First Crystal Structures of the Antihypertensive Drug Perindopril

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First Crystal Structures of the Antihypertensive Drug Perindopril Erbumine: A Novel Hydrated Form and Polymorphs r and β V^ania Andre,† Luís Cunha-Silva,†,‡ M. Teresa Duarte,*,† and Pedro Paulo Santos† † ‡

Centro de Química Estrutural, DEQB, Instituto Superior Tecnico, Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal REQUIMTE & Departamento de Química e Bioquímica, Faculdade de Ci^encias, Universidade do Porto, 4169-007 Porto, Portugal

bS Supporting Information ABSTRACT: The first crystalline structures of the antihypertensive drug perindopril unveiled by single crystal X-ray diffraction are reported herein. Structures of forms R and β of perindopril erbumine have been determined. A novel perindopril erbumine hydrated form was also synthesized and fully characterized.

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tudy of crystalline forms, including polymorphs, solvates/ hydrates, cocrystals, and salts, has become one of the most important issues of modern solid-state and materials chemistry.1 7 In particular, the research of new crystal forms involving active pharmaceutical ingredients (APIs) has a remarkable potential for new discoveries and innovations of existing drug products.8 Usually, each crystal form possesses its own exclusive mechanical, thermal, and physicochemical properties affecting solubility, bioavailability, hygroscopicity, melting point, stability, compressibility, and other characteristics of the drug.9 14 Consequently, a systematic understanding of the relationship between a particular crystal form and its functional properties is crucial for selecting the most suitable form of the API for development into a drug product.15 19 Perindopril, 2-methylpropane-2-amine-(2S,3aS-7aS)-1-[(2S)2-[[(1S)-1-ethoxycarbonyl-butyl]amino]propanoyl]octahydro1H-indole-2-carboxylate (Scheme S1 in Supporting Information), is an antihypertensive drug that also comprises vasculoprotective and antithrombotic effects, playing a favorable role in terms of cardiovascular morbility.20 23 Perindopril is a prodrug ester that is converted into the active diacid perindoprilat by hydrolysis after administration.20,24 It is orally administered in the form of tablets containing its 1:1 salts with erbumine (tert-butylamine) (Aceon) or L-arginine (Coversyl).25,26 Over the past few years, several forms of perindopril erbumine have been disclosed and several patents have been filed mainly based on their typical powder X-ray diffraction (PXRD) patterns.27 32 Perindopril erbumine is known to exist in several polymorphic forms,27,28,30,33 36 as well as mono-, di-, and sesqui-hydrated forms, characterized by r 2011 American Chemical Society

PXRD, vibrational spectroscopy, and thermal analysis methods.37,38 As part of our recent research in the preparation, structural characterization, and properties studies of new crystalline forms of APIs,39 42 we have determined by single-crystal XRD (SCXRD) the first molecular structures of perindopril. Careful searches in the literature and in the Cambridge Structural Database43 revealed that, although this API is known since 1981, no crystal structure had been reported so far. The novel SCXRD structures correspond to the patented R and β polymorphs32,44 of perindopril erbumine and an unprecedented hydrated form which,45 to the best of our knowledge, is not reported elsewhere and is part of a patent recently filed by us:46 (C4H12N)(C19H31N2O5) 3 1.25H2O. The three forms of perindopril erbumine were further characterized by PXRD, vibrational spectroscopy (ATR-FT-IR and FT-Raman), and thermal analysis methods (thermogravimetric analysis - TGA, differential scanning calorimetry - DSC, and hot-stage microscopy - HSM). Crystalline materials suitable for SCXRD analysis of the two polymorphic forms (forms R and β) were obtained by controlled recrystallization in ethyl acetate and dichloromethane, respectively. While form R crystallizes in the orthorhombic P212121 space group, form β was isolated in the monoclinic P21 space group, both with one perindopril anion (C19H31N2O5 ) and one erbumine cation (tert-butylamine; C4H12N+) in the asymmetric unit (asu) (Figure S1 in Supporting Information). Received: April 6, 2011 Revised: July 1, 2011 Published: July 13, 2011 3703

