improvement in its formulation. Yet, it is a model pharmaceutical system to

study phase relationships among the four polymorphs, which was reported for the first time in the published literature only very recently. Castro et al.15 described thermal and Fourier transform infrared (FT-IR) analysis of PZA polymorphs, and an amorphous phase at subzero temperature was reported by Borba et al.16 We report X-ray crystal structures of PZA polymorphs along with phase transformations monitored by X-ray powder diffraction (XRPD), FT-IR, near IR and Raman spectroscopy, and differential scanning calorimetry (DSC). Phase transition of PZA polymorphs was studied under different conditions such as the influence of polymorphic seeds, mechanical stress, solvent effect, and storage. Our results are at variance with a recent paper on PZA polymorphs in the same journal (hereafter Castro15). The R polymorph is the stable modification under ambient conditions in our experiments, whereas Castro15 concluded that the δ polymorph is the stable phase. In a very recent paper, Borba et al.16 quoted the δ polymorph as the stable phase of pyrazinamide by citing Castro’s paper15 just published at that time. Hence, it is imperative that the correct stability order of pyrazinamide polymorphs is shared with researchers. Furthermore, we report X-ray crystal structure of the γ polymorph with better accuracy (R=0.0392) compared to Castro’s crystal structure (R = 0.1066). Crystallographic data on the γ polymorph are now reported with disorder being modeled (R = 0.0392) and unmodeled (R = 0.0796) in the refinement cycles. The best crystallographic data (100 K) on all four polymorphs of pyrazinamide are summarized in Table 1. Results

*To whom correspondence should be addressed. E-mail: ashwini.nangia@ gmail.com.

Commercially available pyrazinamide (Merck) is in the R form (XRPD plot is shown in Figure S1, Supporting Information),

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and this material was used in all our experiments. Polymorphs R, γ, and δ were obtained in pure form as confirmed by their XRPD profile (Figure 2); the β form was always contaminated with the γ form in a 80:20 ratio (Figure 3) and hereafter represented as β(þγ). The R form was obtained as needles exclusively from water, acetonitrile, and nitromethane and also as the major form concomitantly with other forms from several solvents. The β form was obtained in less quantity as β(þγ) mixture of plate morphology concomitantly with R and δ forms from dioxane and toluene-chloroform solvent mixture. Crystals of β and δ form, both of plate morphology, can be separated because of the better extinction of the former polymorph under polarized light. In addition to sublimation and melt crystallization,17 single crystals of the γ form suitable for X-ray diffraction were obtained during an attempted cocrystallization of PZA with pyrazinoic acid in water, along with the R form. The occurrence of a new polymorph of one of the components in an experiment set up to prepare their cocrystal is not uncommon.18 Metastable crystallites of the γ form were obtained from benzene and toluene (Figure S2, Supporting Information). The δ form was obtained as plates exclusively from benzene and toluene and as a concomitant mixture with the R form from EtOAc, THF, and acetic acid. Our experience after several experiments is that all the four forms are obtained concomitantly from several solvents, but it is possible to identify each polymorph based on its morphology and extinction under polarized light microscope (see the hot stage microscopy (HSM) pictures in Figure S3,

Figure 1. Molecular structure of pyrazinamide (PZA) to show the intramolecular hydrogen bond. The hydrogen bonded conformer is E and the other conformer is Z. The amide group in the Z conformer is twisted out of the aromatic plane to minimize H-H and O-N repulsions.

