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Volume 68 
Part 11 
Pages o443-o446  
November 2012  

Received 24 September 2012
Accepted 4 October 2012
Online 18 October 2012

Perindoprilat monohydrate

aInstitute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lódz, Poland,bPolfarmex SA, Józefów 9, 99-300 Kutno, Poland,cDepartment of Synthesis and Technology of Drugs, Medical University Lódz, Muszynskiego 1, 90-145 Lódz, Poland, and dDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University Bratislava, Odbojárov 10, SK-832 32 Bratislava, Slovakia
Correspondence e-mail: waldemar.maniukiewicz@p.lodz.pl

The title compound [systematic name: (1S)-2-((S)-{1-[(2S,3aS,7aS)-2-carboxyoctahydro-1H-indol-1-yl]-1-oxopropan-2-yl}azaniumyl)pentanoate monohydrate], C17H28N2O5·H2O, (I)·H2O, the active metabolite of the antihypertensive and cardiovascular drug perindopril, was obtained during polymorphism screening of perindoprilat. It crystallizes in the chiral orthorhombic space group P212121, the same as the previously reported ethanol disolvate [Pascard, Guilhem, Vincent, Remond, Portevin & Laubie (1991[Pascard, C., Guilhem, J., Vincent, M., Remond, G., Portevin, B. & Laubie, M. (1991). J. Med. Chem. 34, 663-669.]). J. Med. Chem. 34, 663-669] and dimethyl sulfoxide hemisolvate [Bojarska, Maniukiewicz, Sieron, Fruzinski, Kopczacki, Walczynski & Remko (2012[Bojarska, J., Maniukiewicz, W., Sieron, L., Fruzinski, A., Kopczacki, P., Walczynski, K. & Remko, M. (2012). Acta Cryst. C68, o341-o343.]). Acta Cryst. C68, o341-o343]. The asymmetric unit of (I)·H2O contains one independent perindoprilat zwitterion and one water molecule. These interact via strong hydrogen bonds to give a cyclic R22(7) synthon, which provides a rigid molecular conformation. The geometric parameters of all three forms are similar. The conformations of the perhydroindole group are almost identical, but the n-alkyl chain has conformational freedom. A three-dimensional hydrogen-bonding network of O-H...O and N-H...O interactions is observed in the crystal structure of (I)·H2O, similar to the other two solvates, but because of the presence of different solvents the three crystal structures have diverse packing motifs. All three solvatomorphs are additionally stabilized by nonclassical weak C-H...O contacts.

Comment

Perindopril is an angiotensin-converting-enzyme (ACE) inhibitor and has an established position in the main clinical treatment guidelines (Brugts et al., 2009[Brugts, J. J., Ferrari, R. & Simoons, M. L. (2009). Expert Rev. Cardiovasc. Ther. 7, 345-360.]). As an active pharmaceutical ingredient, perindopril is contained in numerous drugs, for example coversyl (L-arginine salt) and aceon (perindopril erbumine) (Telejko, 2007[Telejko, E. (2007). Curr. Med. Res. Opin. 23, 953-960.]; Remko, 2009[Remko, M. (2009). Eur. J. Med. Chem. 44, 101-108.]). There is an official standard for perindopril salts in the European Pharmacopoeia (European Directorate for the Quality of Medicines and HealthCare, 2011[European Directorate for the Quality of Medicines and HealthCare (2011). European Pharmacopoeia, 7th ed. Strasbourg: Council of Europe.]; Malenovic et al., 2011[Malenovic, A., Dotsikas, Y., Maskovic, M., Jancic-Stojanovic, B., Ivanovic, D. & Medenica, M. (2011). Microchem. J. 99, 454-460.]). Perindopril is a non-sulfhydryl acid-ester prodrug, which after oral administration undergoes hydrolysis, promoted by the esterases in the liver and plasma, to the active dicarboxylic acid perindoprilat (Laubie et al., 1984[Laubie, M., Schiavi, P., Vincent, M. & Schmitt, H. (1984). J. Cardiovasc. Pharmacol. 6, 1076-1082.]; Lecocq et al., 1990[Lecocq, B., Funckbrentano, C., Lecocq, V., Ferry, A., Gardin, M. E., Devissaguet, M. & Jaillon, P. (1990). Clin. Pharmacol. Ther. 47, 397-402.]). It has wide-ranging pharmacodynamic properties which include, inter alia, vasodilation, restriction of cardiovascular remodelling, anti-atherogenic, anti-ischaemic and antithrombotic activity, enhanced endothelial function and improved fibrinolytic balance. With high tissue ACE affinity and a long duration of action, it has a positive safety and tolerability profile (Ferrari, 2005[Ferrari, R. (2005). Expert Rev. Cardiovasc. Ther. 3, 15-29.]; Opie, 2011[Opie, L. H. (2011). Cardiovasc. Drugs Ther. 25, 77-84.]). Moreover, perindopril, and also ramipril, have been associated with lower mortality than other ACE inhibitors (Pilote et al., 2004[Pilote, M., Abrahamowicz, E., Rodrigues, M., Eisenberg, M. J. & Rahme, E. (2004). Ann. Intern. Med. 141, 102-112.]). More than 20 years ago, Pascard et al. (1991[Pascard, C., Guilhem, J., Vincent, M., Remond, G., Portevin, B. & Laubie, M. (1991). J. Med. Chem. 34, 663-669.]) characterized a preferential solid-state conformation of perindoprilat ethanol disolvate [denoted (I)·2EtOH] [Cambridge Structural Database (CSD; Allen, 2002[Allen, F. H. (2002). Acta Cryst. B58, 380-388.]) refcode SIWBUV], but in that structure, determined at room temperature, the ethanol molecules and the alkyl chain of perindoprilat were disordered (0.8:0.2), with some imprecisely refined and some missing H atoms. Thus, hydrogen-bonding interactions could not be defined reliably.