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Crystal Growth & Design The new hydrated form was initially obtained by controlled evaporation of an ethanolic solution of form R. After 4 5 days colorless plate-like crystals with a triclinic symmetry P1 chiral space group were grown. This hydrated form was also obtained by liquid-assisted grinding (LAG), which has several advantages not only in the preparation process, where equal yield and purity are obtained, but also in an environmental context.47 51 Its asu consists of two crystallographic independent perindopril anions, two erbumine cations and 2.5 water molecules (Figure S1 in Supporting Information). The CO distances in the carboxylate moiety and the location of the three hydrogen atoms in the amine moieties from the electron density map confirmed the presence of the salt. The chiral centers in both perindopril crystallographic independent anions exhibit the (S) configuration, corresponding exactly to the same configuration of the starting form R as well as of form β. The main conformational differences between these crystallographic independent anions are noted in the CH2CH2CH3 terminal groups (torsion angles of 58.2(14) vs 175.1(9) A and B, respectively) (Figure S2 in SI).

Figure 1. Detail of the asymmetric unit for the hydrated form of perindopril erbumine, showing the labeling scheme for all drawn atoms; chiral centers are labeled in blue, and hydrogen atoms were omitted for clarity.

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The crystal packing of both the polymorphic forms and the hydrated form show similar hydrogen bonding interactions involving the perindopril and the erbumine ions. Perindopril anions interact with erbumine cations in an extended N H 3 3 3 O hydrogen bonding network leading to a supramolecular structure with the moieties organized in a double-chain arrangement (Figures 2a, S3 and S6). Each erbumine cation connects with three perindopril anions via the amine moiety: two of them are in the same chain, whereas the other perindopril belongs to the opposite chain. Therefore, two related types of C22(6) graph set motifs are formed in both chains and these are connected among them by D11(2) motifs (Figures 2a, S4 and S7 in Supporting Information). When the positioning of the anions in their respective chains are compared, it is possible to notice that they assume antiparallel orientations, i.e., perindopril anions of one chain are rotated of 180° relative to the anions in the adjacent chain. The N H 3 3 3 O hydrogen bond distances are within the ranges of 2.707 2.803 Å, 2.738 2.788 Å, and 2.75 2.781 Å in R, β and hydrated forms, respectively (Table S1 in Supporting Information). These double chains do not establish classical hydrogen bonds among them either in R or β forms, but in the hydrated form water molecules play an important role by linking adjacent chains through interactions between two crystallographically independent perindopril anions via the carbonyl group of one [OW 3 3 3 OCdO distance of 2.717 Å] and the amine moiety of the other [NN H 3 3 3 OW distance of 2.430 Å]. Water molecules lie in the free spaces arising from the supramolecular arrangement described (Figure S5 in Supporting Information) and interact through OW H 3 3 3 OW hydrogen bonds forming trimeric water clusters [O 3 3 3 O distances in the cluster: 2.644, 2.687, and 2.932 Å] (Figures 2b and S8 in Supporting Information). The two polymorphic structures (forms R and β) do not reveal any crystallization water molecule in the network, as also confirmed by the TGA (Figure S13 in Supporting Information). Elemental and Karl Fischer analyses (Tables II and III in Supporting Information) confirmed the water content of the R form and the novel hydrate as being 0.4 and 4.83%, respectively. The phase purity of the bulk samples and its perfect agreement with the crystal structures obtained were established by PXRD (Figure 3). Furthermore, the powder diffraction pattern obtained for the hydrated form was compared with all the perindopril

Figure 2. Crystal packing of the hydrated form: (a) supramolecular arrangement with the perindopril anions and erbumine cations organized in doublechains; H bonds represented as blue dashed lines; water molecules were omitted for clarity; (b) detailed hydrogen bonding within the water cluster. Only hydrogen atoms involved in hydrogen bonding are shown, with the exception of water molecules for which no hydrogen atoms are displayed. 3704

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Crystal Growth & Design

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the commercially available drug.46 A probable reason for this is the enhanced stability provided by the presence of the water molecules linking the erbumine perindopril double chains. Analysis of crystal structure has again proven to be quite important for the establishment of the intermolecular interactions responsible for the supramolecular arrangement and thus the physicochemical properties of APIs.