Supporting Information). No new polymorph of PZA was discovered during our numerous experiments. IR, NIR, and Raman Analysis of PZA Polymorphs. All four forms of PZA can be readily distinguished by their N-H and CdO stretching vibrations in FT-IR spectra (Figure 4) and from the difference in their N-H first overtone and CdO second overtone bands in FT-NIR spectra (Figure 5). The overtones are in concurrence with the fundamental frequencies (Table 2). According to the “infrared rule”,19 the structure with the higher frequency in bond stretching mode may be assumed to have the larger entropy, and so the R polymorph with its lower stretching frequency is assigned as the lower entropy form and hence the one with stronger intermolecular hydrogen bonds. All four forms of PZA have distinct Raman spectra and can be readily distinguished by their signature peaks (Figure 6, Table 2). Crystal Structure Analysis. The intramolecular hydrogen bond in PZA makes the molecule rigid and planar. The E conformer (Figure 1) is 30 kJ mol-1 lower in energy than the Z conformer,16 and this stable E conformer is observed in all polymorphs. PZA crystal structures may be analyzed in terms of supramolecular synthons.20 At the primary level, the cyclic synthon of strong N-H 3 3 3 O hydrogen bonds for the carboxamide dimer is present in R, β, and δ forms compared to N-H 3 3 3 N hydrogen bond in the γ form. The weak C-H 3 3 3 N and C-H 3 3 3 O interactions are different at the secondary level.18e Whereas the carboxamide syn NH makes the dimer synthon in R, β and δ forms, these polymorphs differ in their anti-NH hydrogen bonding. The R form has N-H 3 3 3 N dimer, the β form has N-H 3 3 3 O hydrogen bond, the γ form has a relatively short intramolecular anti-N-H 3 3 3 N bond along with an intermolecular syn-N-H 3 3 3 N bond, and finally in the δ form the anti-NH donor is kind of unused due to a very long N-H 3 3 3 O contact of 2.62 A˚. Hydrogen bond metrics are given in Table 3. The crystal structure of the γ form reported by Castro15 has a high R-factor of 0.1066. Careful analysis of this structure showed residual electron density of 0.88 e A-3, which is due to disorder in the structure that was not modeled. We collected reflections on a good crystal of the γ form at 100 K and modeled the disorder into two parts with site occupancy

Table 1. Crystallographic Parameters of PZA Polymorphs polymorph

R forma

β form

γ form (disorder unmodeled)

γ form (disorder modeled)

δ formb

chemical formula formula weight crystal system space group T/K a/A˚ b/A˚ c/A˚ R/ β/ γ/ Z V/A˚3 Dcalc/g cm-3 μ/mm-1 reflns collected unique reflns observed reflns R1 [I > 2σ(I)] wR2 [all] goodness-of-fit CCDC no.

C5H5N3O 123.12 monoclinic P21/n 100(2) 3.6147(4) 6.7384(8) 22.464(3) 90 92.499(2) 90 4 546.63(11) 1.496 0.111 2581 1070 978 0.0387 0.0938 1.059 PYRZIN15a

C5H5N3O 123.12 monoclinic P21/c 100(2) 14.315(2) 3.6238(5) 10.6158(15) 90 101.119(2) 90 4 540.34(13) 1.513 0.112 5047 1062 1026 0.0340 0.0880 1.121 771182

C5H5N3O 123.12 monoclinic Pc 100(2) 7.170(3) 3.6477(15) 10.648(4) 90 106.350(6) 90 2 267.21(19) 1.530 0.114 2116 960 926 0.0796 0.2145 1.072 771184

C5H5N3O 123.12 monoclinic Pc 100(2) 7.1756(14) 3.6508(7) 10.663(2) 90 106.337(3) 90 2 268.05(9) 1.525 0.113 961 684 681 0.0392 0.0960 1.116 771183

C5H5N3O 123.12 triclinic P1 100(2) 5.1186(10) 5.7053(11) 9.857(2) 97.46(3) 98.17(3) 106.47(3) 2 268.82(9) 1.521 0.113 2225 1045 963 0.0372 0.1029 1.057 PYRZIN16b

a

Nangia, A.; Srinivasulu, A. CCDC-PYRZIN15, 2005 (ref 4g). b Nangia, A.; Srinivasulu, A. CCDC-PYRZIN16, 2005 (ref 4h).

