The Zn²⁺ salt of pamidronate: a role for water in the metal-cation binding properties of bis­phospho­nates

Pamidronate (3-ammonium-1-hydroxy­propyl­idene-1,1-bis­phos­pho­nate) is used clinically in the treatment of diseases affecting bone tissue. In the salt zinc pamidronate dihydrate, Zn²⁺·2C₃H₁₀NO₇P₂^-·2H₂O, pamidronate is a zwitterion with an overall charge of -1. The carbon chain adopts a trans conformation, separating maximally the positively charged N atom from the negative phospho­nate groups. The Zn²⁺ ion lies on an inversion center and is surrounded by a sixfold coordination sphere provided by two bidentate chelating zwitterions and two water mol­ecules. The bidentate O...Zn...O bond angle is 92.70 (7)°, while the O...O bite distance is 3.018 (3) Å.

S1. Comment

Metal cations are strongly bound by bisphosphonates (alternatively named diphosphonates) through their phosphonate O atoms. This ability gives them? a high tropism to the skeleton, where they interact readily with calcium hydroxyapatite crystals. In clinical practice, a number of bisphosphonates are available for the treatment of diseases affecting bone tissue (Martin & Grill, 2000; Watts, 2003). Pamidronate, a potent inhibitor of osteoclast-mediated bone-resorption, is indicated for hypercalcaemia, osteolytic metastases and Paget's disease of the bone (Widler et al., 2002). Novel roles of bisphosphonates in other diseases have also been suggested (Wolf & Stoller, 1994; Dunn et al., 1998; Reid, 2003). Additional fields where compounds of this type have found useful applications include diagnosis (Degrossi et al., 1985), bone imaging (Love et al., 2003), nuclear medicine (Elder et al., 1997; Larsen et al., 1999) and organometallic chemistry (Distler et al., 1999; Stock & Bein, 2002).

Recent structural studies of pamidronate, in particular those of its sodium (Vega et al., 2002) and calcium (Fernández et al., 2002) salts, showed that, concomitantly with its chelating behavior, its carbon chain was able to adopt different conformations. Such an observation inspired a further exploration of the conformational diversity among bisphosphonates, and so the structural determination of the zinc salt of pamidronate was undertaken. In addition, the binding of the hydration water in two salts of pamidronate has been characterized by a thermogravimetric analysis. The results obtained, together with the single-crystal X-ray diffraction analysis of (I), are reported in the present communication.

In the molecular anion in (I), the geminal atom C1 is substituted by the phosphonate groups, the alcohol function and the alkylamine side chain (Fig. 1). Both P atoms have tetrahedral geometry, which is defined by the bridging C atom and by three O atoms, two of which are unprotonated. The P—C and P—O bond lengths, the P—C—P, O—P—O and O—P—C bond angles, and the mutual orientation of the PO₃ groups (Table 1) are in good agreement with the values found in related structures (Fernández & Vega, 2003; Fernández et al., 2003). The carbon chain adopts a different configuration with respect to that in the Ca²⁺ pamidronate salt (Fernández et al., 2002), hereafter CaH₂PAM, being trans in (I) [C1—C2—C3—N1 = 174.2 (2)°] but close to gauche⁻ in the latter [−72.1 (2)°]. To illustrate this difference, the position of atom N1 relative to the least-squares mean plane defined by atoms C1, C2 and C3 is −0.144 (6) Å for (I) and 1.311 (4) Å for CaH₂PAM. Possibly, the twisting of the chain is stabilized intramolecularly in CaH₂PAM by a hydrogen bond between atom N1 and the hydroxy O atom [the parameters of the N—H···O interaction are D···A = 2.692 (2) Å, H···A = 1.93 (4) Å and D—H···A = 132 (3)°]. In (I), atom N1 is maximally separated from atom O7, and thus no intramolecular interaction was observed. An inspection of the four interactions listed in Table 2 leads to the conclusion that the hydrogen bonds involving atom N1 are weaker than those in CaH₂PAM.

