Journal of Crystallography

Journal of Crystallography / 2013 / Article

Research Article | Open Access

Volume 2013 |Article ID 249672 |

Noriaki Hirayama, "Crystal Structure of Apraclonidine Hydrochloride", Journal of Crystallography, vol. 2013, Article ID 249672, 3 pages, 2013.

Crystal Structure of Apraclonidine Hydrochloride

Academic Editor: P. M. Matias
Received12 May 2013
Accepted05 Sep 2013
Published23 Oct 2013


Apraclonidine is used for the treatment of postsurgical elevated intraocular pressure. The crystal structure of its hydrochloride, C9H10Cl2N4·HCl, was determined by X-ray analysis. The crystal belongs to space group with the cell dimensions , ,  Å, and °. The final (all reflections) value is 0.053. Apraclonidine has a more twisted structure than its related drug of clonidine. The nitrogen atom bridging the two rings is protonated.

1. Introduction

Apraclonidine (2,6-dichloro-N1-(4,5-dihydro-1H-imidazol-2-yl)-1,4-benzenediamine) is a potent α-adrenergic agent similar to clonidine. The chemical structures of apraclonidine hydrochloride and clonidine are compared in Figure 1. Apraclonidine reduces aqueous humor formation. In clinical evaluation in the treatment of intraocular pressure, Robin et al. have showed that apraclonidine is effective in preventing the acute large postoperative intraocular pressure rise associated with argon laser iridotomy [1]. Apraclonidine is now used widely for the treatment of postsurgical elevated intraocular pressure. The additional amino group in apraclonidine makes it more polar than clonidine and reduces the penetration through the blood-brain barrier. Therefore, the pharmacological profile of apraclonidine is characterized by peripheral than central effects. Apraclonidine hydrochloride is clinically used now, but the crystal structure has not been determined yet. Therefore, the X-ray analysis of this drug was undertaken to disclose the inherent three-dimensional structure.

2. Method

Apraclonidine hydrochloride was purchased from Sigma-Aldrich Co. The single crystals of the compound were grown from a methanol solution. A colorless platelet crystal with the size of 0.35 × 0.30 × 0.15 mm was mounted on a glass fiber and used for data collection. The structure was solved by direct methods, and non-H atoms were refined by a full-matrix least squares method with anisotropic temperature factors. Positions of H-atoms attached to carbon and nitrogen atoms were geometrically calculated and located from difference Fourier synthesis, respectively. All H-atoms were refined by the riding model. The crystal and experimental data are given in Table 1.

Formula: C9H10Cl2N4·HClFormula weight = 281.57
Crystal system: monoclinicSpace group:
210.2(2)   g/cm3
No. of observations with Cu Kα
Measurement: Rigaku RAXIS-RAPIDProgram system: CrystalStructure 4.0.1 [5]
Structure determination: SIR92 [6]Refinement: full-matrix

3. Results and Discussion

An ORTEP drawing [2] of apraclonidine hydrochloride is shown in Figure 2. Selected bond lengths, bond angles, torsion angles, and possible hydrogen bonds in the crystal structure are given in Table 2. Bond lengths and angles are within the expected ranges. The dihedral angle between the least squares planes of the phenyl and imidazolidine rings is 86.65(5)°. In clonidine hydrochloride [3], the angle is 74.7°. The C1–N1–C7–N3 torsion angle in apraclonidine is 168.2(1)° and the corresponding angle in clonidine 178°. It means that in apraclonidine the imidazolidine ring is more twisted around the N1–C1 bond than that in clonidine. The exocyclic bond angles around the C7 atom are slightly asymmetrical with the N1–C7–N3 and N1–C7–N4 angles being 122.8(1) and 125.6(1)°, respectively. There are five intermolecular hydrogen bonds in the crystal as illustrated in Figure 3 drawn by Mercury [4]. All nitrogen atoms are engaged in hydrogen bonds with the chloride ion. Although the intermolecular distance between the N2 and Cl1[ ] atoms is 3.132(1) Å, no significant electron density corresponding to the hydrogen atom was observed between the two atoms on the difference Fourier map. On the other hand, two electron density peaks corresponding to the H2 and H3 atoms which are bonded to the N2 atom were located from the difference map. The relevant geometrical parameters shown in Table 2 indicate that these two N2Cl3 contacts should be regarded as weak hydrogen bonds. The N3Cl3 hydrogen bond is also regarded as a rather weak hydrogen. In clonidine, however, N3 is not engaged in hydrogen bonding. Moreover, the N1 atom in clonidine forms a stronger hydrogen bond with the chloride ion with the NCl distance being 3.09 Å. The corresponding hydrogen bond in apraclonidine, however, is not so strong with the NCl distance of 3.226(1) Å.

