Cinnarizine

Comprehensive Profile

Nadia G. Haress1    Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
1 Corresponding author: email address: nharess@ksu.edu.sa, nadiaharess@hotmail.com

Abstract

Cinnarizine is a piperazine derivative with antihistaminic, antiserotonergic, antidopaminergic, and calcium channel-blocking activities. A comprehensive profile was performed on cinnarizine including its description and the different methods of analysis. The 1H NMR and 13C one- and two-dimensional NMR methods were used. In addition, infrared and mass spectral analyses were performed which all confirmed the structure of cinnarizine.

Keywords

Cinnarizine

Antihistaminic

Spectroscopy

Metabolism

Pharmacokinetics

Pharmacology

1 Description

1.1 Nomenclature

1.1.1 Systemic Chemical Names

- 1-(Diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine

- 1-Cinnamyl-4-diphenylmethylpiperazine

- N-Benzhydryl-N-trans-cinnamylpiperazine

- 1-trans-Cinnamyl-4-diphenylmethylpiperazine

- 1-Cinnamyl-4-benzhydrylpiperazine

- 1-Diphenylmethyl-4-trans-cinnamylpiperazine [1-4]

1.1.2 Nonproprietary Names

Cinnarizine, cinnarizin [1-4]

1.1.3 Proprietary Names

1.1.3.1 Cinnarizine

Cinniprine®, 516-MD®, Aplactan®, Aplexal®, Apotomin®, Artate®, Carecin®, Cerebolan®, Cerepar®, Cinnaperazine®, Cinazyn®, Cinnacet®, Cinnageron®, Corathiem®, Denapol®, Dimitron®, Eglen®, Folcodal®, Giganten®, Glanil®, Hilactan®, Ixertol®, Katoseran®, Labyrin®, Midronal®, Mitronal®, Olamin®, Processine®, Sedatromin®, Sepan®, Siptazin®, Spaderizine®, Stugeron®, Stutgin®, Toliman® [1-4].

1.1.3.2 Cinnarizine Hydrochloride

Linazine®, Siarizine®, Silicin®, Sorebral®.

1.1.3.3 Mixture with Vitamin B6

Emasazine®, C-Sik®

1.2 Formulae

1.2.1 Empirical Formula, Molecular Weight, and CAS Number

1.2.2 Structural Formulae

1.3 Elemental Analysis

1.4 Appearance

Cinnarizine is a white or almost white powder [1-3].

1.5 Uses and Applications

Cinnarizine is a piperazine derivative with antihistaminic, antiserotonergic, antidopaminergic, and calcium channel-blocking activities. It is currently used for the treatment of nausea, vomiting, and vertigo caused by Meniere's disease and other vestibular disorders. Cinnarizine is also used for prevention and treatment of motion sickness. It is also widely used for the treatment of cerebral thrombosis, cerebral embolism, cerebral arteriosclerosis, and diseases caused by poor peripheral circulation [3]. It is also reported that cinnarizine is effective in the treatment of some allergic diseases, such as chronic urticaria and senile skin pruritus [3].

Cinnarizine is given orally as tablets or capsules which may result in a very slow bioavailability and a wide individual variation [3,4].

Intravenous cinnarizine administration is an alternative to oral administration which provides greater bioavailability, faster therapeutic effect, and lower individual difference than oral dosing. However, any injectable dosage forms can cause pain at the injection site, venous irritation, and possible precipitation of the drug after intravenous administration resulting in restriction of their clinical applications and industrial-scale production [3,4].

2 Methods of Preparation

Cinnarizine was prepared by Janssen Pharmaceutical Companies [5] by two methods. The first one was achieved by reacting 1-trans-cinnamylpiperazine with benzhydryl chloride in an alkaline medium (Scheme 1), while the other method was performed by the addition of cinnamyl chloride to 1-benzylpiperazine in the presence of sodium carbonate (Scheme 2).

Cinnarizine was also prepared by the reaction of piperazine with benzhydryl chloride, followed by N-alkylation with cinnamyl bromide or chloride (Scheme 3) [6].

In addition, Sheng et al. [7] reported a convenient synthesis of cinnarizine by Mannich reaction of 1-benzhydrylpiperazine with HCHO and PhCOMe, followed by the reduction of the resultant propiophenone derivative and subsequent dehydration of the alcohol to afford cinnarizine in quantitative yield.

3 Physical Characteristics

3.1 Ionization Constant

pKa = 7.8

Log ? = 6.14 [8]

3.2 Solubility Characteristics

Cinnarizine: Practically insoluble in water. Slightly soluble in ethanol (96%) and methanol. Soluble in acetone and freely soluble in dichloromethane. Protect from light [1-3].

Cinnarizine hydrochloride: Soluble 2 mg/100 mL in water [1-3].

3.3 X-Ray Powder Diffraction Pattern

The X-ray powder diffraction pattern of cinnarizine was performed using a Bruker-Nonius FR590 diffractometer. Figure 1 shows the X-ray powder diffraction pattern of cinnarizine, which was obtained on a pure sample of the drug substance. Table 1 shows the values for the scattering angles (deg, 2?), the interplanar d-spacing (Å), and the relative intensities (%) observed for the major diffraction peaks of cinnarizine.

Table 1

The X-Ray Powder Diffraction Pattern of...