As with the Ca²⁺ salt, the molecular anion has an overall charge of −1 and zwitterionic character, given by one −1 charge on each PO₃ group and the +1 charge on the N1 atom. A 2:1 relation exists between pamidronate and the metal cation. The Zn²⁺ ion is located on an inversion center and the geometry defined by the coordinated atoms is octahedral (Fig. 2). In the coordination sphere around the Zn²⁺ ion there are three symmetry-independent oxygen ligands, namely two from the zwitterion (atoms O2 and O4) and the crystallization water atom O8. The Zn—O contact distances have a mean value of 2.100 (2)°, while the O—Zn—O bond angles are 180° or depart slightly from 90° (Table 1). The zwitterionic oxygen ligands have a cis geometry, sustaining an O2—Zn—O4 bond angle of 92.70 (7)°, while the bite O2···O4 distance is 3.018 (3) Å. The corresponding values found in the Ca²⁺ octahedron are 81.48 (4)° and 3.065 (2) Å, respectively. The Zn²⁺octahedra pack along the a axis in a column, where the metal cation is at the centre and the zwitterion disposes its negative groups towards the Zn²⁺ ion, while its positive end is elongated in the opposite direction. Inside a column, there are hydrogen bonds between zwitterions related by a center of symmetry [O8—H7···O3(-x, −y, −z); see Table 2] and by [100]-translated ones? via N1—H1···O4(1 + x, y, z), N1—H1···O2(1 − x, −y, −z), and O8—H8···O1(1 − x, −y, −z). This column interacts with three neighbors via the remaining hydrogen bonds listed in Table 2.

Pamidronate functions as a bidentate ligand in the zinc salt, while it is both mono- and bidentate in its calcium salt. This difference could originate in a number of factors, including the steric hindrance of the coordinated ligands and the energy of hydration of the particular metal cation. The volume of the Ca²⁺ coordination sphere is \sim1.5 times larger than that of Zn²⁺ [the mean Ca···O distance is 2.3276 (12) Å], suggesting that in the former there is sufficient space for two bidentate and two monodentate zwitterions to be accommodated. In (I), as less room is available around the Zn²⁺ ion, two water molecules are placed as monodentate ligands instead of two zwitterions. The water molecule in CaH₂PAM is too far from the metal cation to form contacts with it and is hydrogen bonded to the N atom. In (I), the water is retained in the coordination sphere of the metal cation, possibly because of the higher energy of hydration of the zinc ion with respect to that of calcium, in keeping with the smaller ionic radius of the former (Gutiérrez Ríos, 1994; Pavlov et al., 1998). This fact is in good agreement with the results obtained from the thermogravimetric analysis made on samples of the Ca²⁺ and Zn²⁺ salts of pamidronate. A weight loss of 7.0%, corresponding to two water molecules per formula unit (calculated weight 6.6%), takes place at 369 K in CaH₂PAM, while for the Zn²⁺ salt, the dehydration (weight loss 7.2%; calculated 6.3%) occurred at a higher temperature (473 K).

S2. Experimental

A sample of pamidronic acid was obtained from LABORATORIOS GADOR SA, Buenos Aires, Argentina. A powdered sample of the bisphosphonate (M_w 239.12) was added to ZnCO₃ in a 1:1 proportion, and then dissolved in an excess of hot water. Crystals suitable for X-ray diffraction were obtained by evaporating this solution at room temperature. Thermogravimetric analysis measurements were recorded on a Shimadzu DTG50 thermal analyzer under an atmosphere of air at a heating rate of 10 K min⁻¹.

S3. Refinement

H atoms attached to C atoms were placed 0.97 Å from their hosts and refined using a riding model, with the isotropic displacement parameters fixed to 1.2U_eq(C). The positional parameters of H atoms attached to O and N-atom hosts were refined with O—H and N—H distances restrained to 0.85 (3) and 0.89 (3) Å, respectively. The displacement parameters of these H atoms were fixed to 1.5 times those of their carrier atoms.

Computing details

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994); cell refinement: CAD-4 EXPRESS; data reduction: XCAD4 (Harms & Wocadlo, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLUTON (Spek, 2003) and ZORTEP (Zsolnai & Pritzkow, 1995); software used to prepare material for publication: PLATON and WinGX (Farrugia, 1999).

Figures

	Fig. 1. : A view of (I), showing the atomic numbering scheme used and displacement ellipsoids at the 50% probability level.
	Fig. 2. : A portion of the packing of (I), showing the zinc coordination sphere (dashed lines). All H atoms have been omitted for clarity. [Symmetry code: −x, −y, −z.]

