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ORIGINAL ARTICLE

Characterization of molecular associationsinvolving l-ornithine and �-ketoglutaricacid: Crystal structure of l-ornithinium�-ketoglutarate

Caractérisation des associations moléculaires entre l-ornithine etacide �-cétoglutarique : structure cristalline de l’�-cétoglutaratede l-ornithinium

H. Allouchia, R. Céolinc, L. Berthonb, F. Tombretb,I.B. Rietveldc,∗

a Recherche et innovation en chimie médicinale (RICM, ISP-UMR 1282), faculté de pharmacie,université Francois-Rabelais, 31, avenue Monge, 37200 Tours, Franceb Biocodex, centre de recherche, ZAC de Mercière, chemin d’Armancourt, 60200 Compiègne,Francec Laboratoire de chimie physique, faculté de pharmacie, université Paris-Descartes, 4,avenue de l’observatoire, case 23, 75006 Paris, France

Received 10 February 2014; accepted 14 April 2014

KEYWORDSCrystal structure;l-ornithinium�-ketoglutarate;l-ornithineconformation;�-ketoglutaric acid

Summary The crystal structure of l-ornithinium �-ketoglutarate (C5H13N2O2, C5H5O5) hasbeen solved by direct methods using single crystal X-ray diffraction data. It crystallizes inthe monoclinic system, space group P21, unit cell parameters a = 15.4326(3), b = 5.2015(1),c = 16.2067(3) Å and ˇ = 91.986(1)◦, containing two independent pairs of molecular ions in theasymmetric unit. An extensive hydrogen-bond network and electrostatic charges due to protontransfer provide an important part of the cohesive energy of the crystal. The conformationalversatility of l-ornithine and �-ketoglutaric acid is illustrated by the present results and crystal

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conformation;Zwitterion

structures available from the Cambridge Structural Database.© 2014 Elsevier Masson SAS. All rights reserved.

∗ Corresponding author. Tel.: +33153739675.E-mail addresses: ivo.rietveld@parisdescartes.fr, rietveld010@gmail.com (I.B. Rietveld).

http://dx.doi.org/10.1016/j.pharma.2014.04.0050003-4509/© 2014 Elsevier Masson SAS. All rights reserved.

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2 H. Allouchi et al.

MOTS CLÉSStructure cristalline ;�-cétoglutarate del-ornithinium ;Conformation de lal-ornithine ;Conformation del’acide�-cétoglutarique ;Zwitterion

Résumé La structure cristalline de l’�-cétoglutarate de L-ornithinium (C5H13N2O2, C5H5O5)a été resolue par les méthodes directes en utilisant les intensités du rayonnement X diffractépar un monocristal. Ce composé cristallise dans le système monoclinique, groupe d’espaceP21. La maille élémentaire, de paramètres a = 15,4326(3), b = 5,2015(1), c = 16,2067(3) Ået ˇ = 91.986(1)◦, montre deux paires indépendantes d’ions moléculaires dans son unitéasymétrique. L’énergie de cohésion du cristal résulte principalement du réseau tridimension-nel de liaisons hydrogène et des charges électrostatiques créées par transfert de protons.L’adaptabilité conformationnelle de la l-ornithine et celle de l’acide �-cétoglutarique sontillustrées par les résultats de la présente étude et par ceux extraits des structures cristallinesdisponibles dans la base de données structurales de Cambridge.© 2014 Elsevier Masson SAS. Tous droits réservés.

