Calcium acamprosate: a triclinic polymorph

Abstract

The title compound, poly[bis­(μ₃-4-acetamido­propane­sulfon­ato)­calcium], [Ca(C₅H₁₀NO₄S)₂]_n, is a triclinic polymorph of the previously reported monoclinic structure [Toffoli et al. (1988 ▶). Acta Cryst. C44, 1493–1494]. The triclinic modification was found to have an all-trans configuration of the acetamido­propane chain, in contrast with the monoclinic polymorph which shows an angle of 74.66 (8)° between the S—C—C—C chain plane and that of the amide group. The Ca²⁺ cation is situated on an inversion centre and is hexa­coordinated by six O atoms belonging to different anions in a distorted octa­hedral geometry. This arrangement leads to a layered structure parallel to (011). The layers are held together by N—H⋯O hydrogen bonds and by short C—H⋯O inter­actions, both involving the sulfonate O atoms not coordinated to the Ca²⁺ cations. The structure was determined from a crystal twinned by non-merohedry [twin law (00, 00, −0.335 −0.85 1), with a fractional contribution of the minor twin domain of 46.7 (1)%].

Related literature

For the characterization of the monclinic polymorph and related structures, see: Toffoli et al. (1988 ▶). The title compound is a drug used successfully in the treatment of alcoholism. For the synthesis, see: Laboratorio Chimico Inter­nazionale SpA (2010 ▶). For its therapeutic effect and a tolerability study, see: Rösner et al. (2010 ▶). For proposed mechanisms of action, see: De Witte et al. (2005 ▶). Programs used for identifying the twin system were PLATON (Spek, 2009 ▶) and CELL_NOW (Bruker, 2008 ▶). For standard bond lengths, see: Allen et al. (1987 ▶).

Experimental

Crystal data

• [Ca(C₅H₁₀NO₄S)₂]

• M _r = 400.48

• Triclinic,

• a = 5.5372 (4) Å

• b = 8.1487 (6) Å

• c = 9.7578 (7) Å

• α = 69.159 (1)°

• β = 84.305 (2)°

• γ = 89.329 (2)°

• V = 409.31 (5) ų

• Z = 1

• Mo Kα radiation

• μ = 0.68 mm⁻¹

• T = 293 K

• 0.29 × 0.23 × 0.08 mm

Data collection

• Bruker SMART APEX CCD diffractometer

• Absorption correction: multi-scan (TWINABS; Bruker, 2008 ▶) T _min = 0.827, T _max = 0.948

• 22542 measured reflections

• 8721 independent reflections

• 7647 reflections with I > 2σ(I)

• R _int = 0.027

Refinement

• R[F ² > 2σ(F ²)] = 0.034

• wR(F ²) = 0.088

• S = 1.02

• 8721 reflections

• 109 parameters

• H-atom parameters constrained

• Δρ_max = 0.39 e Å⁻³

• Δρ_min = −0.33 e Å⁻³

Data collection: SMART (Bruker, 2003 ▶); cell refinement: SAINT (Bruker, 2003 ▶); data reduction: SAINT; program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL/NT (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N—H1N⋯O1i	0.86	2.15	3.0025 (12)	169
C5—H5C⋯O1i	0.96	2.48	3.3569 (15)	152
C1—H1B⋯O1ii	0.97	2.53	3.3007 (14)	137

Symmetry codes: (i) ; (ii) .

supplementary crystallographic information

Comment

Calcium acamprosate (Fig. 1), systematic name: calcium bis(3-acetylamino-propane)-1-sulphonate, also known as N-acetyl homotaurine, is a white crystalline synthetic compound which crystallizes as discrete acetylamino-propane-sulphonate anions, (C₅H₁₀N O₄S)^-, and Ca²⁺ cations, connected by Ca···O interactions. It is used in the treatment of alcoholism and it is specifically indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence (Rösner et al., 2010). The mechanism of action of calcium acamprosate in prevention of relapses is not completely understood, but it is believed to restore the normal chemical balance between neuronal excitation and inhibition that would be disrupted by long-term or chronic alcohol abuse. In other words, it helps the brain begin working normally again (De Witte et al., 2005).