(I)

Crystal data

Zn^2+·2C3H10NO7P2^−·2H2O	F(000) = 584
Mr = 569.52	Dx = 2.183 Mg m^−3
Monoclinic, P21/n	Cu Kα radiation, λ = 1.5418 Å
Hall symbol: -P 2yn	Cell parameters from 25 reflections
a = 7.3531 (2) Å	θ = 20–30°
b = 10.8223 (2) Å	µ = 6.37 mm^−1
c = 10.9197 (2) Å	T = 293 K
β = 94.469 (2)°	Prism, colorless
V = 866.32 (3) Å^3	0.25 × 0.22 × 0.1 mm
Z = 2

Data collection

Enraf–Nonius CAD-4 diffractometer	Rint = 0.046
non–profiled ω/2θ scans	θmax = 66.9°, θmin = 5.8°
Absorption correction: ψ scan (North et al., 1968)	h = −1→8
Tmin = 0.271, Tmax = 0.529	k = −12→1
2128 measured reflections	l = −13→13
1535 independent reflections	1 standard reflections every 60 min
1434 reflections with I > 2σ(I)	intensity decay: 5%

Refinement

Refinement on F^2	8 restraints
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.037	w = 1/[σ^2(Fo^2) + (0.0703P)^2 + 0.7592P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.100	(Δ/σ)max = 0.007
S = 1.06	Δρmax = 0.88 e Å^−3
1535 reflections	Δρmin = −0.76 e Å^−3
157 parameters

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
C1	0.3630 (3)	0.1352 (2)	0.2135 (2)	0.0132 (5)
C2	0.4940 (4)	0.0251 (3)	0.2040 (3)	0.0170 (6)
H9	0.4227	−0.0493	0.1874	0.02*
H10	0.5673	0.0385	0.1351	0.02*
C3	0.6204 (4)	0.0050 (3)	0.3194 (3)	0.0218 (6)
H11	0.7029	0.0746	0.3318	0.026*
H12	0.5495	−0.0015	0.3904	0.026*
N1	0.7268 (4)	−0.1108 (3)	0.3052 (3)	0.0256 (6)
H1	0.788 (5)	−0.109 (4)	0.239 (3)	0.038*
H2	0.654 (5)	−0.175 (3)	0.301 (4)	0.038*
H3	0.800 (5)	−0.114 (4)	0.369 (3)	0.038*
O1	0.4992 (2)	0.2430 (2)	0.01897 (17)	0.0184 (4)
O2	0.2239 (2)	0.10346 (17)	−0.02351 (17)	0.0161 (4)
O3	0.1874 (3)	0.31121 (17)	0.07359 (19)	0.0186 (4)
H4	0.234 (5)	0.383 (3)	0.079 (4)	0.028*
O4	0.0602 (3)	−0.01002 (17)	0.19518 (17)	0.0186 (4)
O5	0.0361 (3)	0.19813 (18)	0.29969 (18)	0.0193 (4)
H5	0.023 (5)	0.216 (3)	0.373 (2)	0.029*
O6	0.2119 (3)	0.02907 (19)	0.40896 (17)	0.0178 (4)
O7	0.4544 (3)	0.22774 (19)	0.29072 (18)	0.0195 (4)
H6	0.403 (5)	0.297 (3)	0.282 (4)	0.029*
O8	0.1459 (3)	−0.16789 (19)	−0.0212 (2)	0.0212 (4)
H7	0.087 (5)	−0.221 (3)	0.015 (3)	0.032*
H8	0.261 (4)	−0.178 (4)	−0.009 (4)	0.032*
P1	0.31579 (8)	0.20030 (6)	0.05875 (6)	0.0115 (2)
P2	0.15576 (8)	0.08119 (6)	0.28276 (6)	0.0119 (2)
Zn	0	0	0	0.0151 (2)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0107 (11)	0.0148 (13)	0.0140 (12)	−0.0005 (10)	−0.0011 (9)	−0.0006 (10)
C2	0.0141 (13)	0.0185 (13)	0.0183 (13)	0.0056 (10)	0.0002 (10)	0.0005 (11)
C3	0.0160 (14)	0.0222 (16)	0.0263 (15)	0.0026 (10)	−0.0051 (11)	−0.0007 (11)
N1	0.0182 (12)	0.0258 (13)	0.0323 (15)	0.0046 (10)	−0.0012 (11)	0.0094 (12)
O1	0.0110 (9)	0.0263 (11)	0.0177 (9)	−0.0052 (7)	−0.0004 (7)	0.0044 (8)
O2	0.0135 (9)	0.0188 (9)	0.0159 (9)	−0.0037 (7)	0.0005 (7)	−0.0035 (8)
O3	0.0164 (9)	0.0118 (9)	0.0271 (10)	0.0005 (7)	−0.0009 (8)	0.0010 (8)
O4	0.0189 (10)	0.0205 (10)	0.0162 (10)	−0.0074 (7)	0.0009 (8)	−0.0026 (7)
O5	0.0208 (10)	0.0204 (10)	0.0166 (9)	0.0085 (8)	0.0016 (7)	0.0009 (8)
O6	0.0216 (9)	0.0174 (9)	0.0141 (9)	0.0025 (8)	0.0001 (7)	0.0027 (8)
O7	0.0207 (10)	0.0148 (9)	0.0217 (10)	−0.0021 (8)	−0.0062 (8)	−0.0027 (8)
O8	0.0127 (9)	0.0196 (11)	0.0313 (11)	0.0005 (8)	0.0019 (8)	0.0016 (9)
P1	0.0081 (3)	0.0137 (4)	0.0123 (4)	−0.0018 (2)	−0.0011 (2)	0.0009 (2)
P2	0.0112 (3)	0.0125 (4)	0.0119 (4)	−0.0007 (2)	0.0000 (2)	−0.0001 (2)
Zn	0.0123 (3)	0.0154 (3)	0.0173 (3)	−0.00240 (17)	−0.0004 (2)	−0.00120 (18)