[Scheme 1]

Very recently, we reported a more precise molecular structure of perindoprilat dimethyl sulfoxide (DMSO) hemisolvate, (I)·0.5DMSO (Bojarska et al., 2012[Bojarska, J., Maniukiewicz, W., Sieron, L., Fruzinski, A., Kopczacki, P., Walczynski, K. & Remko, M. (2012). Acta Cryst. C68, o341-o343.]). We have now investigated a new crystal form of perindoprilat, which crystallizes as a monohydrate, with one perindoprilat entity and one water molecule in the asymmetric unit, (I)·H2O[link]. From a pharmaceutical point of view, a hydrate is considerably better. Thus, perindoprilat monohydrate, (I)·H2O[link], is the subject of this article as a continuation of our studies.

A view of the molecular structure of (I)·H2O[link] is shown in Fig. 1[link]. Like the two structures reported previously, (I)·H2O[link] crystallizes in an orthorhombic setting. The Sohnke space group P212121, which is the most common for solvates with a chiral main component (Cruz Cabeza et al., 2007[Cruz Cabeza, A. J., Pidcock, E., Day, G. M., Motherwell, W. D. S. & Jones, W. (2007). CrystEngComm, 9, 556-560.]), was unambiguously determined. The stereochemical configuration of the main molecule was established to be S at its five chiral centres (C atoms C1, C3, C8, C10 and C11) (Eliel & Wilen, 1994[Eliel, E. L. & Wilen, S. H. (1994). In Stereochemistry of Organic Compounds. New York: Wiley Interscience.]) and was confirmed by the Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]) and Hooft (Hooft et al., 2008[Hooft, R. W. W., Straver, L. H. & Spek, A. L. (2008). J. Appl. Cryst. 41, 96-103.]) parameters of 0.04 (14) and 0.05 (3), respectively, which is important for its pharmacological activity (Vincent & Schiavi, 1991[Vincent, M. & Schiavi, P. (1991). Modelling, Synthesis and Pharmacological Study of Perindopril, an Angiotensin I Converting Enzyme Inhibitor, in Molecular Recognition Mechanisms, edited by M. Delaage, ch. 5. Paris: VCH Publisher/Lavoisier TEC and DOC.]).

Intramolecular proton transfer from atom O3 of the carboxy group to alanine atom N2 leads to the zwitterionic form of perindoprilat (see Scheme[link] and Fig. 1[link]). The C17-O3 and C17-O2 bond lengths are equal, at 1.2580 (16) and 1.2451 (16) Å, respectively, indicating that electron delocalization has increased in this group. All the bond lengths and angles are in the usual ranges (Orpen et al., 1994[Orpen, A. G., Brammer, L., Allen, F. H., Kennard, O., Watson, D. G. & Taylor, R. (1994). Structure Correlation, Vol. 2, edited by H.-B. Burgi & J. D. Dunitz, Appendix A. Weinheim: VCH Publishers.]).

The molecular structure of (I)·H2O[link] is largely comparable with the previously reported analogues. There is a fairly close resemblance between the perhydroindole group conformations, while the n-alkyl chains have different conformations. The six-membered ring (C3-C8) adopts a slightly deformed chair conformation, as confirmed by the puckering parameters Q = 0.5445 (16) Å, [theta] = 165.17 (16)° and [varphi] = 3.4 (6)° (Cremer & Pople, 1975[Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354-1358.]; Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]). The proline ring (N1/C1-C3/C8) is in an envelope conformation [puckering parameters Q = 0.3973 (14) Å and [varphi] = 284.50 (19)°]. The torsion angle (O1-C9-C10-C16) between the alanine methyl group and the amide plane is 74.70 (15)°. The terminal alkyl chain conformation of (I)·H2O[link] is synclinal [the N2-C11-C12-C13 torsion angle is -60.04 (15)°]. The conformational difference between the perindoprilat molecules in all three known solvates involves only the orientation of the n-alkyl chain, which in (I)·0.5DMSO and (I)·2EtOH has a synclinal or antiperiplanar orientation. In Fig. 2[link], all the solvates are superimposed to emphasize the different n-alkyl chain orientations. It is worth mentioning that the geometric parameters of perindoprilat hydrate are in good agreement with those of two perindopril erbumine structures (CSD refcodes IVEGIA and IVEGOG; Remko et al., 2011[Remko, M., Bojarska, J., Jezko, P., Sieron, L., Olczak, A. & Maniukiewicz, W. (2011). J. Mol. Struct. 997, 103-109.]).

In the crystal structure of (I)·H2O[link], the perindoprilat molecules are connected to each other via intermolecular hydrogen bonding. Additional hydrogen bonds to the water molecules are also formed (Fig. 3[link] and Table 1[link]). Classical strong intermolecular interactions of O-H...O and N-H...O types create a three-dimensional network. The N-H...O hydrogen bonds are rather stronger and the O-H...O hydrogen bonds rather weaker in (I)·H2O[link] than in (I)·0.5DMSO. Among the hydrogen bonds listed, O5-H5O...O3iii has the shortest O...O distance [2.5929 (14) Å; symmetry code given in Table 1[link]] and O1W-H2W...O1 the longest [2.8307 (15) Å].

At the first level of graph-set theory (Etter et al., 1990[Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256-262.]), there are two chains perpendicular to each other: a five-membered chain with a C(5) graph-set motif which runs along the a axis, and a C(11) chain along the b axis, formed through N2-H2NB...O2(x + [{1\over 2}], -y + [{3\over 2}], -z + 2) and O5-H5O...O3(-x + 2, y + [{1\over 2}], -z + [{3\over 2}]) interactions, respectively (Fig. 3[link]). At the second level of graph-set theory (Bernstein et al., 1995[Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.]), ten-membered helical and seven-membered extended chains are present, namely a C22(10) chain formed through O1W-H1W...O3(x + 1, y, z) and O1W-H2W...O1 interactions, and a C22(7) chain formed via N2-H2NA...O1W and O1W-H1W...O3(x + 1, y, z) interactions, forming a sheet along the a axis in which an R22(7) motif can be identified (Fig. 3[link]).

The water molecule acts as both a donor, donating its H atoms to the O atoms of the COO- and CO groups [O1W-H1W...O3(x + 1, y, z) and O1W-H2W...O1, respectively], and an acceptor (N2-H2NA...O1W), linking perindoprilat molecules. In the case of carbonyl atom O1, H2W participates in O-H...O hydrogen bonds with quite an acute angle. N2-H2NB...O2(x + [{1\over 2}], -y + [{3\over 2}], -z + 2), O1W-H1W...O3(x + 1, y, z) and N2-H2NA...O1W interactions form other R44(13) edge-fused rings connecting three perindoprilat molecules and one water molecule. In addition, at the third level of graph-set theory, a large ring motif with graph-set notation R65(29) formed through O1W-H2W...O1, O1W-H1W...O3(x + 1, y, z), O5-H5O...O3(-x + 2, y + [{1\over 2}], -z + [{3\over 2}]) and N2-H2NA...O1W contacts can be identified.

There are also short weak intermolecular C-H...O contacts present (Table 1[link]). The contact C1-H1...O4(-x + 2, y - [{1\over 2}], -z + [{3\over 2}]) is between the proline ring and the COOH group of an adjacent molecule, while the other hydrogen bond, C4-H4A...O1(x - 1, y, z), is between the six-membered ring and the carbonyl group of a different adjacent molecule.

In conclusion, the crystal structure of (I)·H2O[link] has been resolved, revealing interesting conformational resemblances but also certain differences, especially different crystal packing motifs, compared with the (I)·0.5DMSO and (I)·2EtOH solvates reported previously. The solvent water molecule appears to play a crucial role in the crystal packing and is a significant building element in the formation of a three-dimensional hydrogen-bond network.