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Figure 2. Overlay of the simulated X-ray crystal structure (red) and experimental XRPD pattern (black). (a) R polymorph of PZA crystallized from water, (b) γ polymorph of PZA crystallized from the melt, and (c) δ polymorph of PZA crystallized from toluene.

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Figure 3. Overlay of the simulated X-ray crystal structure of β (red) and γ (blue) polymorph on the XRPD pattern of the experimental material (black) shows an 80:20 composition of the mixture by Rietveld refinement (Rp = 30.14).

Figure 4. FT-IR spectra of R (blue), β(þγ) (green), γ (magenta), and δ (red) forms show marked differences in the (a) N-H and (b) CdO stretching vibrations.

factor (sof) of 0.87 and 0.13. Now the R-factor improved to 0.0392. The structural analysis and hydrogen bonding deals with the major 87% site occupancy of atoms. When disorder was not modeled, the R-factor is higher at 0.0796. The centrosymmetric N-H 3 3 3 O dimer present in R, β, and δ forms has R22(8) graph set notation,21 while the carboxamide tape in the δ form is a C(4)R42(8) motif (the tape repeat distance is 5.7 A˚ instead of the usual 5.1 A˚). The N-H 3 3 3 N cyclic synthon in the R form makes the R22(10) ring and the C-H 3 3 3 N cyclic synthon in the δ form makes the R22(6) ring. The γ form has an N-H 3 3 3 N tape of C(6) notation. These synthon differences, associated hydrogen bonding and graph set patterns, and different molecular packing arrangements

(shown in Figure 7) in the four polymorphs of PZA imply their more accurate classification as synthon22 and packing23 polymorphs. The π-stacking in crystal structures has a varying degree of offset (β, three-fourth ring > γ, half ring >R, one-third ring > δ, double bonds overlap) and perpendicular distance between the ring planes (δ, 3.01 < β, 3.22 0.99) was used to determine the intrinsic dissolution rate of the polymorph as [slope of the amount dissolved ÷ surface area of the pellet] per unit time (Table S3, Supporting Information). IDR for R, γ, and δ polymorphs is 2.07, 2.78, 2.05 mg cm-2 min-1.

Acknowledgment. S.C. and R.T. thank the ICMR and UGC for fellowship. We thank the DST for research funding (SR/S1/OC-67/2006 and SR/S1/RFOC-01/2007) and DST (IRPHA) and UGC (PURSE grant) for providing instrumentation and infrastructure facilities. Srinivasulu Aitipamula determined the X-ray crystal structure of R and δ polymorphs in this project. Supporting Information Available: XRPD plots, HSM snapshots, FT-IR and TG-IR, and crystallographic .cif files are available free of charge via the Internet at http://pubs.acs.org/.

References (1) Zhang, Y.; Mitchison, D. Int. J. Tuberculosis Lung Dis. 2003, 7, 6. (2) WHO Model List of Essential Medicines; World Health Organization: Geneva, Switzerland, 2009; http://www.who.int/selection_medicines/ committees/expert/17/sixteenth_adult_list_en.pdf. (3) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon: Oxford, UK, 2002.