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The asymmetric unit contains two independent pairs ofl-ornithinium �-ketoglutarate ions (Orn1 - Glu1 and Orn2

Figure 1. l-ornithinium (Orn1 and Orn2) and �-ketoglutarate(Glu1 and Glu2) ions together with the labels for the non-hydrogenatoms in the asymmetric unit. Hydrogen bonds in the asymmetricunit are indicated by broken lines.

ntroduction

-ornithine �-ketoglutarate (or l-ornithine 2-oxoglutarate)s a ‘‘co-crystalline’’ active pharmaceutical ingredient usedn nutrition for elderly undernourished patients [1,2]. Theommercial form consists of a crystalline powder, whichay contain different stoichiometries of l -ornithine/�-

etoglutaric acid and different amounts of water ofrystallization:

a monohydrate with molar ratio 2/1 (CAS:5144-42-3);a dihydrate with molar ratio 1/1 (CAS:5191-97-9);an anhydrous form with molar ratio 1/1 (CAS: 34414-83-0).As part of a more general investigation into these com-pounds, the crystal structure of the anhydrous form ispresented in the present paper as a reference for unam-biguous identification of this form in the solid state.

aterials and methods

aterials

pale yellow crystalline powder of medicinal grade con-aining anhydrous l-ornithine �-ketoglutarate was providedy Biocodex (Compiègne, France). Needle-shaped crystalsere observed in the sample and one, cut in approximateimensions 0.05 × 0.15 × 0.15 mm, was found to be suitableor X-ray single-crystal diffraction studies.

ingle crystal X-ray diffraction

-ray diffraction intensities were collected at 296 K on aruker Nonius Kappa CCD diffractometer up to �max = 30◦

0 ≤h ≤21, 0 ≤k ≤7, −22 ≤ l ≤22) using Mo K˛ radiation� = 0,71069 A). It was equipped with a graphite monochro-ator. Both ϕ and ω were varied, with 1◦ per rotation

rame and 30 s of collection time per frame. The distanceetween the crystal and the detector was 32 mm. The unitell determination and data reduction were performed usinghe Denzo and Scalepack programs [3] on the full dataet consisting of 7610 reflections collected, 4164 indepen-ent reflections of which 3164 were considered observed

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I > 2�(I)). The structure was solved by direct methods, andhe refinement of atomic parameters based on full-matrixeast-squares on F2 were performed using the SHELX-97rograms [4] in the WinGX package [5]. The diffraction

IGdl

ntensities have not been corrected for absorption. Scat-ering factors were taken from the International Tables forrystallography [6]. All non-hydrogen atoms were refinedith anisotropic thermal parameters. Hydrogen atoms werelaced at calculated positions generated according to ste-eochemistry and refined using a riding model in SHELXL-97.he final reliability factor R is 0.0470 and the goodness of fit

s 1.034. The minimum and maximum residual electron den-ities were equal to −0.452 and 0.408 e Å−3, respectively.

esults and discussion

he crystal structure at 296 K was found to be mono-linic, chiral space group P21, with lattice parame-ers a = 15.4326(3) A, b = 5.2015(1) A, c = 16.2067(3) A, and

= 91.986(1)◦. Crystallographic information is compiled inable 1. CCDC 984657 contains the supplementary crystallo-raphic data for this paper. These data can be obtained freef charge from The Cambridge Crystallographic Data Centre

Characterization of molecular associations involvingl-ornithinium �-ketoglutarate. Ann Pharm Fr (2014),

ons l-ornithinium (Orn1 et Orn2) et �-cétoglutarate (Glu1 etlu2) avec la numérotation des atomes (à l’exception des atomes’hydrogène) dans l’unité asymétrique. Les liaisons hydrogène dans’unité asymétrique sont représentées par des lignes brisées.

ARTICLE IN PRESS+ModelPHARMA-351; No. of Pages 6

Crystal structure of l-ornithinium �-ketoglutarate 3

Table 1 Crystal data and structure refinement for l-ornithinium �-ketoglutarate.Données cristallines et affinement de la structure de l’�-cétoglutarate de l-ornithinium.

