Trihexyphenidyl hydro­chloride: a powder diffraction study

Elisabetta Maccaroni; Luciana Malpezzi; Norberto Masciocchi

doi:10.1107/S1600536810035294

. 2010 Sep 4;66(Pt 10):o2511. doi: 10.1107/S1600536810035294

Trihexyphenidyl hydrochloride: a powder diffraction study

Elisabetta Maccaroni ^a,^*, Luciana Malpezzi ^a, Norberto Masciocchi ^b

PMCID: PMC2983296 PMID: 21587506

Abstract

In the cation of the title compound [systematic name: 1-(3-cyclohexyl-3-hydroxy-3-phenylpropyl)piperidinium chloride], C₂₀H₃₂NO⁺·Cl⁻, the cyclohexyl and piperidine rings are in chair conformations. In the crystal structure, cations and anions are linked into chains along the c-axis direction via O—H⋯Cl and N—H⋯Cl hydrogen bonds. Weak intermolecular C—H⋯Cl interactions link further these chains into layers parallel to the bc plane. The salt, obtained from a racemic solution, was found to crystallize in the chiral P2₁2₁2 space group, indicating that, in the absence of any evident chirality-inducing process, the polycrystalline powders consist of an equivalent mixture of R and S enantiomers, forming a racemic conglomerate.

Related literature

For characterization of related structures, see Camerman & Camerman (1971a ▶, 1972a ▶); Codding (1986 ▶); Marubayashi et al. (1999 ▶). For structure–activity relationships, see Camerman & Camerman (1970 ▶, 1971a ▶,b ▶, 1972a ▶,b ▶, 1981 ▶). For the profile function, see: Cheary & Coelho (1992 ▶) and for the March–Dollase orientation correction, see: Dollase (1986 ▶).

Experimental

Crystal data

C₂₀H₃₂NO⁺·Cl⁻
M _r = 337.93
Orthorhombic,
a = 30.0265 (8) Å
b = 11.2297 (4) Å
c = 5.8931 (2) Å
V = 1987.08 (12) Å³
Z = 4
Cu Kα radiation, λ = 1.540562, 1.544390 Å
T = 298 K
Flat sheet, 15 × 20 mm

Data collection

Bruker D8 Advance diffractometer
Specimen mounting: packed powder
Data collection mode: reflection
Scan method: step
2θ_min = 5°, 2θ_max = 104.86°, 2θ_step = 0.02°

Refinement

R _p = 0.051
R _wp = 0.075
R _exp = 0.008
R _Bragg = 0.023
χ² = 91.317
4994 data points
100 parameters
46 restraints
H-atom parameters constrained

Data collection: D8 Software (Bruker, 2005 ▶); cell refinement: TOPAS-R (Coelho, 2005 ▶); data reduction: TOPAS-R; program(s) used to solve structure: TOPAS-R; program(s) used to refine structure: TOPAS-R; molecular graphics: SHELXTL/NT (Sheldrick, 2008 ▶); software used to prepare material for publication: enCIFer (Allen et al., 2004 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810035294/cv2721sup1.cif

e-66-o2511-sup1.cif^{(22.7KB, cif)}

Rietveld powder data: contains datablocks I. DOI: 10.1107/S1600536810035294/cv2721Isup2.rtv

e-66-o2511-Isup2.rtv^{(175.6KB, 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
N1—H1⋯Clⁱ	0.91	2.25	3.141 (13)	166
O1—H2⋯Cl	0.88	2.11	2.986 (13)	173
C20—H20B⋯Cl	0.97	2.76	3.623 (12)	149

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Symmetry code: (i) Inline graphic .

supplementary crystallographic information

Comment

The title compound, THPD-HCl (THPD = trihexyphenidyl) (1), crystallizes in the non-centrosymmetric space group P2₁2₁2, thus powders of 1 are formed by an equivalent mixture of enantiomorphic crystals in a racemic conglomerate. 1 consists of an ionic packing of N-protonated cations and chloride anions. The organic cation is formed by a phenyl and a cyclohexyl groups connected to the asymmetric carbon atom (C3) which is further linked to an hydroxyl group and to a protonated N-ethyl piperidine moiety (see Fig. 1). Trihexyphenidyl hydrochloride (1), is a salt used in the treatment of all forms of Parkinson's disease. Trihexyphenidyl and other pharmacological agents of the same class, such as procyclidine hydrochloride and biperiden, were completely characterized by single-crystal X-ray analyses (Camerman & Camerman, 1971a, 1972a; Codding, 1986; Marubayashi et al., 1999), which showed some common stereochemical features which were correlated to their common pharmacological activity. The presence of the electron donating OH group and of the heterocyclic nitrogen has been considered as the typical stereochemical feature of these compounds.The distance between the two groups is 4.00 Å, 2.76 Å and 3.55 Å for 1, THPD, biperiden and procyclidine hydrochloride, in sequence. The shorter N—O distance observed in THPD allows the formation of intramolecular hydrogen bonds O—H···N. At variance, 1 and procyclidine hydrochloride form intermolecular hydrogen bonds through chloride anions. In the crystal, the NH group is pointing away from the direction of the OH group, allowing the formation of molecular chains running along the c axis, through intermolecular O—H···Cl and N—H···Cl hydrogen bonds (Table 1). Moreover, weaker C—H···Cl interactions (Table 1) link the chains in a three-dimensional network.

Experimental

Samples of the racemic mixture of the title compound were kindly provided by Dr. C. Pellegatta (Solmag, Divisione di Fidia Farmaceutici S.p.A., Garbagnate Milanese, Italy)