Cherukuvada et al. (4) (a) Takaki, Y.; Sasada, Y.; Watanabe, T. Acta Crystallogr. 196013, 693 (R form: CCDC-PYRZIN). (b) Tamura, C; Sasada, Y.; Kuwano, H. Acta Crystallogr. 1961, 14, 693. (c) Ro, G.; Sorum, H. Acta Crystallogr. 1972, B28, 991 (β form: CCDC-PYRZIN01). (d) Ro, G.; Sorum, H. Acta Crystallogr. 1972, B28, 1677 (δ form: CCDC-PYRZIN02). (e) Tiwari, R. K.; Patel, T. C.; Singh, T. P. Indian J. Phys. 1982, A56, 413 (R form: CCDC-PYRZIN14). (f) Nakata, K.; Takaki, Y. Mem. Osaka Kyoiku Univ. Ser. III 1987, 36, 93 (γ form: CCDC-PYRZIN05). (g) Nangia, A.; Srinivasulu, A. Private communication, 2005 (R form: CCDC-PYRZIN15). (h) Nangia, A.; Srinivasulu, A. Private communication, 2005 (δ form: CCDC-PYRZIN16). The Cambridge Crystallographic Data Center refcodes are mentioned for each polymorphic structure. (5) (a) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-State Chemistry of Drugs; SSCI: West Lafayette, IN, 1999. (b) Hilfiker, R., Ed. Polymorphism in the Pharmaceutical Industry; Wiley-VCH: Weinheim, Germany, 2006. (6) (a) Zhang, G. G. Z.; Law, D.; Schmitt, E. A.; Qiu, Y. Adv. Drug Delivery Rev. 2004, 56, 371. (b) 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. (7) (a) Matzger, A. J., Guest Ed. Special Section on Facets of Polymorphism in Crystals; Cryst. Growth Des. 2008, 8, 2-161. (b) Childs, S. L.; Zaworotko, M. J., Guest Eds. Virtual Issue on Pharmaceutical Cocrystals; Cryst. Growth Des. 2009, 9, 4208. (c) Shan, N.; Zaworotko, M. J. Drug Disc. Today 2008, 13, 440. (d) Gardner, C. R.; Walsh, C. T.; € Nat. Rev. 2004, 3, 926. (e) Morissette, S. L.; Almarsson, Almarsson, O. € Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; O.; Cima, M. J.; Gardner, C. R. Adv. Drug Delivery Rev. 2004, 56, 275. (8) Nangia, A. J. Ind. Inst. Sci. 2007, 87, 133. (9) (a) Yoshida, S. Chem. Pharm. Bull. 1963, 11, 628. (b) Delgado, M. J. M.; Marquez, F.; Suero, M. I.; Marcos, J. I. Spectrosc. Lett. 1988, 21, 841. (c) Kalkar, A. K.; Bhosekar, N. M.; Kshirsagar, S. T. Spectrochim. Acta Part A 1989, 45, 635. (d) Akyuz, S. J. J. Mol. Struct. 2003, 651, 541. (e) Chis, V.; Pirnau, A.; Jurca, T.; Vasilescu, M.; Simon, S.; Cozar, O.; David, L. Chem. Phys. 2005, 316, 153. (f) Favila, A.; Gallo, M.; Glossman-Mitnik, D. J. Mol. Modeling 2007, 13, 505. (g) Gunasekaran, S.; Sailatha, E. Indian J. Pure Appl. Phys. 2009, 47, 259. (10) Goher, M. A. S.; Mautner, F. A. Polyhedron 2000, 19, 601. (11) Barich, D. H.; Clawson, J. S.; Stueber, D.; Strohmeier, M.; Pugmire, R. J.; Grant, D. M. J. Phys. Chem. A 2000, 106, 11375. (12) Reddy, C. M.; Padmanabhan, K. A.; Desiraju, G. R. Cryst. Growth Des. 2006, 6, 2720. (13) Becker, C.; Dressman, J. B.; Amidon, G. L.; Junginger, H. E.; Kopp, S.; Midha, K. K.; Shah, V. P.; Stavchansky, S.; Barends, D. M. J. Pharm. Sci. 2008, 97, 3709. (14) Gallo, G. G.; Radaelli, P. In Analytical Profiles of Drug Substances; Florey, K., Ed.; Academic Press: London, 1976; pp 467-513.  (15) Castro, R. A. E.; Maria, T. M. R.; Evora, A. O. L.; Feiteira, J. C.; Silva, M. R.; Beja, A. M.; Canotilho, J.; Eusebio, M. E. S. Cryst. Growth Des. 2010, 10, 274 (γ form: CCDC-754512). . (16) Borba, A.; Albrecht, M.; Gomez-Zavaglia, A.; Suhm, M. A.; Fausto, R. J. Phys. Chem. A 2010, 114, 151. (17) Sarma, B.; Roy, S.; Nangia, A. Chem. Commun. 2006, 4918. (18) (a) Vishweshwar, P.; McMahon, J. A.; Oliveira, M.; Peterson, M. L.; Zaworotko, M. J. J. Am. Chem. Soc. 2005, 127, 16802. (b) Ahn, S.; Guo, F.; Kariuki, B. M.; Harris, K. D. M. J. Am. Chem. Soc. 2006, 128, 8441. (c) Day, G. M.; Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2006, 54. (d) Babu, N. J.; Nangia, A. CrystEngComm 2007, 9, 980. (e) Babu, N. J.; Reddy, L. S.; Aitipamula, S.; Nangia, A. Chem. Asian. J. 2008, 3, 1122. (f) Lou, B.; Bostr€om, D.; Velaga, S. P. Cryst. Growth Des. 2009, 9, 1254. (19) Burger, A.; Ramberger, R. Mikrochim. Acta II 1979, 273. (20) (a) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311. (b) Nangia, A.; Desiraju, G. R. Top. Curr. Chem. 1998, 198, 57. (21) (a) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr. 1990, B46, 256. (b) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. 1995, 34, 1555. (22) (a) Jetti, R. K. R.; Boese, R.; Sarma, J. A. R. P.; Reddy, L. S.; Vishweshwar, P.; Desiraju, G. R. Angew. Chem., Int. Ed. 2003, 42, 1963. (b) Sreekanth, B. R.; Vishweshwar, P.; Vyas, K. Chem. Commun. 2007, 2375. (23) Vippagunta, S. R.; Brittain, H. G.; Grant, D. J. W. Adv. Drug Delivery Rev. 2001, 48, 3. (24) Roy, S.; Aitipamula, S.; Nangia, A. Cryst. Growth Des. 2005, 5, 2268. (25) (a) Trask, A. V.; Shan, N.; Motherwell, W. D. S.; Jones, W.; Feng, S.; Tan, R. B. H.; Carpenter, K. J. Chem. Commun. 2005, 880.