Empirical formula C20H36N4O14

Formula weight 556.53Temperature 296(2) KWavelength 0.71069 ACrystal system MonoclinicSpace group P21

Unit cell dimensionsa = 15.4326(3) Å = 90◦

b = 5.2015(1) Å ˇ = 91.986(1)◦

c = 16.2067(3) Å � = 90◦

Volume 1300.17(4) Å3

Z 2Density (calculated) 1.422 mg/m3

Absorption coefficient 0.121 mm−1

F(000) 592Crystal size 0.15 × 0.15 × 0.05 mm3

Theta range for data collection 4.04 to 30.03◦

Index ranges 0 ≤ h ≤ 21, 0 ≤ k ≤ 7,−22 ≤ l ≤ 22

Reflections collected 7610Independent reflections 4164Completeness to theta = 30.03◦ 99.3%Refinement method Full-matrix

least-squares on F2

Data/restraints/parameters 4164/6/386Goodness-of-fit on F2 1.034Final R indices [I > 2�(I)] R1 = 0.0470,

wR2 = 0.1024R indices (all data) R1 = 0.0708,

wR2 = 0.11141Absolute structure parameter 0.2(12)Extinction coefficient 0.030(3)

Table 2 Fractional atomic coordinates (×104) andequivalent isotropic displacement parameters (Å2 × 103)for the non-hydrogen atoms of l-ornithinium �-ketoglutaratea.Coordonnées atomiques réduites (×104) et paramètresd’agitation thermique isotrope (Å2 × 103) des atomes del’�-cétoglutarate de l-ornithinium à l’exception des atomesd’hydrogène.

x y z Ueqb

N(1) 672(2) −6487(5) 8844(2) 30(1)N(2) 3816(2) −4873(5) 7714(2) 29(1)N(3) 4283(2) 4553(5) 4285(2) 31(1)N(4) 1166(2) 6037(5) 2765(2) 30(1)O(1) 510(1) −688(4) 7641(1) 36(1)O(2) 104(1) −4720(5) 7361(1) 41(1)O(3) 826(1) −125(7) 10368(1) 61(1)O(4) 1649(2) −1723(11) 11373(2) 114(2)O(5) 2274(1) 1478(6) 9659(1) 56(1)O(6) 3852(1) −2109(5) 9249(1) 41(1)O(7) 4723(1) 1273(5) 9099(1) 42(1)O(8) 4837(2) 7286(5) 3010(1) 44(1)O(9) 4785(2) 3934(5) 2146(1) 47(1)O(10) 4016(1) −467(5) 5110(1) 42(1)O(11) 3498(2) −1869(6) 6298(1) 58(1)O(12) 2685(1) 3016(5) 5137(2) 50(1)O(13) 219(1) 1667(5) 4167(2) 45(1)O(14) 1294(2) −1168(6) 4238(1) 54(1)C(1) 487(2) −3059(6) 7795(2) 28(1)C(2) 997(2) −3939(6) 8565(2) 26(1)C(3) 1973(2) −3997(6) 8407(2) 28(1)C(4) 2214(2) −5769(6) 7699(2) 32(1)C(5) 3125(2) −6838(6) 7767(2) 33(1)C(6) 1548(2) −552(8) 10714(2) 45(1)C(7) 2328(2) 318(7) 10315(2) 36(1)C(8) 3202(2) −171(8) 10727(2) 42(1)C(9) 3960(2) 1083(8) 10319(2) 38(1)C(10) 4165(2) −83(6) 9503(2) 31(1)C(11) 4668(2) 5035(6) 2825(2) 30(1)C(12) 4250(2) 3296(6) 3457(2) 27(1)C(13) 3319(2) 2574(6) 3193(2) 30(1)C(14) 2710(2) 4858(6) 3063(2) 33(1)C(15) 1809(2) 3923(7) 2831(2) 38(1)C(16) 3440(2) −566(6) 5649(2) 34(1)C(17) 2653(2) 934(6) 5504(2) 29(1)C(18) 1800(2) 26(7) 5828(2) 33(1)C(19) 1019(2) 1348(7) 5431(2) 35(1)C(20) 860(2) 470(6) 4558(2) 34(1)

a e.s.d.’s in parentheses.b U(eq) is defined as one third of the trace of the orthogonalized

ip

T

Largest diff. peak and hole 0.408 and −0.452 e.Å−3

- Glu2) presented in Fig. 1. These units form alternatinglayers parallel to the ab plane as shown in Fig. 2. Thefractional atomic coordinates for non-H atoms are listedin Table 2 together with their equivalent isotropic dis-placement parameters. More data can be found in thesupplementary materials.

