Eric Oldfield

Scott R Wilson

William L Gossman

CiteSeerX

Three hydrates of the bisphosphonate
risedronate, consisting of one mole-
cular and two ionic structures
William L. Gossman, Scott R. Wilson and Eric Oldfield*
Department of Chemistry, University of Illinois, 600 South Mathews Avenue,
Urbana, Illinois 61801, USA
Correspondence e-mail: eo@chad.scs.uiuc.edu
Received 8 October 2002
Accepted 27 November 2002
Online 11 January 2003
Three different hydrates of risedronate were obtained by
varying the pH of a solution containing the compound. At the
pH values used, the N atom of the pyridine group is
protonated and the compounds are zwitterionic. Crystals
obtained directly from the synthesis resulted in risedronate
monohydrate, or [1-hydroxy-1-phosphono-2-(pyridinium-3-
yl)ethyl]phosphonate monohydrate, C7H11NO7P2H2O, (I),
in which just one phosphonate group is negatively charged.
Recrystallizations at pH values of 2 and 4 yielded risedronate
dihydrate, or sodium [1-hydroxy-2-(pyridinium-3-yl)ethane-
1,2-diyl]bis(phosphonate) dihydrate, Na+C7H10NO7P2ÿ-
2H2O, (II). Finally, recrystallizations at pH values of 7 and 8
produced risedronate 2.5-hydrate, or sodium [1-hydroxy-2-
(pyridinium-3-yl)ethane-1,2-diyl]bis(phosphonate) 2.5-hy-
drate, Na+C7H10NO7P2ÿ2.5H2O, (III). At these four pH
values, both phosphonate groups in (II) and (III) are
negatively charged and coordinated to an Na+ ion. Crystals
of (II), i.e. those grown at pH values of 2 and 4, have
isomorphous polymeric ion aggregate structures with geminal
phosphonate and alcohol groups coordinated to the same Na+
ion. On the other hand, crystals of (III), i.e. those grown at pH
values of 7 and 8, have isomorphism polymeric ion aggregate
structures with geminal phosphonate and alcohol groups
coordinated to different Na+ ions.
Comment
Risedronate (Actonel; Procter & Gamble) is a potent inhi-
bitor of osteoclast-mediated bone resorption and has found
widespread use in the treatment of osteoporosis. More
recently, risedronate has also been shown to have antiparasitic
properties, in particular against the organisms which cause
sleeping sickness, Chagas' disease, leishmanasis, toxoplasmosis
and cryptosporidiosis (Martin et al., 2001; Urbina et al., 1999;
Moreno et al., 2001). With the knowledge that several million
people contract these diseases worldwide each year, it is
important to explore the structural origins of bisphosphonate
activity against these parasites. Only one structural form of
risedronate, one of the most potent antiparasitic and anti-
resorptive agents, has been published to date (Barbey &
Lecouvey, 2002). Here, the structures of three different forms
of risedronate, viz. (I), (II) and (III), are reported.
All three hydrates exist as zwitterions, a common char-
acteristic of bisphosphonates (Vega et al., 1996, 1998). The
monohydrate, (I) (Fig. 1), has an overall charge of zero, with
one positively charged N atom and one negatively charged
phosphonate group (Barbey & Lecouvey, 2002). The dihy-
drate, (II) (Fig. 2), and the 2.5-hydrate, (III) (Fig. 3), both have
an overall charge of ÿ1, again with a positively charged N
atom but with two negatively charged phosphonate groups.
These protonation states are correlated with the PÐO bond
lengths.
Fig. 4 shows a histogram of the PÐO bond distances
observed in these three hydrates, along with those in two other
bisphosphonate structures explored recently (isozoledronate
and incadronate; Gossman et al., 2002; Van Brussel et al.,
2003), together with values found in 62 three-dimensional
X-ray crystal structures of similar phosphonate-containing
compounds that are listed in the Cambridge Structural
Database (Version 1.4; Allen, 2002). The two histograms are
very similar and show a clear bimodal distribution. PÐO
bonds in which the O atom is unprotonated are between 1.47
and 1.53 AÊ long, but this increases to 1.54±1.60 AÊ if the O
atom is protonated.