A monoclinic polymorph (A) of the title compound has been previously reported (Toffoli et al. 1988). The new polymorph form (B) crystallizes in the centrosymmetric P1 space group with the Ca²⁺ located on a crystallographic inversion centre, so there is only one single anion in the asymmetric unit of the elementary cell. The conformation of the acetylamino-propane chain shows the main geometric difference between polymorph A and polymorph B: in the triclinic modification (B) the conformation is all trans, while in the monoclinic form (A) an angle of 74.66 (8)° between the S—C—C—C chain plane and that of the amide group was found. Bond lengths and angles are within normal ranges (Allen et al., 1987) and are comparable with those of polymorph (A). Each Ca²⁺ cation is coordinated in a distorted octahedral geometry to six different anions via Ca···O interactions with four sulfonyl O atoms and two carbonyl O atoms with a Ca···O distance in the range 2.283 (1)–2.394 (1) Å. The coordination of the Ca²⁺ cations to two terminal sides of the anions leads to a polymeric bidimensional structure extended in layers parallel to the (011) plane. The layers are connected into a three-dimensional network by N—H···O hydrogen bonds and by short C—H···O interactions, both involving the sulfonyl O atoms not coordinated to the Ca²⁺ cations.

Experimental

The title compound was prepared according to the procedure patented by Laboratorio Chimico Internazionale SpA (2010). Polymorph B precipitates by adding 500 ml of isopropyl alcohol to a water solution of calcium acamprosate kept at 348–353 K and stirred for 53 h. The white solid obtained was filtered hot (348–353 K) and purified by washing with 300 ml of a 75/25 solution (preheated to 343 K) of isopropyl alcohol and deionized water. The wet product was dried under reduced pressure for 6 h at 318 K. Some crystals were suitable for single-crystal XR analysis. The XRPD pattern, carried out on the crystalline powder of this product, is completely in agreement with the powder pattern calculated from the data obtained by single-crystal XR analysis, thus confirming the purity of the crystalline phase of the batch.

Refinement

The crystal under investigation was found to be non-merohedrally twinned. All reflections for both domains (10284 total) were integrated using Saint, obtaining a number of 4143 reflections (1692 unique ones) for component 1 only (mean I/σ = 12.3), 4146 reflections (1702 unique ones) for component 2 only (mean I/σ = 12.1) and 1974 reflections (929 unique ones) involving both components (mean I/σ = 16.7). The twin law (-1 0 0 0 - 1 0 - 0.335 - 0.85 1) was obtained by the TwinRotMat routine of the PLATON software (Spek, 2009). The orientation matrices for the two components were identified using the program CELL_NOW (Bruker, 2008), with the two twin components resulting related by a 180° rotation around the reciprocal c axis. The reflection data were corrected for absorption using TWINABS (Bruker, 2008), obtaining the HKLF-5 type list of reflections (Sheldrick, 2008) with twin-contributor indicators. The structure was solved using direct methods with only the non-overlapping reflections of component 1 and refined with all reflections of component 1, including the overlapping ones. The fractional contribution of the minor twin component refined to 46.7 (1). H atoms were placed in calculated positions and refined in a riding model with C—H distances of 0.96–0.97 Å and and N—H distance of 0.86 Å. All H atoms were refined with U_iso(H) values equal to 1.5 U_eq of the carrier atom for the methyl group and 1.2 U_eq for all remaining atoms.

Figures

Fig. 1.

A view of the calcium acamprosate salt (B), showing the anion and cation of the asymmetric unit and the second anion, labeled with a prime symbol, generated by the symmetry operation [1 - x, 2 - y, 1 - z], to complete the unit formula.

Fig. 2.

A view of the crystal packing of calcium acamprosate (B), showing a layer of the two dimensional structure running parallel to the (011) plane.

Fig. 3.

Crystal packing of calcium acamprosate (B), viewed along a axis. N—H···O1 hydrogen bonds and C—H···O1 short interactions are shown as dashed lines.

Crystal data

[Ca(C5H10NO4S)2]	Z = 1
Mr = 400.48	F(000) = 210
Triclinic, P1	Dx = 1.625 Mg m−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71069 Å
a = 5.5372 (4) Å	Cell parameters from 4793 reflections
b = 8.1487 (6) Å	θ = 2.3–27.1°
c = 9.7578 (7) Å	µ = 0.68 mm−1
α = 69.159 (1)°	T = 293 K
β = 84.305 (2)°	Plate, colourless
γ = 89.329 (2)°	0.29 × 0.23 × 0.08 mm
V = 409.31 (5) Å3

