Monoclinic form I of clopidogrel hydrogen sulfate from powder diffraction data

Vladimir V Chernyshev; Sergey V Pirogov; Irina N Shishkina; Yurii A Velikodny

doi:10.1107/S1600536810028783

. 2010 Jul 24;66(Pt 8):o2101–o2102. doi: 10.1107/S1600536810028783

Monoclinic form I of clopidogrel hydrogen sulfate from powder diffraction data

Vladimir V Chernyshev ^a,^*, Sergey V Pirogov ^b, Irina N Shishkina ^a, Yurii A Velikodny ^a

PMCID: PMC3007342 PMID: 21588394

Abstract

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—C_chiral—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.

Related literature

For the characterization of six polymorphic forms of Clopidogrel hydrogensulfate, see: Badorc & Frehel (1989 ▶) (form I); Bousquet et al. (2003 ▶) (orthorhombic form II); Lifshitz-Liron et al. (2006 ▶) (forms III-VI). For recent studies of forms I and II, see: Raijada et al. (2010 ▶); Zupancic et al. (2010 ▶); Srivastava et al. (2010 ▶); Song et al. (2010 ▶). For details of the indexing algorithm, see: Werner et al. (1985 ▶). The methodology of the refinement (including applied restraints and constraints) was described in detail by Chernyshev et al. (2009 ▶).

Experimental

Crystal data

C₁₆H₁₇ClNO₂S⁺·HSO₄ ⁻
M _r = 419.89
Monoclinic,
a = 10.4315 (12) Å
b = 15.3345 (18) Å
c = 12.6320 (16) Å
β = 113.28 (2)°
V = 1856.1 (5) Å³
Z = 4
Cu Kα₁ radiation, λ = 1.54059 Å
μ = 4.23 mm⁻¹
T = 295 K
Flat sheet, 15 × 1 mm

Data collection

Guinier camera G670 diffractometer
Specimen mounting: thin layer in the specimen holder of the camera
Data collection mode: transmission
Scan method: continuous
2θ_min = 4.00°, 2θ_max = 90.00°, 2θ_step = 0.01°

Refinement

R _p = 0.019
R _wp = 0.025
R _exp = 0.015
R _Bragg = 0.049
χ² = 2.982
8601 data points
205 parameters
155 restraints
H-atom parameters not refined

Data collection: G670 Imaging Plate Guinier Camera Software (Huber, 2002 ▶); cell refinement: MRIA (Zlokazov & Chernyshev, 1992 ▶); data reduction: G670 Imaging Plate Guinier Camera Software; method used to solve structure: simulated annealing (Zhukov et al., 2001 ▶); program(s) used to refine structure: MRIA; molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: MRIA and SHELXL97 (Sheldrick, 2008 ▶).

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810028783/lh5082sup1.cif

e-66-o2101-sup1.cif^{(22.8KB, cif)}

Rietveld powder data: contains datablocks I. DOI: 10.1107/S1600536810028783/lh5082Isup2.rtv

e-66-o2101-Isup2.rtv^{(286KB, rtv)}

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
N5A—H5A⋯O3A	0.91	1.91	2.785 (16)	161
N5B—H5B⋯O6A	0.91	1.94	2.795 (19)	157
O5A—H51⋯O6B	0.82	1.85	2.640 (17)	161
O5B—H52⋯O4A	0.82	1.82	2.567 (17)	152
C4A—H4A1⋯O4Bⁱ	0.97	2.35	3.17 (2)	142
C4A—H4A2⋯O1B	0.97	2.52	3.225 (17)	129
C3B—H3B⋯O4Bⁱⁱ	0.93	2.41	3.28 (2)	154
C6A—H6A2⋯O3Bⁱ	0.97	2.31	3.175 (19)	149
C4B—H4B2⋯O3Bⁱⁱⁱ	0.97	2.23	3.13 (2)	154

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

supplementary crystallographic information

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.

Experimental

The title compound I was synthesized in accordance with the known procedure (Badorc & Frehel, 1989), and obtained as a white polycrystalline powder. Optical rotation [α]_D +53.8° (c<ι> 1.9, CH₃OH).