Geometric parameters (Å, º)

C1—O7	1.441 (3)	O3—P1	1.5433 (19)
C1—C2	1.541 (3)	O3—H4	0.85 (3)
C1—P1	1.838 (3)	O4—P2	1.5094 (19)
C1—P2	1.849 (2)	O5—P2	1.5603 (19)
C2—C3	1.522 (4)	O5—H5	0.84 (3)
C2—H9	0.97	O6—P2	1.5161 (19)
C2—H10	0.97	O7—H6	0.84 (2)
C3—N1	1.492 (4)	O8—H7	0.84 (3)
C3—H11	0.97	O8—H8	0.85 (3)
C3—H12	0.97	Zn—O2^i	2.0236 (17)
N1—H1	0.88 (3)	Zn—O8^i	2.132 (2)
N1—H2	0.88 (3)	Zn—O4^i	2.1454 (19)
N1—H3	0.85 (3)	O2—Zn	2.0236 (17)
O1—P1	1.5208 (18)	O4—Zn	2.1454 (19)
O2—P1	1.5058 (19)	O8—Zn	2.132 (2)
O7—C1—C2	108.1 (2)	Zn—O8—H8	126 (3)
O7—C1—P1	108.54 (17)	H7—O8—H8	112 (4)
C2—C1—P1	108.01 (17)	O1—P1—O2	114.07 (11)
O7—C1—P2	110.00 (17)	O1—P1—O3	110.93 (12)
C2—C1—P2	108.79 (18)	O2—P1—O3	110.74 (11)
P1—C1—P2	113.25 (13)	O1—P1—C1	105.70 (11)
C3—C2—C1	113.5 (2)	O2—P1—C1	108.99 (12)
C3—C2—H9	108.9	O3—P1—C1	105.94 (11)
C1—C2—H9	108.9	O4—P2—O5	111.50 (11)
C3—C2—H10	108.9	O4—P2—O6	114.39 (12)
C1—C2—H10	108.9	O5—P2—O6	108.06 (11)
H9—C2—H10	107.7	O4—P2—C1	107.79 (11)
N1—C3—C2	109.0 (2)	O5—P2—C1	106.39 (11)
N1—C3—H11	109.9	O6—P2—C1	108.37 (11)
C2—C3—H11	109.9	O2—Zn—O2^i	180.00 (14)
N1—C3—H12	109.9	O2—Zn—O8^i	87.89 (8)
C2—C3—H12	109.9	O2^i—Zn—O8^i	92.11 (8)
H11—C3—H12	108.3	O2—Zn—O8	92.11 (8)
C3—N1—H1	112 (3)	O2^i—Zn—O8	87.89 (8)
C3—N1—H2	110 (3)	O8^i—Zn—O8	180.00 (9)
H1—N1—H2	109 (4)	O2—Zn—O4	92.70 (7)
C3—N1—H3	104 (3)	O2^i—Zn—O4	87.30 (7)
H1—N1—H3	110 (4)	O8^i—Zn—O4	90.11 (8)
H2—N1—H3	111 (4)	O8—Zn—O4	89.89 (8)
P1—O2—Zn	129.88 (11)	O2—Zn—O4^i	87.30 (7)
P1—O3—H4	118 (3)	O2^i—Zn—O4^i	92.70 (7)
P2—O4—Zn	130.25 (11)	O8^i—Zn—O4^i	89.89 (8)
P2—O5—H5	114 (3)	O8—Zn—O4^i	90.11 (8)
C1—O7—H6	112 (3)	O4—Zn—O4^i	180.00 (14)