Acta Cryst. (2003). C59, m33±m36 DOI: 10.1107/S0108270102021996 # 2003 International Union of Crystallography m33
metal-organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
ISSN 0108-2701
Figure 1
A view of the molecule of (I), showing 35% probability displacement
ellipsoids and the atom-numbering scheme. H atoms are shown as small
spheres of arbitrary radii. Secondary sites for the disordered water
molecule, O9, have been omitted for clarity.
metal-organic compounds
m34 William L. Gossman et al.  Three hydrates of C7H11NO7P2 Acta Cryst. (2003). C59, m33±m36
Using this description to inspect the PÐO bond lengths in
the three hydrates studied here (Tables 1, 3 and 5), compound
(I), with P1ÐO1 = 1.548 (2), P1ÐO2 = 1.524 (2) and P1ÐO3 =
1.494 (2) AÊ , and P2ÐO4 = 1.479 (2), P2ÐO5 = 1.555 (2) and
P2ÐO6 = 1.562 (2) AÊ , shows three protonated O atoms on the
phosphonate groups, namely O1, O5 and O6, and three
unprotonated O atoms, namely O2, O3, and O4, leading to the
conclusion that atom P1 is negatively charged, while atom P2
is neutral. Inspection of (II), with P1ÐO1 = 1.513 (2),
P1ÐO2 = 1.514 (2) and P1ÐO3 = 1.579 (2) AÊ , and P2ÐO4 =
1.515 (2), P2ÐO5 = 1.495 (2) and P2ÐO6 = 1.600 (2) AÊ ,
results in only two protonated O atoms, namely O3 and O6,
and four unprotonated O atoms, namely O1, O2, O4 and O5,
showing that both phosphonate groups in (II) carry a ÿ1
charge, unlike (I). Analysis of (III), with P1ÐO1 = 1.510 (1),
P1ÐO2 = 1.510 (1) and P1ÐO3 = 1.566 (1) AÊ , and P2ÐO4 =
1.498 (1), P2ÐO5 = 1.509 (1) and P2ÐO6 = 1.581 (1) AÊ ,
shows that the phosphonate groups have the same protonation
state as in (II).
The conformation of risedronate in all three hydrates is very
similar. The P1ÐC1ÐP2 angles are nearly identical [113.2 (2),
113.2 (2) and 111.8 (1) in (I), (II) and (III), respectively], and
the P1ÐC1ÐC2ÐC3 torsion angles between the phosphonate
group and the ring are also similar [57.6 (3), 61.8 (3) and
53.8 (1) in (I), (II) and (III), respectively]. One noticeable
difference found in the structures is a rotation of almost 180
of the ring in the dihydrate compared with the mono- and 2.5-
hydrates, as re¯ected in the C1ÐC2ÐC3ÐC4 torsion angles
of the C atom closest to the N atom [82.9 (4), ÿ97.2 (3) and
68.2 (1) in (I), (II) and (III), respectively].
The main distinguishing structural feature between these
three hydrates lies in their ion aggregate propagation. In the
monohydrate, only the hydrogen-bonding network inter-
connects the host bisphosphonate molecules (Table 2). In the
dihydrate, (II), atoms O1, O5 and O7 coordinate to Na1, atom
O5 coordinates to a site on an inversion-related Na1, and atom
O2 bridges another Na1 through a different inversion centre
(Table 4). The ion aggregate propagates along the a axis. In the
2.5-hydrate, (III), atoms O1 and O5 coordinate to Na1, atom
O7 coordinates to the terminal site on a c-glide-related Na
atom, and water molecule O8 bridges two Na atoms related by
an inversion centre (Table 6). The ion aggregate propagates
parallel to the bc plane. All three conformations show an
extensive hydrogen-bonding network, with each structure
having at least ten hydrogen bonds.
Figure 2
A view of the molecule of (II), showing 35% probability displacement
ellipsoids and the atom-numbering scheme. H atoms are shown as small
spheres of arbitrary radii.
Figure 3
A view of the molecule of (III), showing 35% probability displacement
ellipsoids and the atom-numbering scheme. H atoms are shown as small
spheres of arbitrary radii. Secondary sites for the disordered positions
O10, O11, O12 and Na2 have been omitted for clarity.