From the crystal structure, it can be seen that four pro-tons are transferred between different molecules in theasymmetric unit. Both �-ketoglutaric acids have donated aproton to an l-ornithine moiety. On Glu1 this is O3 donat-ing to an N1 outside of the asymmetric unit (at −x, y + ½,−z + 2) and on Glu2 this is O10 donating a proton to N3(there exist multiple possibilities, see Table 3). Thus, both�-ketoglutaric acids are actually �-ketoglutarate anions. Itcan be seen in Fig. 1 that the l-ornithine moieties eachpossess two primary amines with three hydrogen atoms. Theprotons originate from the carboxylic acid functionality onneighboring l-ornithine molecules. N2 on Orn1 has received

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the hydrogen atom from O8 on an Orn2 (at −x + 1, y − 3/2,−z + 1) outside of the shown asymmetric unit in Fig. 1 andN4 (Orn2) from an O1 (Orn1 at −x, y + 1/2, −z + 1) outside ofthe depicted asymmetric unit. Thus, l-ornithinium is present

gcbo

Uij tensor.

n the crystal structure as a charged zwitterion with twoositive and one negative charge.

Hydrogen bonds and their geometries are listed inable 3. A complicated three-dimensional network of hydro-

Characterization of molecular associations involvingl-ornithinium �-ketoglutarate. Ann Pharm Fr (2014),

en bonds provides part of the cohesion in the structure. It islear from Table 3 that there is a large number of hydrogenonds and it is very difficult to appreciate the complexityf the network in a two-dimensional figure; therefore just a

ARTICLE IN PRESS+ModelPHARMA-351; No. of Pages 6

4 H. Allouchi et al.

Figure 2. Projection of alternating layers of the two l-ornithinium �-ketoglutarate ion pairs on the ac plane. The projected layers(Orn1-Glu1 = blue background, Orn2-Glu2 = yellow background) are perpendicular to the c axis.Projection, sur le plan ac, des couches alternées des deux paires ioniques �-cétoglutarate de l-ornithinium. Les couches projetées (Orn1-Glu1 = fond bleu, Orn2-Glu2 = fond jaune) sont perpendiculaires à l’axe c.

Table 3 Hydrogen-bonds for l-ornithinium �-ketoglutaratea.Liaisons hydrogène de l’�-cétoglutarate de l-ornithinium.

Hydrogen bond Distance (Å) Distance (Å) Distance (Å) Angle (◦)

D—–H···A D—–H H···A D···A D—–H···AN(2)—–H(22N)···O(6) 0.872 (6) 2.024 (11) 2.874 (3) 165 (3)N(2)—–H(23N)···O(11) 0.84 (4) 1.97 (4) 2.806 (3) 175 (4)N(3)—–H(32N)···O(12) 0.99 (4) 2.10 (4) 2.978 (3) 146 (3)N(3)—–H(32N)···O(10) 0.99 (4) 2.23 (4) 2.969 (4) 131 (3)N(1)—–H(12N)···O(1)i 0.873 (6) 2.074 (10) 2.933 (3) 168 (3)N(1)—–H(13N)···O(5)i 0.92 (4) 2.10 (4) 2.958 (3) 154 (3)N(1)—–H(13N)···O(3)i 0.92 (4) 2.45 (4) 3.114 (4) 129 (3)N(3)—–H(33N)···O(10)ii 0.872 (6) 2.24 (2) 2.951 (4) 139 (3)N(4)—–H(43N)···O(14)ii 0.96 (4) 1.84 (4) 2.795 (3) 176 (3)N(4)—–H(42N)···(O4)iii 0.87 (4) 1.84 (4) 2.668 (4) 158 (4)N(4)—–H(41N)···O(1)iv 0.95 (4) 1.86 (4) 2.795 (3) 169 (3)O(13)—–H(13O)···O(2)iv 0.91 (4) 1.71 (4) 2.610 (3) 169 (4)N(3)—–H(31N)···O(10)v 1.00 (3) 1.77 (3) 2.771 (3) 176 (4)O(7)—–H(7O)···O(9)vi 0.92 (4) 1.59 (4) 2.498 (3) 170 (4)N(1)—–H(11N)···O(3)vii 0.96 (3) 1.82 (4) 2.772 (3) 168 (3)N(2)—–H(21N)···O(8)viii 0.93 (4) 1.96 (4) 2.838 (3) 156 (3)

