Journal of Crystallography

Journal of Crystallography / 2013 / Article

Research Article | Open Access

Volume 2013 |Article ID 741483 | 5 pages |

Bis(ammonium) Zoledronate Dihydrate

Academic Editor: P. Macchi
Received23 Apr 2013
Accepted27 Aug 2013
Published03 Oct 2013


Neutralization of 2-(1-imidazole)-1-hydroxyl-1,1′-ethylidenediphosphonic acid (zoledronic acid) by an excess of ammonia yielded bis(ammonium) zoledronate dihydrate, { , 2(H4N+), 2(H2O)}. The product is readily soluble in water and forms monocrystals for which the X-ray structural analysis was carried out. The zoledronic anion is of double negative charge due to deprotonation of three P–OH groups and protonation of the nitrogen in the imidazole ring. The structure is stabilized by extensive network of N–HO and O–HO hydrogen bonds expanding through the crystal in plane (002). The imidazole ring is involved in - stacking interactions with its symmetry equivalents related by inversion centers at (100) and (11/20), with distances between centroids (Cg–Cg) of 3.819 (2) and 3.881 (2) Å, respectively.

1. Introduction

Bisphosphonates have been subject of intensive research mainly due to their application in medicine as bone resorption inhibitors [1]. 2-(1-imidazole)-1-hydroxyl-1,1′-ethylidenediphosphonic acid, known as zoledronic acid, is regarded as the third generation of drugs for osteoporosis. Due to its structure, imidazolyl –CH2–C(OH){O=P(OH)2}2, the acid may be deprotonated at all four P–OH groups and protonated at the imidazolic N atom. The kind of the ion formed should influence not only coordination mode and intermolecular interactions but also the water solubility of the product, which may alter bioavailability.

Salts of zoledronic acid in the solid state usually contain monovalent anion resulting from deprotonation of two OH groups and protonation of the imidazole nitrogen. Examples include salts of sodium Na+ C5H9N2O7 4H2O [3] and a series of compounds of general formula (C5H9N2O7 )2M(H2O)2 M=Mg [4], Zn [5], Mn [6], Cu [7], Co, and Ni [8]. In some cases (for Cu, Co, Mn, and Ni), polynuclear complexes or coordination polymers are formed, with potentially interesting magnetic properties (e.g., [9]). Doubly negative anion was encountered in the catena((μ3-zoledronato)aqua calcium) [10]. Triply negative anion was found in a tris(dicyclohexylammonium) zoledronate ethanol solvate monohydrate [11]. It is one of the few structures reported with nonprotonated imidazole ring. The other two are the cobalt derivative with coordination of the ring nitrogen to a metal atom Co N [9] and the mentioned above calcium salt [10]. Structure of another organic ammonium salt of the acid was recently reported (albeit with mononegative anion)—cytosinium zoledronate trihydrate [12]. In this paper, we carried out neutralization of zoledronic acid with excess of ammonia to reveal whether mono-, bis-, or trisammonium salt will be formed in the solid state and to study the basic properties and the structure of the obtained product.

2. Materials and Methods

Starting material 2-(1-imidazole)-1-hydroxyl-1,1′-ethylidenediphosphonic acid monohydrate (zoledronic acid monohydrate) was supplied by Polpharma SA (Starogard Gdanski, Poland) and used as such (m.p. 239°C). Other reagents were of analytical grade and were used without further workup.

2.1. Synthesis

Preparation of C5H20N4O9P2 is given as follows. Solution of 3 mol/dm3 ammonia (eight-fold excess, 0.86 mL, 2.6 mmol) and solid zoledronic acid (88 mg, 0.325 mmol) were added to a mixture of water (8 mL) and ethanol (4 mL). The contents were stirred and heated to boiling. The solution was concentrated under vacuum to ca 2 mL and left to crystallize by slow evaporation, and after, a few days, colorless crystals (m.p. 260-261°C) suitable for X-ray diffraction were obtained.

Elemental analysis, CHNS, found the following (calculated for C5H20N4O9P2): C 17.73% (17.55), H 5.75% (5.89), N 16.01% (16.37), and S 0% (0). Apparatus used is Vario El Cube CHNS (Elementar).