Figure 4
Histograms of PÐO bond lengths in compounds in the Cambridge
Structural Database (black; see text for details), and those measured in
bisphosphonates (white).
Experimental
For (I), crystals were obtained directly from the synthesis mixture.
For (II), crystals of (I) were recrystallized by vapour diffusion of
ethanol into a buffered (glycine±HCl, pH = 2 or 4) aqueous solution.
For (III), crystals of (I) were recrystallized by vapour diffusion of
ethanol into a buffered [Tris±HCl, pH = 7 or 8; Tris is 2-amino-2-
(hydroxymethyl)-1,3-propanediol] aqueous solution.
Compound (I)
Crystal data
C7H11NO7P2H2O
Mr = 301.12
Monoclinic, P21=n
a = 7.1219 (15) AÊ
b = 10.694 (2) AÊ
c = 14.710 (3) AÊ
 = 101.996 (4)
V = 1095.9 (4) AÊ 3
Z = 4
Dx = 1.825 Mg m
ÿ3
Mo K radiation
Cell parameters from 940
re¯ections
 = 3.4±27.4
 = 0.43 mmÿ1
T = 193 (2) K
Plate, colorless
0.15  0.08  0.02 mm
Data collection
Bruker Platform CCD area-detector
diffractometer
Pro®le data from ! scans
Absorption correction: by
integration (XPREP in
SHELXTL; Bruker, 2001)
Tmin = 0.936, Tmax = 0.991
8978 measured re¯ections
2236 independent re¯ections
1534 re¯ections with I > 2(I)
Rint = 0.079
max = 26.4

h = ÿ8! 8
k = ÿ13! 13
l = ÿ18! 18
100 standard re¯ections
frequency: 731 min
intensity decay: 1%
Re®nement
Re®nement on F 2
R[F 2 > 2(F 2)] = 0.043
wR(F 2) = 0.108
S = 1.01
2236 re¯ections
200 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
w = 1/[2(Fo
2) + (0.0469P)2
+ 0.5123P]
where P = (Fo
2 + 2Fc
2)/3
(/)max < 0.001
max = 0.46 e AÊ
ÿ3
min = ÿ0.37 e AÊ ÿ3
Compound (II)
Crystal data
Na+C7H10NO7P2ÿ2H2O
Mr = 341.12
Triclinic, P1
a = 7.663 (4) AÊ
b = 8.039 (4) AÊ
c = 10.770 (5) AÊ
 = 93.655 (8)
 = 95.277 (9)
 = 96.017 (8)
V = 655.2 (6) AÊ 3
Z = 2
Dx = 1.729 Mg m
ÿ3
Mo K radiation
Cell parameters from 914
re¯ections
 = 3.1±27.5
 = 0.41 mmÿ1
T = 193 (2) K
Tabular, colorless
0.20  0.16  0.06 mm
Data collection
Bruker Platform CCD area-detector
diffractometer
Pro®le data from ! scans
Absorption correction: by
integration (XPREP in
SHELXTL; Bruker, 2001)
Tmin = 0.935, Tmax = 0.976
4297 measured re¯ections
2586 independent re¯ections
2007 re¯ections with I > 2(I)
Rint = 0.027
max = 26.3

h = ÿ9! 9
k = ÿ9! 9
l = ÿ13! 12
104 standard re¯ections
frequency: 490 min
intensity decay: 2%
Re®nement
Re®nement on F 2
R[F 2 > 2(F 2)] = 0.040
wR(F 2) = 0.100
S = 1.02
2586 re¯ections
237 parameters
All H-atom parameters re®ned
w = 1/[2(Fo
2) + (0.0513P)2
+ 0.2778P]
where P = (Fo
2 + 2Fc
2)/3
(/)max < 0.001
max = 0.50 e AÊ
ÿ3
min = ÿ0.31 e AÊ ÿ3
Acta Cryst. (2003). C59, m33±m36 William L. Gossman et al.  Three hydrates of C7H11NO7P2 m35
metal-organic compounds
Table 2
Hydrogen-bonding geometry (AÊ , ) for (I).
