Salbutamol

Absorption

Inhalation delivers the medication directly into the airways and lungs, thereby minimizing side effects because of reduced systemic absorption of the inhaled medications.

Description

Levalbuterol was launched in the US for the treatment or prevention of bronchospasm in patients with reversible obstructive airway disease. It is the single R-enantiomer version of racemic albuterol (salbutamol) marketed for more than 30 years as a mainstay in the treatment of asthma. The R-isomer can be obtained with an excellent optical purity by enantiomeric purification based on the separation of diastereomeric tartrates. This isomer retains solely the desired bronchodilating effect of the racemic mixture due to a potent agonistic effect on β2-adrenoceptors, with a lower incidence of β- mediated side effects such as pulse rate increase, tremor and decrease in blood glucose and potassium levels. A pivotal clinical trial with two doses of levalbuterol and racemic albuterol, given by nebulization, demonstrated a greater improvement in lung function for the pure enantiomer levalbuterol.

Originator

Sepracor (US)

The Uses of Salbutamol

Salbutamol is the β2-agonist used most commonly for the prevention and treatment of bronchospasm. I t is most commonly administered in its inhaled form by metered-dose inhaler (1–2 puffs of 100μg each) or via nebuliser in more severe cases of bronchospasm (2.5–5mg). In patients with lifethreatening asthma it may be administered i.v. as both a bolus (250μg) and infusion (3–20μgmin –1). Intravenous administration requires cardiac monitoring as tachyarrhythmias may be significant. Salbutamol may also be used in the management of hyperkalaemia, temporarily driving K+ intracellularly via stimulation of the Na+–K+ ATPase pump.

The Uses of Salbutamol

(R)-Salbutamol is used in composition and methods to reduce beta-agonist-mediated tachyphylaxis.

Definition

ChEBI: (R)-salbutamol is an albuterol.

Background

Levosalbutamol, or levalbuterol, is a short-acting β2 adrenergic receptor agonist used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Salbutamol has been marketed as a racemic mixture, although beta2-agonist activity resides almost exclusively in the (R)-enantiomer. The enantioselective disposition of salbutamol and the possibility that (S)-salbutamol has adverse effects have led to the development of an enantiomerically pure (R)-salbutamol formulation known as levosalbutamol (levalbuterol).

Indications

Indicated for the management of COPD (chronic obstructive pulmonary disease, also known as chronic obstructive lung disease) and asthma.

Manufacturing Process

Preparation of 5-glyoxyloyl-salicylic acid methyl ester hydrate using aqueous HBr
To a 3-neck flask immersed in an oil bath containing a solution of 40 g (0.206 mole) methyl 5-acetylsalicylate in 6 ml methylene chloride is charged with 82 ml of isopropanol. The solution is distilled to remove excess methylene chloride. When the internal temperature reaches 77°C, 126 ml (1.77 mole or 8.6 equivalents) of DMSO is added to the reaction mixture and the temperature of the mixture is increased to a temperature of 85° to 90°C. Then 33 ml (0.29 mole or 1.4 equivalents) of HBr (aqueous, 48%) is added to the mixture over a period of 20 minutes (exothermic), and the bath temperature is maintained at 95° to 100°C. As the addition of HBr nears completion distillation is initiated and dimethysulfide and isopropanol are distilled off. The mixture is stirred and the volume of the distillate monitored. After distillation of 82 ml of solvent, 20 ml of isopropanol is added slowly to maintain a steady rate of distillation. After the reaction completed asdetermined by high performance liquid chromatography (HPLC), the reaction mixture is quenched with 70 ml of 2.4 N H2SO4, the temperature of the reaction mixture is allowed to drop to 75°C and residual isopropanol is distilled off under vacuum. After a total of 165 ml distillate is collected, the title compound begins to precipitate. A mixture of 30 ml of acetonitrile and 70 ml of water is added slowly at 75°C with stirring. After 30 minutes of stirring, the reaction mixture is cooled to 15°C over a period of 90 minutes to complete the precipitation. The reaction mixture is filtered and the cake is washed with three 300 ml portions of water. The cake is dried in a draft oven at 50°C for 16 hours to give 39.5 g of the title compound (85% yield).
Preparation of albuterol from 5-glyoxyloyl-salicylic acid methyl ester
To a solution of 5-glyoxyloylsalicylic acid methyl ester hydrate (50 g, 0.221 mol) in ethylene glycol diethyl ether, 440 mL is added tertiary butylamine (16.2 g, 0.221 mol) at room temperature. The resulting light orange solution is stirred for 5 min until a clear solution is formed. The clear solution is then heated to reflux. Water and DME are distilled off azeotropically. After a total of 200 ml of distillate are collected, the solution is cooled to 25°C. The reaction mixture is slowly added to a solution containing 49 mL (0.49 mol) of 10.0 M borane-dimethyl sulfide in 220 mL of ethylene glycol diethyl ether (DME) at 70°C. The resulting reaction mixture is further refluxed for 2.5 hrs. After the reaction is completed as monitored by HPLC, excess DME is removed via vacuum distillation. The residue containing complexes of boron and arylethanolamine is subsequently cooled to 0°C. Quenching of the residue with 300 mL methanol gives the methylborate of arylethanolamine. The borate is then removed by azeotropic distillation as trimethylborate, leaving behind the desired arylethanolamine in the reaction mixture. An additional 300 ml of methanol and acetic acid (85 mL) are added to ensure the complete removal of trimethylborate via vacuum distillation to near dryness. The residue containing the boron-free arylethanolamine is cooled to 25°C and concentrated sulfuric acid (10.4 g, 0.221 mole) in water (64 mL) is added following by 570 ml of isopropyl alcohol. Albuterol sulfate is precipitated out as a white solid. After the reaction mixture is stirred at room temperature for 12 hrs and 0°C for 30 min the albuterol sulfate is filtered, washed with isopropyl alcohol (two 50 mL portions) and dried at 50°C for 12 hrs to give 49.75 g of the title compound (78% yield) as racemate.
The optically pure albuterol may be prepared by resolving a mixture of enantiomers methyl benzoate albuterol precursors which prepared by procedures well known to persons skilled in the art. The starting material 4- benzyl albuterol is commercially available from Cipla (Bombay, India).
(-)-D-Dibenzoyltartaric acid (D-DBTA) (32.2 g, 90 mmol, 1.0 eq) is added to a hot solution of racemic 4-benzyl albuterol (29.6 g, 90 mmol, 1.0 eq) in 180 mL of anhydrous denatured ethanol (type 3A, denatured with 5 vol % 2- propanol). The resulting solution is refluxed for 15 min and cooled to room temperature over 40 min and seeded with 99% ee (R)-4-benzyl albuterol DDBTA salt. The mixture is cooled to 5°-10°C and stirred for 1 hour. The white solid is collected by filtration and dried at 40°C and 28 inches of Hg for 1 hour to give (R)-4-benzyl albuterol D-DBTA salt (31.8 g, 50% yield, 83.6% ee). The solid is redissolved in 240 mL of ethanol at 55°-60°C and the solution is cooled to room temperature and stirred at room temperature for 2 hours and at 0°-5°C for 1 hour. The resulting solid is collected by filtration and dried at40°C and 28 inches of Hg for 2 hours as (R)-4-benzyl albuterol D-DBTA salt (22.9 g, 37.1% yield, 99.3% ee). The salt (22.9 g) is then treated with 204 mL of 5 wt % aq. Na2CO3 solution in 570 mL of ethyl acetate. The solid is worked-up, and recrystallization from 30 mL of ethyl acetate and 30 mL of nheptane gives optically pure (R)-4-benzyl albuterol free base as a white powder (10.1 g, 34.1% yield from racemic compound 99.6% ee and 99.8% purity).
A mixture of (R)-4-benzyl albuterol as a free base (3.2 g, 9.73 mmol) and 10% Pd/C (0.64 g) in 24 mL of ethanol (denatured with 5 vol % 2-propanol) is shaken on a Parr-hydrogenator under 50 psi of hydrogen at room temperature for 3 hours. The catalyst is removed by filtration and the filtrate is concentrated to ca. 9 mL in volume containing crude (R)-albuterol and treated with anhydrous HCl in ether (1.0 M, 9.5 mL, 0.98 eq) at 0°-5°C. After 30 min at room temperature, 9 mL of methyl t-butyl ether (MTBE) is added, the resulting mixture is stirred at room temperature for 30 min and at 0°-5°C for 2 hours. The white solid (R)-albuterol hydrochloride is collected by filtration and recrystallized from 25 mL of ethanol and 12.5 mL of MTBE to give pure (R)-albuterol hydrochloride (2.17 g, 80.9% yield, 99.6% purity), white powder.

brand name

Xopenex

Therapeutic Function

Bronchodilator

Pharmacokinetics

It acts by relaxing smooth muscle in the bronchial tubes to increase air flow and relieve acute shortness of breath.

Clinical Use

Beta2 -adrenoceptor agonist:
Reversible airways disease

Drug interactions

Potentially hazardous interactions with other drugs
Increased risk of hypokalaemia when diuretics, theophylline or large doses of corticosteroids are given with high doses of salbutamol.
Antihypertensives: acute hypotension with IV infusion of salbutamol and methyldopa.

Metabolism

Salbutamol is subject to first-pass metabolism in the liver and possibly in the gut wall but does not appear to be metabolised in the lung; the main metabolite is the inactive sulphate conjugate.
Salbutamol is rapidly excreted, mainly in the urine, as metabolites and unchanged drug; a smaller proportion is excreted in the faeces.

Metabolism

Pure (R)-salbutamol formulation known as levosalbutamol is metabolised up to 12 times faster than (S)-salbutamol by intestine.