2.2. X-Ray Crystallography

Diffraction data were collected using KM4CCD (Kuma), Sapphire2, large Be window, 4-axis kappa diffractometer with graphite monochromator, and Mo radiation, at ambient temperature. More details are given in Table 1.

Empirical formulaC5H20N4O9P2
Formula weight342.19
Crystal systemTriclinic
Space group
Temperature293 K
Wavelength0.71073 Å
Unit cell dimensionsa = 6.8415 (4) Å
b = 7.5070 (5) Å
c = 13.9398 (10) Å
α = 81.735 (6)°
β = 82.922 (5)°
γ = 82.780 (5)°
Volume698.84 (8) Å3
Density (calcd.)1.626 Mg m−3
Absorption coeff.µ = 0.36 mm−1
Crystal size0.45 × 0.12 × 0.08 mm
Crystal color and shapeColorless, block
θ range data collectionθ = 2.8–25.1°
Limiting indicesh = −5→8
k = −8→8
l = −16→15
Reflections collected3930
Independent reflections2481 ( = 0.023)
Refinement method Full-matrix least-square on
Goodness-of-fit on 1.07
Final indices = 0.0481
= 0.1153
indices (all data) = 0.0586
( ) = 0.1279
Residual el. density = 0.49 e Å−3
= −0.34 e Å−3

Structure was refined with all heavy atoms treated as anisotropic and H-atoms as isotropic. All C–H and C–OH hydrogen atoms were refined as riding on their bonded counterpart atoms with the usual constrains. Hydrogen atoms belonging to water molecules were found in the Fourier map and refined with O–H bond length constrained to 0.82 Å. The same location method was applied to the H atoms bound to ammonium nitrogen atoms, whose N–H distances were constrained to 0.86 Å. Hydrogen atom at O6 was found in the electron density map and refined as riding on the oxygen atom.

Programs used are the following: for data collection, CrysAlis PRO (Agilent Technologies) [13]; for cell refinement and data reduction, CrysAlis PRO [13]; for solving structure, SUPERFLIP [14]; for refineing structure, SHELXL97 [15] and WinGX [16]; for molecular graphics, Mercury [17] and ORTEP-3 [18]; software used for preparing material for publication, PLATON [2], CSD [19], and publCIF [20].

Supplementary crystallographic data for C5H20N4O9P2, CCDC 935170, can be obtained free of charge via or from the Cambridge Crystallographic Data Centre, Cambridge, UK.

3. Results and Discussion

Reaction of zoledronic acid with an excess of ammonia yielded the title compound: C5H8N2O7 2(H4N+) 2(H2O).

Its molecular structure is shown in Scheme 1 and Figure 1, and geometric parameters are given in Table 2. The bisphosphonate anion is of double negative charge due to deprotonation of three P–OH groups and protonation of the nitrogen in the imidazole ring. The longest P–O bond is noted for the only P–OH group (at O6 atom). Contrary to tris(dicyclohexylammonium) zoledronate [11], no intramolecular P–OH O hydrogen bond was formed. Protonation at the ring nitrogen N2 is confirmed by location of H2N from the electron density peak in the Fourier map. Presence of a strong hydrogen bond N2–H2N O (charge assisted, see Table 3) is an additional evidence of the protonation.

P1–O11.516 (2)O7–C51.443 (3)
P1–O31.526 (2)N2–C31.325 (4)
P1–O21.537 (2)N2–C21.366 (4)
P1–C51.879 (3)N1–C31.337 (4)
P2–O41.509 (2)N1–C11.384 (4)
P2–O51.514 (2)N1–C41.478 (4)
P2–O61.578 (2)C1–C21.353 (5)
P2–C51.861 (3)C5–C41.543 (4)