Data collection

Bruker SMART APEX CCD diffractometer	8721 independent reflections
Radiation source: fine-focus sealed tube	7647 reflections with I > 2σ(I)
graphite	Rint = 0.027
ω scans	θmax = 27.5°, θmin = 2.2°
Absorption correction: multi-scan (TWINABS; Bruker, 2008)	h = −7→7
Tmin = 0.827, Tmax = 0.948	k = −10→10
22542 measured reflections	l = −12→12

Refinement

Refinement on F2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.034	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.088	H-atom parameters constrained
S = 1.02	w = 1/[σ2(Fo2) + (0.0478P)2] where P = (Fo2 + 2Fc2)/3
8721 reflections	(Δ/σ)max = 0.006
109 parameters	Δρmax = 0.39 e Å−3
0 restraints	Δρmin = −0.33 e Å−3

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.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
Ca	1.0000	0.5000	0.0000	0.02008 (8)
S	0.46696 (4)	0.53055 (3)	0.23925 (3)	0.02053 (7)
O1	0.39518 (14)	0.65813 (9)	0.30610 (8)	0.03333 (19)
O2	0.71997 (12)	0.55429 (9)	0.17559 (8)	0.02862 (18)
O3	0.30448 (15)	0.52304 (11)	0.13414 (8)	0.0383 (2)
O4	0.06178 (14)	−0.20198 (9)	0.83520 (8)	0.0340 (2)
N	−0.01015 (17)	0.07771 (11)	0.69942 (10)	0.0334 (2)
H1N	−0.1087	0.1630	0.6866	0.040*
C1	0.44992 (19)	0.32245 (13)	0.38187 (11)	0.0257 (2)
H1A	0.4796	0.2327	0.3388	0.031*
H1B	0.5769	0.3165	0.4450	0.031*
C2	0.20568 (19)	0.28297 (13)	0.47557 (12)	0.0282 (2)
H2A	0.1742	0.3719	0.5193	0.034*
H2B	0.0776	0.2860	0.4138	0.034*
C3	0.20577 (19)	0.10418 (14)	0.59580 (12)	0.0305 (3)
H3A	0.2108	0.0138	0.5524	0.037*
H3B	0.3493	0.0946	0.6474	0.037*
C4	−0.0642 (2)	−0.07020 (14)	0.81257 (12)	0.0294 (3)
C5	−0.2877 (2)	−0.07026 (17)	0.91136 (14)	0.0541 (4)
H5A	−0.2469	−0.0998	1.0105	0.081*
H5B	−0.4034	−0.1553	0.9080	0.081*
H5C	−0.3566	0.0442	0.8791	0.081*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
Ca	0.01787 (15)	0.02063 (15)	0.01751 (15)	−0.00083 (11)	0.00031 (11)	−0.00214 (12)
S	0.01931 (13)	0.02153 (13)	0.01727 (13)	−0.00037 (10)	0.00084 (10)	−0.00333 (10)
O1	0.0406 (5)	0.0242 (4)	0.0332 (4)	0.0049 (3)	0.0042 (4)	−0.0100 (3)
O2	0.0207 (4)	0.0316 (4)	0.0274 (4)	−0.0034 (3)	0.0064 (3)	−0.0052 (3)
O3	0.0328 (4)	0.0520 (5)	0.0267 (4)	−0.0053 (4)	−0.0088 (4)	−0.0081 (4)
O4	0.0360 (5)	0.0221 (4)	0.0337 (5)	0.0035 (3)	0.0052 (4)	0.0001 (3)
N	0.0362 (6)	0.0223 (5)	0.0295 (5)	0.0062 (4)	0.0106 (4)	0.0018 (4)
C1	0.0271 (6)	0.0208 (5)	0.0229 (5)	0.0011 (4)	0.0026 (5)	−0.0016 (4)
C2	0.0254 (6)	0.0244 (6)	0.0265 (6)	−0.0001 (4)	0.0047 (5)	−0.0006 (5)
C3	0.0309 (6)	0.0235 (6)	0.0284 (6)	−0.0001 (4)	0.0065 (5)	−0.0011 (5)
C4	0.0339 (6)	0.0225 (6)	0.0247 (6)	−0.0003 (5)	0.0047 (5)	−0.0019 (5)
C5	0.0578 (9)	0.0355 (7)	0.0443 (8)	0.0108 (6)	0.0261 (7)	0.0076 (6)

Geometric parameters (Å, °)