Symmetry codes: (i) x, y-1, z; (ii) x, y + 1, z; (iii) x, y + 1, z-1; (iv) −x, y + 1/2, −z + 1; (v) −x + 1, y + 1/2, −z + 1; (vi) −x + 1, y − 1/2,−z + 1; (vii) −x, y − 1/2, −z + 2; (viii) −x + 1, y − 3/2, −z + 1.a e.s.d.’s in parentheses.

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Characterization of molecular associations involvingl-ornithinium �-ketoglutarate. Ann Pharm Fr (2014),

ARTICLE IN PRESS+ModelPHARMA-351; No. of Pages 6

Crystal structure of l-ornithinium �-ketoglutarate 5

Table 4 Torsion angles (◦) of l-ornithine (neutral or charged) in available crystal structuresa.Angles de torsion (◦) de la l-ornithine (neutre ou ionisée) dans les structures cristallines disponiblesa.

Ca-Cb-Cc-Cd Cb-Cc-Cd-Ce Na-Cb-Cc-Cd Cc-Cd-Ce-Nb Ref

Orn1 −58.9(3) −153.0(3) 64.5(3) −65.0(3) This workOrn2 −58.9(3) −178.3(2) 64.5(3) 175.1(3) This workCAPRAM −176.2 178.5 −56.2 58.429 [8]ORNBDL01 −70.9 176.0 165.9 −169.3 [9]ORNBDL10 70.1 −177.4 −168.4 169.5 [10]ORNHCL 66.8 −173.1 −172.8 174.9 [11]ORNHCL11 67.9 −173.4 −172.5 174.7 [12]ORNHCL12 66.3 −172.9 −173.0 175.2 [13]PUYVUA 66.8 −169.4 −173.5 172.1 [14]VUYHII 64.2 −173.5 −175.6 173.4 [15,16]

Atom identificationa Nomenclature according to the codes given by the CCDC (Cambridge Crystallographic Data Centre): CAPRAM = l-ornithinel-aspartate hemihydrate, ORNBDL01 = ORNBDL10 = dl-ornithine hydrobromide, ORNCL = ORNCL11 = ORNCL12 = l-ornithine hydrochlo-ride, PUYVUA = l-ornithine nitrate, and VUYHII = l-ornithine d-aspartate monohydrate.aNomenclature selon les codes donnés parle CCDC (Centre de Cambridge pour les données cristallographiques): CAPRAM = hémihydrate du l-aspartate de l-ornithine,ORNBDL01 = ORNBDL10 = bromhydrate de dl-ornithine, ORNCL = ORNCL11 = ORNCL12 = chlorhydrate de l-ornithine, PUYVUA = nitrate del-ornithine et VUYHII = monohydrate du d-aspartate de l-ornithine.

it(mt

few features will be highlighted in the text. It can be seenin Fig. 1 that ions Orn1 and Glu1 are linked by the hydrogenbond N2—–H···O6, while ions Orn2 and Glu2 are linked by abifurcated hydrogen bond involving atoms N3, O10 and O12.The graph set of this so-called ring (R) with one donor (N3—

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–H) and two acceptors (O10 and O12) involving a total of 5atoms is R1

2(5). Furthermore, Orn1 is involved in an infinitechain (C) of hydrogen bonds consisting of one unique hydro-gen bond between N1—–H···O1 with graph set C1

1(5). Another

dgNf

Table 5 Torsion angles (◦) of �-ketoglutaric acid (or deprotonAngles de torsion (◦) de l’acide �-cétoglutarique (neutre ou déprotoné