O1–P1–O3112.51 (12)C3–N1–C1108.4 (3)
O1–P1–O2111.12 (13)C3–N1–C4124.2 (3)
O3–P1–O2112.06 (12)C1–N1–C4127.4 (2)
O1–P1–C5109.45 (12)C2–C1–N1106.5 (3)
O3–P1–C5105.41 (12)C1–C2–N2107.6 (3)
O2–P1–C5105.88 (12)O7–C5–C4104.3 (2)
O4–P2–O5116.33 (13)O7–C5–P2109.87 (18)
O4–P2–O6109.22 (13)C4–C5–P2106.06 (18)
O5–P2–O6110.01 (12)O7–C5–P1111.87 (18)
O4–P2–C5107.62 (12)C4–C5–P1112.52 (19)
O5–P2–C5109.04 (13)P2–C5–P1111.85 (14)
O6–P2–C5103.87 (13)N2–C3–N1108.5 (3)
C3–N2–C2109.0 (3)N1–C4–C5114.0 (2)

C3–N1–C1–C2−0.2 (3)O2–P1–C5–O734.8 (2)
C4–N1–C1–C2178.6 (3)O1–P1–C5–C4157.95 (19)
N1–C1–C2–N20.0 (4)O3–P1–C5–C436.7 (2)
C3–N2–C2–C10.2 (4)O2–P1–C5–C4−82.2 (2)
O4–P2–C5–O7173.78 (18)O1–P1–C5–P238.68 (18)
O5–P2–C5–O7−59.2 (2)O3–P1–C5–P2−82.56 (16)
O6–P2–C5–O758.1 (2)O2–P1–C5–P2158.53 (14)
O4–P2–C5–C4−74.1 (2)C2–N2–C3–N1−0.3 (4)
O5–P2–C5–C452.9 (2)C1–N1–C3–N20.3 (3)
O6–P2–C5–C4170.17 (18)C4–N1–C3–N2−178.6 (3)
O4–P2–C5–P148.92 (17)C3–N1–C4–C584.1 (3)
O5–P2–C5–P1175.92 (13)C1–N1–C4–C5−94.5 (3)
O6–P2–C5–P1−66.81 (16)O7–C5–C4–N1−60.4 (3)
O1–P1–C5–O7−85.1 (2)P2–C5–C4–N1−176.36 (19)
O3–P1–C5–O7153.69 (18)P1–C5–C4–N161.1 (3)


O6–H6O3i0.821.742.552 (3)170
O7–H7O8ii0.821.952.699 (3)151
O8–H8AO50.81 (2)1.95 (2)2.751 (4)168 (4)
O8–H8BO2iii0.80 (2)2.01 (2)2.806 (4)171 (5)
O9–H9AO1iii0.83 (2)1.96 (2)2.769 (3)166 (4)
O9–H9BO3iv0.84 (2)2.00 (2)2.841 (3)179 (4)
N2–H2NO2v0.86 (2)1.77 (2)2.613 (3)165 (4)
N3–H3AO1vi0.88 (2)1.89 (2)2.761 (4)168 (4)
N3–H3BO4iv0.86 (2)2.16 (3)2.968 (4)156 (4)
N3–H3BO6iv0.86 (2)2.61 (3)3.315 (4)140 (4)
N3–H3CO40.88 (2)2.14 (2)3.003 (4)169 (5)
N3–H3DO90.86 (2)2.16 (3)2.909 (4)146 (4)
N4–H4AO9vii0.88 (2)2.02 (3)2.812 (4)149 (3)
N4–H4BO2vi0.87 (2)2.01 (2)2.857 (4)165 (3)
N4–H4CO40.88 (2)2.01 (2)2.893 (4)179 (5)
N4–H4DO5vii0.88 (2)2.16 (2)3.000 (4)159 (4)

Symmetry codes: i ; ii ; iii ; iv ; v ; vi ; vii .

