Monoclinic form I of clopidogrel hydrogen sulfate from powder diffraction data

The asymmetric unit of the title compound, C16H17ClNO2S+·HSO4 −, (I) [systematic name: (+)-(S)-5-[(2-chlorophenyl)(methoxycarbonyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-ium hydrogen sulfate], contains two independent cations of clopidogrel and two independent hydrogensulfate anions. The two independent cations are of similar conformation; however, this differs from that observed in orthorhombic form (II) [Bousquet et al. (2003 ▶). US Patent No. 6 504 030]. The H—N—Cchiral—H fragment shows a trans conformation in both independent cations in (I) and a gauche conformation in (II). In (I), classical intermolecular N—H⋯O and O—H⋯O hydrogen bonds link two independent cations and two independent anions into an isolated cluster, in which two cations interact with one anion only via N—H⋯O hydrogen bonds. Weak intermolecular C—H⋯O hydrogen bonds further consolidate the crystal packing.


Comment
Clopidogrel hydrogensulfate is an antiplatelet drug, which acts by selective and irreversible inhibition of ADP-induced platelet aggregation. The drug is available in the market as oral solid dosage form. Six different polymorphs are known for the drug -I (Badorc & Frehel, 1989), II (Bousquet et al., 2003) and III-VI (Lifshitz-Liron et al., 2006). However, only polymorphs I and II are used in pharmaceutical formulations (Bousquet et al., 2003), and, therefore, they are under intensive studies (Raijada et al., 2010;Zupan˘ci˘c et al., 2010;Srivastava et al., 2010;Song et al., 2010). The crystal structure of orthorhombic polymorph II has been reported by Bousquet et al. (2003). Herewith we report the crystal structure of the monoclinic polymorph I.
The asymmetric unit of I ( Fig. 1), contains two independent cations of clopidogrel and two independent hydrogensulfate anions. The two independent cations are of similar conformation, which, however, differs from that observed in II. The H-N-C chiral -H fragment shows a trans conformation in both independent cations in I and a gauche conformation in II.
The hydrogen-bonding motifs in I and II are essentially different too. In I, the classical intermolecular N-H···O and O-H···O hydrogen bonds (Table 1) link two independent cations and two independent anions into isolated cluster, where two cations interact with one anion only via N-H···O hydrogen bonds (Fig. 1). Weak intermolecular C-H···O hydrogen bonds (Table 1) consolidate further the crystal packing of I. In II, O-H···O hydrogen bonds link anions into linear chains, while N-H···O hydrogen bond attach one cation to one anion. These differences in crystal packings of Forms I and II may explain why II exhibits a lower solubility (and is more stable) than I.

Refinement
During the exposure, the specimen was spun in its plane to improve particle statistics. The monoclinic unit-cell dimensions were determined with the indexing program TREOR (Werner et al., 1985), M 20 =37, using the first 30 peak positions. The same monoclinic unit-cell dimensions were reported in 2003 by Martin Vickers at http://img.chem.ucl.ac.uk/www/reports/ clopi/clopi.htm.
The structure of was solved by simulated annealing procedure (Zhukov et al., 2001) and refined following the methodology described in (Chernyshev et al., 2009). For non-H atoms, ten independent U iso parameters were refined -six for six independent Cl and S atoms, two common U iso for two groups of anion' oxygen atoms, and two common U iso for the rest atoms in independent cations. H atoms were placed in geometrically calculated positions and not refined. The diffraction profiles and the differences between the measured and calculated profiles are shown in Fig. 2. supplementary materials sup-2    supplementary materials sup-9