(a) Selected bond lengths (Å), bond angles (°) and torsion angles (°)


C7–N4–C9 111.0(1)
Cl2–C6–C5 118.08(8)
C1–N1–C7 122.8(1)
N1–C7–N4 125.6(1)
N2–C4–C3 121.6(1)
N3–C7–N4 111.6(1)
N4–C9–C8 102.9(1)

N1–C1–C2–Cl1 2.1(2)
C7–N1–C1–C6 96.2(1)
C1–N1–C7–N4 −12.2(2)

(b) Possible hydrogen bonds

Donor   HAcceptorDA (Å)D–H (Å)HA (Å) D–HA (°)

N1H5Cl3[I] 3.226(1)0.902.38157
N2 H2 Cl3[II] 3.418(1) 0.80 2.65162
N2 H3 Cl3[III]3.400(2) 0.942.52156
N3 H7 Cl3[I] 3.338(1) 0.79 2.67144

Symmetry operators:
[I] , , .
[II] , , .
[III] , , .

The Crystallographic Information Files (CIF) are given as Supplementary Material available online at

4. Concluding Remarks

The molecular and crystal structures of apraclonidine hydrochloride were determined by X-ray analysis. Apraclonidine has a more twisted structure than its related drug of clonidine. The significant different patterns of the intermolecular hydrogen bonds observed in the crystals of apraclonidine hydrochloride and clonidine hydrochloride may contribute to their different drug deliveries. The crystallographic data presented in this work should be useful for designing new potent α-adrenergic agents.


The technical assistance of Mrs. Tomoko Kawamura is gratefully acknowledged. This work was supported by Grants for the Key Technology Research Promotion Program of New Energy and Industrial Technology Development Organization (NEDO) of Japan and also by the Research and Study Program of Tokai University Educational System General Research Organization.

Supplementary Materials

The Crystallographic Information Files (CIF) (crystal data, atomic parameters and structure factors).

  1. Supplementary Material


  1. A. L. Robin, I. P. Pollack, and J. M. deFaller, “Effects of topical ALO 2145 (p-aminoclonidine hydrochloride) on the acute intraocular pressure rise after argon laser iridotomy,” Archives of Ophthalmology, vol. 105, no. 9, pp. 1208–1211, 1987. View at: Google Scholar
  2. M. N. Burnett and C. K. Johnson, “ORTEPIII,” Report ORNL-6895, Oak Ridge National Laboratory, Oak Ridge, Tenn, USA, 1996. View at: Google Scholar
  3. G. Byre, A. Mostad, and C. Romming, “Crystal and molecular structure of clonidine hydrochloride, 2(2,6 dichlorophenylamino) 2 imidazoline hydrochloride,” Acta Chemica Scandinavica, vol. 30, no. 9, pp. 843–846, 1976. View at: Google Scholar
  4. Mercury CSD 3.1 and Cambridge Crystallographic Data Centre, 2013,
  5. CrystalStructure, Version 4.0.1, Crystal Structure Analysis Package, Rigaku and Rigaku/MSC, 2010.
  6. A. Altomare, G. Cascarano, C. Giacovazzo et al., “SIR92—a program for automatic solution of crystal structures by direct methods,” Journal of Applied Crystallography, vol. 27, no. 3, pp. 435–436, 1994. View at: Google Scholar

Copyright © 2013 Noriaki Hirayama. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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