It is worthy noting that P1–O2 bond is longer than other P1–O bonds probably due to the mentioned hydrogen bond. Analysis of Table 3 reveals that it is a bond with the second smallest H A distance. Even stronger is the interaction O6–H6 O , of the only phosphorus hydroxyl group with the negatively charged oxygen, forming a first-level chain C(6) motif passing in parallel to the -axis. The hydrogen bond network is complex with most of the first-level motifs being discrete. Among the second-level graph motifs, notable is a centrosymmetric ring R2,4(8) motif with four N3–H donors and two O9 acceptors placed on the inversion center at ( ). Packing of molecules is organized in hydrophilic and hydrophobic layers parallel to the (i.e., (001)) plane, Figure 2. The hydrogen-bonding network is present in vicinity of the planes at ( , the set of all integers), while close to the planes at dominating are the stacking interactions. The imidazole groups, involved in - ring stacking, interact with their symmetry equivalents related by inversion centers at (1 0 0) and (1 0), with Cg–Cg distances 3.819 (2) and 3.881 (2) Å, respectively; for details, see Table 4. The title compound is very readily soluble in water.

Ring(I)Ring(II)Cg(I)–Cg(II) CgI_perpSlippage

ImidImida3.819 (2)34.2034.20−3.1585 (16)2.147
ImidImidb3.881 (2)27.6427.643.4376 (16)1.800

Symmetry codes: a ; b .

4. Conclusions

Neutralization of 2-(1-imidazole)-1-hydroxyl-1,1′-ethylidenediphosphonic acid (zoledronic acid) by an excess of ammonia gives bis(ammonium) zoledronate dehydrate: {C5H8N2O7 , 2(H4N+), 2(H2O)}. Crystals are readily soluble in water. The anion is of double negative charge due to deprotonation of three OH groups and protonation of the nitrogen atom in the imidazole ring. The structure is stabilized by extensive network of N–H O and O–H O hydrogen bonds and - stacking interactions between the imidazole rings.

Conflict of Interests

The authors have no conflict of interests with the mentioned commercial entity.


The authors thank the Polpharma SA Company (Starogard Gdanski, Poland) for the donation of samples of 2-(1-imidazole)-1-hydroxyl-1, -ethylidenediphosphonic acid monohydrate (zoledronic acid monohydrate).


