Chapter Two - Clenbuterol Hydrochloride

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Abstract

Clenbuterol (Broncodil and trade) is a direct-acting sympathomimetic agent with mainly beta-adrenergic activity and a selective action on β2 receptors (a β2 agonist). It has properties similar to those of salbutamol. It is used as a bronchodilator in the management of reversible airways obstruction, as in asthma and in certain patients with chronic obstructive pulmonary disease. The uses, applications, and the synthetic pathways of this drug are outlined. Physical characteristics including: ionization constant, solubility, X-ray powder diffraction pattern, thermal methods of analysis, UV spectrum, IR spectrum, mass spectrum are all produced. This profile also includes the monograph of British Pharmacopoeia, together with several reported analytical methods including spectrophotometric, electrochemical, chromatographic, immunochemical methods, and capillary electrophoretic methods. The stability, the pharmacokinetic behavior, and the pharmacology of the drug are also provided

Section snippets

Systemic Chemical Names

1-(4-Amino-3,5-dichlorophenyl)-2-tert-butylaminoethanol hydrochloride; 4-amino-3,5-dichloro-α-[[(1,1-dimethylethyl)-amino]methyl]benzenemethanol hydrochloride; and 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride [1].

Nonproprietary Names

Clenbuterol hydrochloride [1], [2], [3].

Proprietary Names

Broncodil; Clenasma; Contrasmina; Contraspasmin; Monores; Prontovent; Spiropent; Ventolase; Ventipulmin [4].

Empirical Formula, Molecular Weight, and CAS Number [4]

Empirical FormulaMolecular WeightCAS Number
C12H18Cl2N2O277.237148-27-9
C12H18Cl2N2O·HCl313.6521898-19-1

Structural Formula for Clenbuterol Hydrochloride (Fig. 1)

Methods of Preparation

By bromination of 4-amino-3,5-dichloroacetophenone (I) with Br2 in CHCl3 to give 4-amino-3,5-dichloro-alpha-bromoacetophenone (II), m.p. 140–145°C, which is condensed with tert-butylamine (III) in CHCl3 to 4-amino-3,5-dichloro-alpha-tert-butylaminoacetophenone hydrochloride (IV), m.p. 252–257°C, this product is finally reduced with NaBH4 in methanol (Scheme 1) [5].

Clenbuterol has also been synthesized from p-aminoacetophenone through benzene ring chlorination using polymer Lewis acid PVC–FeCl3

Ionization Constant

pKa: 5–7 [2].

Solubility Characteristics

Very soluble in water, methanol, and ethanol; slightly soluble in chloroform; and insoluble in benzene [4].

X-Ray Powder Diffraction Pattern

Toro et al. [7] presented a structural characterization of a new form of clenbuterol, the well-known decongestant and bronchodilator which is also used as a performance-enhancing drug.

In the PDF-4/Orgs. 2012 database, there are six entries related to this compound: three for its hydrochloride salt calculated using single-crystal data, two for a methanol and a dimethyl

British Pharmacopeia [10]

Identification

  1. A.

    Infrared absorption spectrophotometry.

    Comparison with clenbuterol hydrochloride CRS; the spectrum of the sample must be equivalent to that of the Standard.

  2. B.

    Thin-layer chromatography

    • 1.

      Test solution: Dissolve 10 mg of the substance to be examined in 10 mL of methanol R.

    • 2.

      Reference solution: Dissolve 10 mg of clenbuterol hydrochloride CRS in 10 mL of methanol R.

      • •

        Plate: TLC silica gel F254 plate R.

      • •

        Mobile phase: ammonia R, anhydrous ethanol R, toluene R (0.15:10:15, v/v/v).

      • •

        Application: 10 μL.

      • •

        Development is

Stability

Signoretti et al. [57] used DSC to study the physicochemical compatibility between this drug and various excipients commonly used in manufacturing of tablets in order to improve the formulation of clenbuterol. Using this method, clenbuterol was found to be compatible with talc, stearic acid, magnesium stearate, and titanium dioxide. An incompatibility was demonstrated with maize starch, pregelatinized starch, sodium starch glycolate, polyvinylpyrrolidone, Avicel PH101, and lactose.

Martin et al.

Pharmacokinetics

Yamamoto et al. [59] reported the pharmacokinetics of clenbuterol therapeutic doses (20, 40, and 80 μg/man) by the oral administration of clenbuterol hydrochloride to healthy volunteers, where the unmetabolized drug in plasma and urine was determined by EIA. The plasma levels of clenbuterol reached maximum values of 0.1, 0.2, and 0.35 ng/mL, respectively, in a dose-dependent manner within 2.5 h, which lasted for over 6 h after administration. The half-life of clenbuterol in plasma was estimated to

Pharmacology

The most important action of clenbuterol and other β2-agonists in the lung is relaxation of airway smooth muscle. For this reason, such drugs are widely used for relief of bronchospasm in human asthma and similar diseases in animals. When these drugs bind to β2-adrenoceptors, they activate adenylyl cyclase, which leads to an increase in the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA). In the tracheobronchial

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