Ca*-Cb*-Cc*-Cd* Cb*-Cc*-Cd*

Glu1 −172.8(3) −70.2(4)

Glu2 −163.6(3) 72.0(3)

COTPAC 160.873 −169.566

RIZWUS 173.411 70.573

Cc*-Cd*-Ce*-O(H) Cc*-Cd*-Ce*-O* OGlu1 169.5(3) −11.4(4) 1Glu2 −176.3(3) 2.6(4) −COTPAC −174.2 4.4 −RIZWUS −176.6 5.3 −

Atom identificationO(l) and O(s) can be identified due to the difference in bond length wia Nomenclature according to the codes given by the CCDylamino)carbonyl)adamantane �-ketoglutaric acid. aNomenclature seloRIZWUS = 1,3-bis((pyrid-2-ylamino)carbonyl)adamantane acide �-cétog

nfinite chain of hydrogen bonds connects Orn2 with Glu2 viawo hydrogen bonds between N3, O10, and an N3 on an Orn2−x + 1, y − 1/2, −z + 1 or x, y − 1, z) outside of the asym-etric unit with the graph set C2

1(4). In fact, N3 and O10ake part in three different infinite chains with N3 as the

Characterization of molecular associations involvingl-ornithinium �-ketoglutarate. Ann Pharm Fr (2014),

onor and O10 as the acceptor all with the aforementionedraph set. Other infinite chains through the crystal involve1, O3, and O5 on Orn1 and Glu1, but it would lead tooar to list all the different hydrogen-bond configurations.

ated form) in available crystal structuresa.) dans les structures cristallines disponiblesa.

-Ce* Oa*-Cb*-Cc*-Cd* Ref

5.9(5) This work18.9(4) This work−18.524 [16]9.200 [17]

(l)-Ca*-Cb*-Oa* O(s)- Ca*-Cb*-Oa* Ref79.6(6)◦ 1.0(6) This work147.0(3) −33.2(4) This work10.6 169.0 [16]12.1 167.0 [17]

th C(a*): O(l)-C(a*) > O(s)-C(a*).C: COTPAC = �-ketoglutaric acid, RIZWUS = 1,3-bis((pyrid-2-

n les codes donnés par le CCDC: COTPAC = acide �-cétoglutarique,lutarique.

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ARTICLEHARMA-351; No. of Pages 6

onetheless, it is clear that the hydrogen-bond network isxtensive and plays an important part in the cohesion ofhe crystal next to the electrostatic interactions due to theroton transfers.

In addition to the complexity of the hydrogen network,-ornithine and �-ketoglutaric acid are very flexible judgingrom the many torsion angles they possess and the largeange of values they exhibit in different structures asan be seen in Table 4 for l-ornithine and in Table 5 for-ketoglutaric acid. l-ornithine possesses at least fivend arguably six different conformations in structuresetrieved from the Cambridge Structural Database [7]. For-ketoglutaric acid four different configurations have beenbserved of which two belong to the structure reported inhis paper. Considering the number of torsion angles in thisolecule, most likely more configurations will be possible.

onclusions

he crystal structure of the anhydrous salt l-ornithinium-ketoglutarate has been solved by single crystal X-rayiffractometry at room temperature. It contains fourolecules in the asymmetric unit. The structure demon-

trates the transfer of a proton from �-ketoglutaric acido l-ornithine; the latter is found to be a zwitterion COO−

C(R)—NH3+ due to an additional proton transfer between

wo ornithine molecules. The hydrogen-bond network in therystal structure is extensive and together with the electro-tatic interactions, due to the proton transfers, it plays anmportant part in the cohesion of the crystal.

isclosure of interest

aurence Berthon and Francis Tombret are employed byiocodex.

ppendix A. Supplementary data

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upplementary data associated with this article can beound, in the online version, at http://dx.doi.org/10.1016/.pharma.2014.04.005.

[

PRESSH. Allouchi et al.

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