  1. R. G. G. Russell, “Bisphosphonates: the first 40 years,” Bone, vol. 49, no. 1, pp. 2–19, 2011. View at: Publisher Site | Google Scholar
  2. A. L. Spek, “Single-crystal structure validation with the program PLATON,” Journal of Applied Crystallography, vol. 36, Part 1, pp. 7–13, 2003. View at: Publisher Site | Google Scholar
  3. W. L. Gossman, Wilson, S. R. ldfield, and E. Oldfield, “Monosodium [1-hydroxy-2-(1H-imidazol-3-ium-4-yl)ethane-1,1-diyl]bis(phosphonate) tetrahydrate (monosodium isozoledronate),” Acta Crystallographica C, vol. 58, pp. m599–m600, 2002. View at: Google Scholar
  4. E. Freire, D. R. Vega, and R. Baggio, “Zoledronate complexes. III. Two zoledronate complexes with alkaline earth metals: [Mg(C5H9N2O7P2)2(H2O)2] and [Ca(C5H8N2O7P2)(H2O)]n,” Acta Crystallographica, vol. C66, pp. m166–m170, 2010. View at: Google Scholar
  5. E. Freire and D. R. Vega, “Diaquabis[1-hydroxy-2-(imidazol-3-ium-1-yl)-1,1′-ethylidenediphosphonato κ2O,O′]zinc(II),” Acta Crystallographica E, vol. 65, pp. m1428–m1429, 2009. View at: κ2O,O′]zinc(II)&author=E. Freire &author=D. R. Vega&publication_year=2009" target="_blank">Google Scholar
  6. Z.-C. Zhang, R.-Q. Li, and Y. Zhang, “Diaquabis{[1-hydroxy-2-(1H-imidazol-3-ium-1-yl)ethane-1,1-diyl]bis(hydrogen phosphonato)}manganese(II),” Acta Crystallographica, vol. E65, pp. m1701–m1702, 2009. View at: Publisher Site | {[1-hydroxy-2-(1H-imidazol-3-ium-1-yl)ethane-1,1-diyl]bis(hydrogen%20phosphonato)}manganese(II)&author=Z.-C. Zhang&author=R.-Q. Li&author=&author=Y. Zhang&publication_year=2009" target="_blank">Google Scholar
  7. D.-K. Cao, X.-J. Xie, Y.-Z. Li, and L.-M. Zheng, “Copper diphosphonates with zero-, one- and two-dimensional structures: Ferrimagnetism in layer compound Cu3(ImhedpH)2• 2H2O [ImhedpH4 = (1-C3H3N2)CH2C(OH)(PO3H2)2],” Dalton Transactions, no. 37, pp. 5008–5015, 2008. View at: Publisher Site | Google Scholar
  8. D.-K. Cao, Y.-Z. Li, and L.-M. Zheng, “Layered cobalt(II) and nickel(II) diphosphonates showing canted antiferromagnetism and slow relaxation behavior,” Inorganic Chemistry, vol. 46, no. 18, pp. 7571–7578, 2007. View at: Publisher Site | Google Scholar
  9. D.-K. Cao, M.-J. Liu, J. Huang, S.-S. Bao, and L.-M. Zheng, “Cobalt and manganese diphosphonates with one-, two-, and three-dimensional structures and field-induced magnetic transitions,” Inorganic Chemistry, vol. 50, no. 6, pp. 2278–2287, 2011. View at: Publisher Site | Google Scholar
  10. D. Liu, S. A. Kramer, R. C. Huxford-Phillips, S. Wang, J. Della Rocca, and W. Lin, “Coercing bisphosphonates to kill cancer cells with nanoscale coordination polymers,” Chemical Communications, vol. 48, no. 21, pp. 2668–2670, 2012. View at: Publisher Site | Google Scholar
  11. A. Sarkar and I. Cukrowski, “Tris(dicyclohexylammonium) hydrogen [1-hydroxy-2-(1H-imidazol-1-yl)-1- phosphonatoethane]phosphonate ethanol monosolvate monohydrate,” Acta Crystallographicaaphica E, vol. 67, no. 11, p. o2980, 2011. View at: Publisher Site | Google Scholar
  12. B. Sridhar and K. Ravikumar, “Multiple hydrogen bonds in cytosinium zoledronate trihydrate,” Acta Crystallographicaaphica C, vol. 67, no. 3, pp. o115–o119, 2011. View at: Publisher Site | Google Scholar
  13. Agilent Technologies, “CrysAlis PRO,” version 1. 171. 35. 15. Yarnton, England, 2011. View at: Google Scholar
  14. L. Palatinus and G. Chapuis, “SUPERFLIP—a computer program for the solution of crystal structures by charge flipping in arbitrary dimensions,” Journal of Applied Crystallography, vol. 40, no. 4, pp. 786–790, 2007. View at: Publisher Site | Google Scholar
  15. G. M. Sheldrick, “A short history of SHELX,” Acta Crystallographica A, vol. 64, part 1, pp. 112–122, 2008. View at: Google Scholar
  16. L. J. Farrugia, “WinGX suite for small-molecule single-crystal crystallography,” Journal of Applied Crystallography, vol. 32 Part 4, pp. 837–838, 1999. View at: Publisher Site | Google Scholar
  17. C. F. Macrae, P. R. Edgington, P. McCabe et al., “Mercury: visualization and analysis of crystal structures,” Journal of Applied Crystallography, vol. 39, no. 3, pp. 453–457, 2006. View at: Publisher Site | Google Scholar
  18. L. J. Farrugia, “ORTEP-3 for Windows—a version of ORTEP-III with a Graphical User Interface (GUI),” Journal of Applied Crystallography, vol. 30, part 5, p. 565, 1997. View at: Publisher Site | Google Scholar
  19. F. R. Allen, “The Cambridge Structural Database: a quarter of a million crystal structures and rising,” Acta Crystallographica B, vol. 58 Part 3, pp. 380–388, 2002. View at: Publisher Site | Google Scholar
  20. S. P. Westrip, “PublCIF: software for editing, validating and formatting crystallographic information files,” Journal of Applied Crystallography, vol. 43, no. 4, pp. 920–925, 2010. View at: Publisher Site | Google Scholar

Copyright © 2013 Małgorzata Sikorska and Jarosław Chojnacki. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

608 Views | 428 Downloads | 0 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder