Calcium acamprosate: a triclinic polymorph

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)%].

The title compound, poly[bis( 3 -4-acetamidopropanesulfonato)calcium], [Ca(C 5 H 10 NO 4 S) 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 Ca 2+ 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-HÁ Á ÁO hydrogen bonds and by short C-HÁ Á ÁO interactions, both involving the sulfonate O atoms not coordinated to the Ca 2+ cations. The structure was determined from a crystal twinned by non-merohedry [twin law (100, 010, À0.335 À0.85 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: Rö sner 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).
Samples of the title compound were kindly provided by Laboratorio Chimico Internazionale SpA (Via T. Salvini 10, I-20122 Milan, Italy).  (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, (C 5 H 10 N O 4 S) -, and Ca 2+ 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 Ca 2+ 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 acetylaminopropane 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)

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.  (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)  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.     (14) 137.