’ ASSOCIATED CONTENT

bS

Supporting Information. Crystallographic information files (CIF); additional detailed synthetic procedures, XRPD, SCXRD, DSC, TGA, and HSM data. This information is available free of charge via the Internet at http://pubs.acs.org/.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

Figure 3. Experimental and simulated powder diffraction patterns for the forms R, β and hydrated of perindopril erbumine.

erbumine forms reported in the literature and registered in patents, being different from all of them and thus confirming the novelty of the new hydrated form reported herein. PXRD analysis was used to follow-up and to confirm the preparation of the novel hydrated form obtained by solution methods and by LAG (Figure S9 in Supporting Information). Vibrational spectroscopy (FT-IR and FT-Raman) studies support the structural features unveiled by SCXRD data which are reflected in the spectra through a number of diagnostic bands (Figures S10 and S11 in Supporting Information). In particular, the strong bands in the range of 3200 2600 cm 1 of the FTRaman spectra are attributed to the υs(C H) and υs(N H) stretching vibrational modes diagnosing the presence of NH and NH3+ groups in the perindopril and erbumine cation, respectively. The strong bands around 1642, 1569, and 1387 cm 1 (observed in both the FT-IR and FT-Raman spectra) are assigned to the υs(COO ) and υas(COO ), respectively, confirming the deprotonation of the carboxylic acid group. Contrasting with the FT-IR spectra of forms R and β, the spectrum of the hydrated form in the 3200 2600 cm 1 range reflects the presence of crystallization water molecules involved in well-defined hydrogen bonds, by the presence of resolved peaks. The combination of data obtained from DSC, TGA, and HSM (Figures S12 14 in Supporting Information) indicates that the novel hydrated form is stable until temperatures of approximately 80 °C, at which a peak is observed in the DSC, a smooth mass loss is detected in the TGA, and bubbles start to appear in the HSM. The water loss occurs from this temperature until approximately 120 °C. At 164 °C melting and decomposition take place. The new hydrate has shown to be as stable on the shelf for several months as form R, and water slurry experiments revealed it as the thermodynamically stable hydrated form. The novel form has also been shown to have a similar dissolution profile as

’ ACKNOWLEDGMENT The authors acknowledge Fundaç ~ao para a Ci^encia e a Tecnologia, MCTES, Portugal, for funding the Project POCI/ QUI/58791/2004, PEst-OE/QUI/UI0100/2011, the programme “Ci^encia 2008” (L.C.-S.) and the Ph.D. Grant SFRH/40474/ 2007 (V.A.). ’ REFERENCES (1) Desiraju, G. R. J.Chem. Sci. 2010, 122 (5), 667–675. (2) Merz, K.; Vasylyeva, V. CrystEngComm 2010, 12 (12), 3989–4002. (3) Desiraju, G. R. Curr. Opin. Solid State Mater. Sci. 2009, 13 (3 4), 35–35. (4) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9 (6), 2950–2967. (5) Peterson, M. L.; Hickey, M. B.; Zaworotko, M. J.; Almarsson, O. J. Pharm. Pharmaceut. Sci. 2006, 9 (3), 317–326. (6) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95 (3), 499–516. (7) Braga, D.; Grepioni, F. Chem. Commun. 2005, 29, 3635–3645. (8) Karpinski, P. H. Chem. Eng. Technol. 2006, 29 (2), 233–237. (9) Chency, M. L.; Shan, N.; Healey, E. R.; Hanna, M.; Wojtas, L.; Zaworotko, M. J.; Sava, V.; Song, S. J.; Sanchez-Ramos, J. R. Cryst. Growth Des. 2010, 10 (1), 394–405. (10) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park, A. Pharm. Res. 2006, 23 (8), 1888–1897. (11) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Int. J. Pharm. 2006, 320 (1 2), 114–123. (12) Good, D. J.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9 (5), 2252–2264. (13) Ma, Z. B.; Moulton, B. J. Chem. Crystallogr. 2009, 39 (12), 913–918. (14) Cherukuvada, S.; Thakuria, R.; Nangia, A. Cryst. Growth Des. 2010, 10 (9), 3931–3941. (15) Bethune, S. J.; Huang, N.; Jayasankar, A.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9 (9), 3976–3988. (16) Reddy, L. S.; Bethune, S. J.; Kampf, J. W.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9 (1), 378–385. (17) Remenar, J. F.; Peterson, M. L.; Stephens, P. W.; Zhang, Z.; Zimenkov, Y.; Hickey, M. B. Mol. Pharmaceutics 2007, 4 (3), 386–400. (18) Serajuddin, A. T. M. Adv. Drug Delivery Rev. 2007, 59 (7), 603–616. (19) Hickey, M. B.; Peterson, M. L.; Scoppettuolo, L. A.; Morrisette, S. L.; Vetter, A.; Guzman, H.; Remenar, J. F.; Zhang, Z.; Tawa, M. D.; 3705