DÐH  A DÐH H  A D  A DÐH  A
N1ÐH1  O2i 0.91 (3) 1.94 (4) 2.847 (4) 172 (3)
O1ÐH1A  O8ii 0.84 (3) 1.66 (4) 2.496 (6) 172 (4)
O1ÐH1A  O9ii 0.84 (3) 1.61 (4) 2.355 (18) 147 (4)
O5ÐH5A  O2iii 0.80 (4) 1.84 (4) 2.634 (3) 174 (4)
O6ÐH6A  O2iv 0.76 (4) 1.91 (4) 2.661 (3) 172 (4)
O7ÐH7A  O3v 0.78 (3) 1.96 (4) 2.730 (3) 168 (3)
O8ÐH8A  O3v 0.84 (3) 1.87 (3) 2.704 (5) 170 (5)
O8ÐH8B  O4vi 0.85 (3) 1.83 (3) 2.675 (5) 174 (5)
Symmetry codes: (i) xÿ 12; 32ÿ y; zÿ 12; (ii) 1 x; y; z; (iii) 2ÿ x; 2ÿ y; 2 ÿ z; (iv)
xÿ 1; y; z; (v) 32ÿ x; yÿ 12; 32ÿ z; (vi) 12ÿ x; yÿ 12; 32ÿ z.
Table 1
Selected geometric parameters (AÊ , ) for (I).
O1ÐP1 1.548 (2)
O2ÐP1 1.524 (2)
O3ÐP1 1.494 (2)
O4ÐP2 1.479 (2)
O5ÐP2 1.555 (2)
O6ÐP2 1.562 (2)
P1ÐC1ÐP2 113.20 (15) C1ÐC2ÐC3 117.6 (2)
P1ÐC1ÐC2ÐC3 57.6 (3) C1ÐC2ÐC3ÐC4 82.9 (4)
Table 4
Hydrogen-bonding geometry (AÊ , ) for (II).
DÐH  A DÐH H  A D  A DÐH  A
O3ÐH3  O2i 0.79 (3) 1.82 (3) 2.613 (3) 177 (4)
N1ÐH1  O4ii 0.97 (4) 1.63 (4) 2.592 (3) 173 (3)
O6ÐH6A  O9 0.80 (3) 1.86 (3) 2.656 (3) 178 (4)
O7ÐH7A  O1iii 0.81 (3) 2.00 (3) 2.791 (3) 166 (3)
O8ÐH8A  O1iv 0.89 (3) 2.03 (3) 2.902 (3) 165 (3)
O8ÐH8A  O3iv 0.89 (3) 2.63 (4) 3.124 (3) 116 (3)
O8ÐH8B  O4i 0.93 (3) 2.25 (4) 2.797 (3) 116 (4)
O8ÐH8B  O3i 0.93 (3) 2.55 (4) 3.283 (3) 136 (4)
O9ÐH9A  O8iii 0.90 (3) 1.81 (3) 2.696 (3) 165 (5)
O9ÐH9B  O6v 0.84 (3) 2.13 (3) 2.914 (3) 156 (4)
Symmetry codes: (i) 1ÿ x;ÿy; 2ÿ z; (ii) ÿx;ÿy; 1ÿ z; (iii) 1ÿ x; 1ÿ y; 2ÿ z; (iv)
1 x; y; z; (v) ÿx; 1ÿ y; 1ÿ z.
Table 3
Selected geometric parameters (AÊ , ) for (II).