Article (b) Trask, A. V.; Jones, W. Top. Curr. Chem. 2005, 254, 41. (c) Gu, C. H.; Young, V., Jr.; Grant, D. J. W. J. Pharm. Sci. 2001, 90, 1878. (d) Hornedo, N. R.; Murphy, D. J. Pharm. Sci. 1999, 88, 651. (e) Zencirci, N.; Gelbrich, T.; Apperley, D. C.; Harris, R. K.; Kahlenberg, V.; Griesser, U. J. Cryst. Growth Des. 2010, 10, 302. (26) (a) Ferrari, E. S.; Davey, R. J. Cryst. Growth Des. 2004, 4, 1061. (b) Davey, R. J.; Blagden, N.; Righini, S.; Alison, H.; Ferrari, E. S. J. Phys. Chem. B 2002, 106, 1954. (27) SAINT-Plus, version 6.45; Bruker AXS Inc.: Madison, WI, 2003. (28) Sheldrick, G. M. SADABS, Program for Empirical Absorption Correction of Area Detector Data; University of G€ ottingen: Germany, 1997.

Crystal Growth & Design, Vol. 10, No. 9, 2010

3941

(29) (a) SMART (Version 5.625) and SHELX-TL (Version 6.12); Bruker AXS Inc.: Madison, WI, 2000. (b) Sheldrick, G. M. SHELXS-97 and SHELXL-97; University of G€ottingen: Germany, 1997. (30) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, Netherland, 2002. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7. (31) Barbour, L. J. X-Seed, Graphical Interface to SHELX-97 and POVRay; University of Missouri-Columbia: Columbia, MO, 1999. (32) Powder Cell for structure visualization, powder pattern calculation and profile fitting, www.ccp14.ac.uk. (33) Cerius2, Ver. 4, www.accelrys.com. (34) Glomme, A.; Marz, J.; Dressman, J. B. J. Pharm. Sci. 2005, 94, 1.