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Crystal Growth & Design Haley, S.; Zaworotko, M. J.; Almarsson, O. Eur. J. Pharm. Biopharm. 2007, 67 (1), 112–119. (20) Pascard, C.; Guilhem, J.; Vincent, M.; Remond, G.; Portevin, B.; Laubie, M. J. Med. Chem. 1991, 34 (2), 663–669. (21) Remkova, A.; Kratochvil’ova, H. Blood Coagulation Fibrinolysis 2000, 11 (7), 641–644. (22) Okrucka, A.; Pechan, J.; Kratochvilova, H. Platelets 1998, 9 (1), 63–67. (23) Remkova, A.; Kratochvil’ova, H.; Durina, J. J. Hum. Hypertens. 2008, 22 (5), 338–345. (24) Lecocq, B.; Funckbrentano, C.; Lecocq, V.; Ferry, A.; Gardin, M. E.; Devissaguet, M.; Jaillon, P. Clin. Pharmacol. Therapeut. 1990, 47 (3), 397–402. (25) Remko, M. Eur. J. Med. Chem. 2009, 44 (1), 101–108. (26) Telejko, E. Curr. Med. Res. Opin. 2007, 23 (5), 953–960. (27) Rucman, R. WO2005068490-A1; EP1709066-A1; EP1709066B1; DE602005009319-E; EP2003142-A1; RU2372353-C2, 2005. (28) Rucman, R. WO2005068425-A1; EP1713771-A1; RU2387641-C2, 2005. (29) Rucman, R.; Zupet, P. WO2007058634-A1; EP1948224-A1; ZA200803889-A, 2007. (30) Rucman, R.; Zupet, P. WO2008150245-A2; WO2008150245A3; EP2164469-A2; CN101742986-A, 2009. (31) Kumar, A.; Soudagar, S. R.; Mathur, A.; Gunjal, S. T.; Panda, N. B.; Jadhav, D. U. EP1987828-A1, 2008. (32) Kumar, A.; Soudagar, S. R.; Mathur, A.; Panda, N. B. US2008183011-A1; EP1964836-A2; IN200601843-I3; EP1964836A3, 2008. (33) Churchley, D.; Amberkhane, A., WO2008050185-A2, 2008. (34) Devarakonda, S. N.; Asnani, M.; Bonnareddy, S. R.; Padi, P. R.; Chandramohan, U. K.; Chitre, S. S.; Nalivella, V.; Vasamsetti, S. K.; Minakshi, A.; Reddy, B. S.; Reddy, P. P., WO2007092758-A2; WO2007092758-A3; IN200804031-P4, 2008. (35) Straessler, C.; Lellek, V.; Faessler, R.; Fassler, R.; Strassler, C.; Strossler, C.; Fossler, R.; Christoph, S.; Vit, L.; Roger, F., WO2004113293-A1; NO200600256-A; EP1636185-A1; AU2004249345-A1; BR200411966-A; KR2006035636-A; MX2005013811-A1; CN1812971-A; JP2007507418-W; US2007135512-A1; ZA200600655-A; CN100395235-C; CN101333181-A; NZ544160-A; AU2004249345-B2; AU2004249345-B8; MX268989-B; US7705046-B2; US2010160404A1, 2005. (36) Ujagare, A.; Kochrekar, D. A.; Sarjekar, P. WO2007017894-A2, 2007. (37) Rucman, R.; Zupet, P. EP1647547-A1, 2006. (38) Ujagare, A.; Kochrekar, D. A.; Sarjekar, P. WO2007017893-A2, 2007. (39) Andre, V.; Braga, D.; Grepioni, F.; Duarte, M. T. Cryst. Growth Des. 2009, 9 (12), 5108–5116. (40) Andre, V.; Marques, M. M.; da Piedade, M. F. M.; Duarte, M. T. J. Mol. Struct. 