O1ÐP1 1.5134 (19)
O2ÐP1 1.514 (2)
O3ÐP1 1.579 (2)
O4ÐP2 1.515 (2)
O5ÐP2 1.495 (2)
O6ÐP2 1.600 (2)
P1ÐC1ÐP2 113.21 (14) C3ÐC2ÐC1 114.8 (2)
P2ÐC1ÐC2ÐC3 61.8 (3) C1ÐC2ÐC3ÐC4 ÿ97.2 (3)
metal-organic compounds
m36 William L. Gossman et al.  Three hydrates of C7H11NO7P2 Acta Cryst. (2003). C59, m33±m36
Compound (III)
Crystal data
Na+C7H10NO7P2ÿ2.5H2O
Mr = 350.13
Monoclinic, C2=c
a = 21.664 (7) AÊ
b = 8.930 (3) AÊ
c = 15.123 (5) AÊ
 = 114.692 (5)
V = 2658.3 (14) AÊ 3
Z = 8
Dx = 1.750 Mg m
ÿ3
Mo K radiation
Cell parameters from 963 re¯ections
 = 2.5±28.2
 = 0.41 mmÿ1
T = 193 (2) K
Plate, colorless
0.30  0.20  0.06 mm
Data collection
Bruker Platform CCD area-detector
diffractometer
Pro®le data from ! scans
Absorption correction: by
integration (XPREP in
SHELXTL; Bruker, 2001)
Tmin = 0.886, Tmax = 0.977
13 009 measured re¯ections
2435 independent re¯ections
2142 re¯ections with I > 2(I)
Rint = 0.035
max = 25.4

h = ÿ26! 26
k = ÿ10! 10
l = ÿ18! 18
161 standard re¯ections
frequency: 458 min
intensity decay: none
Re®nement
Re®nement on F 2
R[F 2 > 2(F 2)] = 0.030
wR(F 2) = 0.082
S = 1.05
2435 re¯ections
298 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
w = 1/[2(Fo
2) + (0.0468P)2
+ 2.8440P]
where P = (Fo
2 + 2Fc
2)/3
(/)max = 0.043
max = 0.37 e AÊ
ÿ3
min = ÿ0.35 e AÊ ÿ3
In (I), the solvate water molecule was disordered over two general
positions. Owing to high correlations, donor H-atom positions were
re®ned under restraint to idealized OÐH and NÐH distances, with
an s.u. of 0.03 AÊ , and HÐR distances for the water molecules were
also restrained (s.u. = 0.06 AÊ ). The remaining CÐH H atoms were
included as riding atoms, with Uiso(H) = 1.2Ueq of their parent atoms.
Disordered OÐH distances were restrained to equivalent idealized
values, with an effective s.u. of 0.03 AÊ ..
For (II), owing to high correlations, OÐH distances were restrained
to equivalent idealized values, with an s.u. of 0.04 AÊ , and HÐR
distances for the water molecules were also restrained (s.u. = 0.04 AÊ ).
The remaining H-atom parameters were re®ned independently.
For (III), the uncoordinated solvate water molecule was disor-
dered about the twofold axis. The proposed model also included two
disordered positions for the Na+ ion, in addition to the bridging and
terminal water ligands. Owing to high correlations, OÐH distances
and angles for the disordered water molecules were restrained to
equivalent idealized values, with s.u. values of 0.03 AÊ and 0.04,
respectively. Displacement parameters for H atoms bound to the
same disordered O atom were restrained to be similar (s.u. = 0.01 AÊ 2).
The remaining H-atom parameters were re®ned independently
without restraints. The highest peaks in the ®nal difference Fourier
maps for all three compounds were located along the CÐP bonds.
For all compounds, data collection: SMART (Bruker, 2001); cell
re®nement: SAINT (Bruker, 2001); data reduction: SAINT;
program(s) used to solve structure: SHELXTL (Bruker, 2001);
program(s) used to re®ne structure: SHELXTL; molecular graphics:
SHELXTL; software used to prepare material for publication:
CIFTAB in SHELXL97-2 (Sheldrick, 2001).
This work was supported in part by the US Public Health
Service (National Institutes of Health grant GM-50694), by
the UNDP/World Bank/WHO Special Programme for
Research and Training in Tropical Diseases (TDR), and by the
American Heart Association, Midwest Af®liate. The Materials
Chemistry Laboratory at the University of Illinois was
supported in part by grant No. NSF CHE 95-03145 from the
National Science Foundation. The crystals were grown by Mr
Yi-Gui Gao.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: GG1145). Services for accessing these data are
described at the back of the journal.
References
Allen, F. H. (2002). Acta Cryst. B58, 380±388.
Barbey, C. & Lecouvey, M. (2002). Z. Kristallogr. New Cryst. Struct. 217, 137±
138.
Bruker (2001). SMART (Version 5.625), SAINT (Version 6.22) and
SHELXTL (Version 6.12). Bruker AXS Inc., Madison, Wisconsin, USA.
Gossman, W. L., Wilson, S. R. & Old®eld, E. (2002). Acta Cryst. C58, m599±
m600.