[Figure 1]
Figure 1
The molecular structure of (I)·H2O[link], showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and dashed lines indicate hydrogen bonds.
[Figure 2]
Figure 2
Overlay plot of all currently known perindoprilat crystal structures, viz. (I)·H2O[link], (I)·0.5DMSO (two symmetry-independent molecules) and (I)·2EtOH, superimposed on their common amide plane.
[Figure 3]
Figure 3
A partial packing diagram for (I)·H2O[link]. Intermolecular hydrogen bonds are indicated by dashed lines. H atoms not involved in the hydrogen bonds have been omitted for clarity. [Symmetry codes: (i) x + [{1\over 2}], -y + [{3\over 2}], -z + 2; (ii) x + 1, y, z; (iii) -x + 2, y + [{1\over 2}], -z + [{3\over 2}].]

Experimental

The title compound was obtained according to the syntheses described by Vincent et al. (1982[Vincent, M., Remond, G., Portevin, B., Serkiz, B. & Laubie, M. (1982). Tetrahedron Lett. B23, 1677-1680.]) and Robert et al. (1984[Robert, F., Jeannin, Y., Vincent, M. & Laubie, M. (1984). Acta Cryst. C40, 1219-1220.]). Recrystallization from a solution in a water-ethanol mixture (1:1 v/v) at room temperature over a period of one month afforded colourless prismatic crystals of (I)·H2O[link].

Crystal data
  • C17H28N2O5·H2O

  • Mr = 358.43

  • Orthorhombic, P 21 21 21

  • a = 8.1645 (2) Å

  • b = 10.0136 (2) Å

  • c = 23.2429 (5) Å

  • V = 1900.25 (7) Å3

  • Z = 4

  • Cu K[alpha] radiation

  • [mu] = 0.78 mm-1

  • T = 100 K

  • 0.30 × 0.25 × 0.20 mm

Data collection
  • Bruker APEXII CCD area-detector diffractometer

  • Absorption correction: multi-scan (SADABS; Sheldrick, 2003[Sheldrick, G. M. (2003). SADABS. University of Göttingen, Germany.]) Tmin = 0.799, Tmax = 0.859

  • 19011 measured reflections

  • 3321 independent reflections

  • 3304 reflections with I > 2[sigma](I)

  • Rint = 0.026

Refinement
  • R[F2 > 2[sigma](F2)] = 0.027

  • wR(F2) = 0.069

  • S = 1.08

  • 3321 reflections

  • 248 parameters

  • H atoms treated by a mixture of independent and constrained refinement

  • [Delta][rho]max = 0.17 e Å-3

  • [Delta][rho]min = -0.15 e Å-3

  • Absolute structure: Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), with 1396 Friedel pairs

  • Flack parameter: 0.04 (14)

Table 1
Hydrogen-bond geometry (Å, °)

D-H...A D-H H...A D...A D-H...A
N2-H2NB...O2i 0.884 (19) 1.954 (17) 2.7063 (15) 142.1 (15)
O1W-H1W...O3ii 0.90 (2) 1.89 (2) 2.7725 (15) 167 (2)
N2-H2NA...O1W 0.959 (16) 1.850 (16) 2.7923 (16) 167.0 (15)
O1W-H2W...O1 0.81 (2) 2.29 (2) 2.8307 (15) 124 (2)
O5-H5O...O3iii 0.890 (19) 1.73 (2) 2.5929 (14) 163.7 (19)
C1-H1...O4iv 1.00 2.45 3.2777 (16) 140
C4-H4A...O1v 0.99 2.56 3.3926 (17) 142
Symmetry codes: (i) [x+{\script{1\over 2}}, -y+{\script{3\over 2}}, -z+2]; (ii) x+1, y, z; (iii) [-x+2, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]; (iv) [-x+2, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]; (v) x-1, y, z.

H atoms were located in difference Fourier maps, and subsequently those bonded to C atoms were geometrically optimized and allowed for as riding atoms, with C-H = 1.00 Å for methine, 0.99 Å for methylene and 0.98 Å for methyl groups, and with Uiso(H) = 1.2Ueq(C) for methine and methylene H atoms or 1.5Ueq(C) for methyl H atoms. H atoms bonded to N or O atoms (including water molecules) were refined freely.

Data collection: APEX2 (Bruker, 2005[Bruker (2005). APEX2. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT-Plus (Bruker, 2008[Bruker (2008). SAINT-Plus. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT-Plus; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) and Mercury (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]); software used to prepare material for publication: PLATON.


Supplementary data for this paper are available from the IUCr electronic archives (Reference: FG3275 ). Services for accessing these data are described at the back of the journal.


References

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Acta Cryst (2012). C68, o443-o446   [ doi:10.1107/S0108270112041583 ]