2010, 973 (1 3), 173–179. (41) Braga, D.; Grepioni, F.; Maini, L.; Rubini, K.; Polito, M.; Brescello, R.; Cotarca, L.; Duarte, M. T.; Andre, V.; Piedade, M. F. M. New J. Chem. 2008, 32 (10), 1788–1795. (42) Braga, D.; Grepioni, F.; Andre, V.; Duarte, M. T. CrystEngComm 2009, 11 (12), 2618–2621. (43) Fabian, L. Cryst. Growth Des. 2009, 9 (3), 1436–1443. (44) Joshi, N. S.; Bhirud, S. B.; Rao, K. E. US2005250706-A1; WO2005108365-A1; IN200400531-I3; IN220637-B, 2005. (45) Crystal data. Form R: C19H31N2O5.C4H12N, Mr = 441.60, orthorhombic, P212121, a = 6.574(6) Å, b = 12.213(7) Å, c = 31.326(9) Å, V = 2515(3) Å3, Z = 4, Dc = 1.166 g/cm3, μ = 0.082 mm 1, θmin = 1.79°, θmax = 25.70°, R1(wR2) = 0.1526 (0.4119) for 4715 observed independent reflection (Rint = 0.0612); form β: C19H31N2O5.C4H12N, Mr = 441.60, monoclinic, P21, a = 12.203(5) Å, b = 6.419(3) Å, c = 17.120(7) Å, β = 97.06(1)°, V = 1330(1) Å3, Z = 2, Dc = 1.102 g/cm3, μ = 0.077 mm 1, θmin = 2.40°, θmax = 25.63°, R1(wR2) = 0.1185 (0.3283) for 4639 observed independent reflection (Rint = 0.0753); hydrated form: C 19 H 31 N2 O 5 3 C 4 H 12 N 3 1.25(H 2 O) M r = 461.60, triclinic, P1,

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a = 6.578(1) Å, b = 12.104(1) Å, c = 16.729(4) Å, R = 97.919(4)°, β = 94.762(4)°, γ = 91.321(4)°, V = 1313.9 Å3, Z = 1, Dc = 1.167 g/cm3, μ = 0.084 mm 1, θmin = 2.79°, θmax = 25.85°, R1(wR2) = 0.0661 (0.1404) for 4996 observed independent reflection (Rint = 0.0760). The “poor” quality of the crystals and their low diffracting power precluded the acquisition of better X-ray data. (46) Andre, V.; Cunha-Silva, L.; Santos, P. P.; Duarte, M. T. PT105315, 2010. (47) Chow, E. H. H.; Strobridge, F. C.; Friscic, T. Chem. Commun. 2010, 46 (34), 6368–6370. (48) Friscic, T. J. Mater. Chem. 2010, 20 (36), 7599–7605. (49) Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9 (2), 1106–1123. (50) Trask, A. V.; Haynes, D. A.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2006, 1, 51–53. (51) Friscic, T.; Jones, W. Cryst. Growth Des. 2009, 9 (3), 1621– 1637.

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