Martin, M. B., Grimley, J. S., Lewis, J. C., Heath, H. T., Bailey, B. N., Kendrick,
H., Yardley, V., Caldera, A., Lira, R., Urbina, J. A., Moreno, S. N. J.,
Docampo, R., Croft, S. L. & Old®eld, E. (2001). J. Med. Chem. 44, 909±916.
Moreno, B., Bailey, B. N., Luo, S., Martin, M. B., Kuhlenschmidt, M., Moreno,
S. N. J., Docampo, R. & Old®eld, E. (2001). Biochem. Biophys. Res.
Commun. 284, 632±637.
Sheldrick, G. M. (2001). SHELXL97-2. University of GoÈ ttingen, Germany.
Urbina, J. A., Moreno, B., Vierkotter, S., Old®eld, E., Payares, G., Sanoja, C.,
Bailey, B. N., Yan, W., Scott, D. A., Moreno, S. N. & Docampo, R. (1999). J.
Biol. Chem. 274, 33609±33615.
Van Brussel, E. M., Gossman, W. L., Wilson, S. R. & Old®eld, E. (2003). Acta
Cryst. C59. In the press.
Vega, D., Baggio, R. & Garland, M. T. (1996). Acta Cryst. C52, 2198±
2201.
Vega, D., Baggio, R. & Piro, O. (1998). Acta Cryst. C54, 324±327.
Table 6
Hydrogen-bonding geometry (AÊ , ) for (III).
DÐH  A DÐH H  A D  A DÐH  A
N1ÐH1  O2i 0.880 (9) 1.765 (9) 2.6440 (11) 177.7 (8)
O3ÐH3  O5ii 0.765 (9) 1.745 (9) 2.5002 (8) 168.9 (9)
O6ÐH6A  O1iii 0.736 (9) 1.922 (9) 2.6538 (10) 172.5 (9)
O7ÐH7A  O4iii 0.827 (9) 1.954 (9) 2.7487 (10) 161.0 (9)
O8ÐH8B  O4iii 0.846 (11) 1.957 (13) 2.7671 (13) 160.1 (17)
O8ÐH8A  O1 0.868 (11) 2.106 (15) 2.7339 (13) 128.7 (14)
O9ÐH9A  O3iii 0.822 (13) 2.253 (12) 2.9671 (15) 145.4 (11)
O9ÐH9B  O10iv 0.832 (10) 2.013 (11) 2.7596 (16) 149.1 (17)
O10ÐH10A  O2 0.841 (13) 1.879 (14) 2.6914 (15) 161.9 (15)
O10ÐH10B  O2v 0.848 (13) 2.081 (14) 2.9097 (15) 165.5 (11)
O11ÐH11A  O4iii 0.841 (14) 2.017 (13) 2.7575 (18) 146.4 (11)
O11ÐH11B  O1 0.863 (12) 1.946 (13) 2.7972 (17) 168.6 (16)
O12ÐH12A  O3iii 0.867 (14) 2.130 (12) 2.9219 (15) 151.7 (17)
O12ÐH12B  O2iv 0.845 (11) 2.167 (11) 2.9804 (15) 161.4 (17)
Symmetry codes: (i) ÿx;ÿy;ÿz; (ii) 12ÿ x; 12 y; 12ÿ z; (iii) 12ÿ x; yÿ 12; 12ÿ z; (iv)
1
2 x; 12ÿ y; 12 z; (v) ÿx; y; 12ÿ z.
Table 5
Selected geometric parameters (AÊ , ) for (III).
O1ÐP1 1.5098 (6)
O2ÐP1 1.5104 (7)
O3ÐP1 1.5657 (6)
O4ÐP2 1.4983 (7)
O5ÐP2 1.5089 (7)
O6ÐP2 1.5808 (6)
P2ÐC1ÐP1 111.84 (4) C3ÐC2ÐC1 116.69 (7)
P1ÐC1ÐC2ÐC3 ÿ53.84 (7) C1ÐC2ÐC3ÐC4 ÿ68.20 (10)


Three hydrates of the bisphosphonate risedronate, consisting of one molecular and two ionic structures

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Three hydrates of the bisphosphonate risedronate, consisting of one molecular and two ionic structures

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