Zn—O8—H7	105 (3)
O7—C1—C2—C3	32.2 (3)	Zn—O4—P2—C1	−45.72 (18)
P1—C1—C2—C3	149.5 (2)	O7—C1—P2—O4	176.97 (16)
P2—C1—C2—C3	−87.2 (2)	C2—C1—P2—O4	−64.78 (19)
C1—C2—C3—N1	174.2 (2)	P1—C1—P2—O4	55.32 (17)
Zn—O2—P1—O1	170.53 (13)	O7—C1—P2—O6	−58.74 (19)
Zn—O2—P1—O3	−63.49 (17)	C2—C1—P2—O6	59.5 (2)
Zn—O2—P1—C1	52.67 (17)	P1—C1—P2—O5	−64.39 (16)
O7—C1—P1—O2	178.79 (15)	P1—C1—P2—O6	179.62 (13)
C2—C1—P1—O2	61.79 (19)	O7—C1—P2—O5	57.25 (19)
P2—C1—P1—O1	178.23 (13)	C2—C1—P2—O5	175.51 (16)
P2—C1—P1—O2	−58.76 (16)	P1—O2—Zn—O8^i	56.06 (15)
O7—C1—P1—O1	55.78 (19)	P1—O2—Zn—O8	−123.94 (15)
C2—C1—P1—O1	−61.2 (2)	P1—O2—Zn—O4	−33.95 (15)
O7—C1—P1—O3	−62.01 (18)	P1—O2—Zn—O4^i	146.05 (15)
C2—C1—P1—O3	−179.02 (16)	P2—O4—Zn—O2	30.74 (16)
P2—C1—P1—O3	60.44 (16)	P2—O4—Zn—O2^i	−149.26 (16)
Zn—O4—P2—O6	−166.31 (13)	P2—O4—Zn—O8^i	−57.15 (16)
Zn—O4—P2—O5	70.71 (17)	P2—O4—Zn—O8	122.85 (16)

Symmetry code: (i) −x, −y, −z.

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O8—H7···O3^i	0.84 (3)	2.38 (4)	2.919 (3)	123 (3)
O8—H7···O7^ii	0.84 (3)	2.23 (3)	2.905 (3)	137 (3)
O8—H8···O1^iii	0.85 (3)	1.91 (3)	2.732 (3)	161 (4)
O3—H4···O6^iv	0.85 (3)	1.64 (3)	2.474 (3)	171 (4)
O7—H6···O4^iv	0.84 (2)	2.12 (3)	2.845 (3)	144 (3)
O5—H5···O1^v	0.84 (3)	1.67 (3)	2.513 (3)	178 (4)
N1—H1···O2^iii	0.88 (3)	2.35 (3)	3.127 (3)	147 (4)
N1—H1···O4^vi	0.88 (3)	2.35 (4)	3.017 (3)	133 (3)
N1—H2···O5^ii	0.88 (3)	2.19 (3)	2.997 (3)	152 (4)
N1—H3···O1^vii	0.85 (3)	2.41 (3)	3.106 (3)	140 (4)

Symmetry codes: (i) −x, −y, −z; (ii) −x+1/2, y−1/2, −z+1/2; (iii) −x+1, −y, −z; (iv) −x+1/2, y+1/2, −z+1/2; (v) x−1/2, −y+1/2, z+1/2; (vi) x+1, y, z; (vii) −x+3/2, y−1/2, −z+1/2.