Ca—O3i	2.2828 (8)	N—C3	1.4523 (13)
Ca—O3ii	2.2828 (8)	N—H1N	0.8600
Ca—O2iii	2.3519 (7)	C1—C2	1.5245 (13)
Ca—O2	2.3519 (7)	C1—H1A	0.9700
Ca—O4iv	2.3941 (7)	C1—H1B	0.9700
Ca—O4v	2.3941 (7)	C2—C3	1.5109 (14)
S—O1	1.4442 (7)	C2—H2A	0.9700
S—O3	1.4471 (8)	C2—H2B	0.9700
S—O2	1.4609 (7)	C3—H3A	0.9700
S—C1	1.7662 (10)	C3—H3B	0.9700
O3—Cavi	2.2828 (8)	C4—C5	1.4910 (16)
O4—C4	1.2382 (12)	C5—H5A	0.9600
O4—Cavii	2.3941 (7)	C5—H5B	0.9600
N—C4	1.3256 (13)	C5—H5C	0.9600
O3i—Ca—O3ii	180.00 (4)	C2—C1—S	113.33 (7)
O3i—Ca—O2iii	88.69 (3)	C2—C1—H1A	108.9
O3ii—Ca—O2iii	91.31 (3)	S—C1—H1A	108.9
O3i—Ca—O2	91.31 (3)	C2—C1—H1B	108.9
O3ii—Ca—O2	88.69 (3)	S—C1—H1B	108.9
O2iii—Ca—O2	180.000 (1)	H1A—C1—H1B	107.7
O3i—Ca—O4iv	92.36 (3)	C3—C2—C1	110.28 (8)
O3ii—Ca—O4iv	87.64 (3)	C3—C2—H2A	109.6
O2iii—Ca—O4iv	97.35 (3)	C1—C2—H2A	109.6
O2—Ca—O4iv	82.65 (3)	C3—C2—H2B	109.6
O3i—Ca—O4v	87.64 (3)	C1—C2—H2B	109.6
O3ii—Ca—O4v	92.36 (3)	H2A—C2—H2B	108.1
O2iii—Ca—O4v	82.65 (3)	N—C3—C2	110.46 (8)
O2—Ca—O4v	97.35 (3)	N—C3—H3A	109.6
O4iv—Ca—O4v	180.00 (2)	C2—C3—H3A	109.6
O1—S—O3	112.42 (5)	N—C3—H3B	109.6
O1—S—O2	112.71 (5)	C2—C3—H3B	109.6
O3—S—O2	111.72 (5)	H3A—C3—H3B	108.1
O1—S—C1	107.12 (5)	O4—C4—N	122.27 (10)
O3—S—C1	106.99 (5)	O4—C4—C5	121.44 (10)
O2—S—C1	105.35 (5)	N—C4—C5	116.28 (9)
S—O2—Ca	144.39 (5)	C4—C5—H5A	109.5
S—O3—Cavi	170.63 (5)	C4—C5—H5B	109.5
C4—O4—Cavii	132.62 (7)	H5A—C5—H5B	109.5
C4—N—C3	123.86 (9)	C4—C5—H5C	109.5
C4—N—H1N	118.1	H5A—C5—H5C	109.5
C3—N—H1N	118.1	H5B—C5—H5C	109.5
O1—S—O2—Ca	−156.68 (7)	O2—S—C1—C2	172.54 (8)
O3—S—O2—Ca	−28.97 (9)	S—C1—C2—C3	−179.41 (8)
C1—S—O2—Ca	86.85 (8)	C4—N—C3—C2	176.87 (11)
O3i—Ca—O2—S	23.48 (8)	C1—C2—C3—N	170.74 (9)
O3ii—Ca—O2—S	−156.52 (8)	Cavii—O4—C4—N	−169.56 (8)
O4iv—Ca—O2—S	−68.73 (8)	Cavii—O4—C4—C5	9.90 (18)
O4v—Ca—O2—S	111.27 (8)	C3—N—C4—O4	−3.33 (19)
O1—S—C1—C2	52.32 (9)	C3—N—C4—C5	177.18 (11)
O3—S—C1—C2	−68.44 (9)

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

Hydrogen-bond geometry (Å, °)

D—H···A	D—H	H···A	D···A	D—H···A
N—H1N···O1viii	0.86	2.15	3.0025 (12)	169.
C5—H5C···O1viii	0.96	2.48	3.3569 (15)	152.
C1—H1B···O1ix	0.97	2.53	3.3007 (14)	137.

Symmetry codes: (viii) −x, −y+1, −z+1; (ix) −x+1, −y+1, −z+1.