Salbutamol

(Ph Eur monograph 0529)

C₁₃H₂₁NO₃ 239.3 18559-94-9

Ph Eur

Definition

(1RS)-2-[(1,1-Dimethylethyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanol.

Content

98.0 per cent to 101.0 per cent (dried substance).

Characters

Appearance

White or almost white, crystalline powder.

Solubility

Sparingly soluble in water, soluble in alcohol.

Mp: about 155C, with decomposition.

Identification

First identification

B.

Second identification

A, C, D.

A.    Dissolve 80.0 mg in a 10 g/l solution of hydrochloric acid R and dilute to 100.0 ml with the same acid. Dilute 10.0 ml of the solution to 100.0 ml with a 10 g/l solution of hydrochloric acid R. Examined between 230 nm and 350 nm (2.2.25), the solution shows an absorption maximum at 276 nm. The specific absorbance at the maximum is 66 to 75.

B.    Infrared absorption spectrophotometry (2.2.24).

Comparison

Salbutamol CRS.

C.    Thin-layer chromatography (2.2.27).

Test solution

Dissolve 10 mg of the substance to be examined in methanol  R and dilute to 50 ml with the same solvent.

Reference solution

Dissolve 10 mg of salbutamol CRS in methanol  R and dilute to 50 ml with the same solvent.

Plate

TLC silica gel plate R.

Mobile phase

Concentrated ammonia R, water  R, ethyl acetate R, 2-propanol  R, methyl isobutyl ketone R (3:18:35:45:50 V/V/V/V/V).

Application

5 ml.

Development

Over a path of 18 cm.

Drying

In air.

Detection

Spray with a 1 g/l solution of methylbenzothiazolone hydrazone hydrochloride R in a 90 per cent V/V solution of methanol  R, followed by a 20 g/l solution of potassium ferricyanide R in a mixture of 1 volume of concentrated ammonia R1 and 3 volumes of water  R, followed by a further spraying with a 1 g/l solution of methylbenzothiazolone hydrazone hydrochloride R in a 90 per cent V/V solution of methanol  R.

Results

The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with the reference solution.

D.    Dissolve about 10 mg in 50 ml of a 20 g/l solution of disodium tetraborate R. Add 1 ml of a 30 g/l solution of aminopyrazolone R, 10 ml of methylene chloride R and 10 ml of a 20 g/l solution of potassium ferricyanide R. Shake and allow to separate. An orange-red colour develops in the methylene chloride layer.

Tests

Solution S

Dissolve 0.50 g in methanol  R and dilute to 25.0 ml with the same solvent.

Appearance of solution

Solution S is clear  (2.2.1) and not more intensely coloured than reference solution BY₅ (2.2.2, Method II).

Optical rotation (2.2.7)

-0.10 to +0.10 determined on solution S.

Related substances

Liquid chromatography (2.2.29).

Test solution

Dissolve 0.100 g of the substance to be examined in the mobile phase and dilute to 50.0 ml with the mobile phase.

Reference solution

Dissolve 2.0 mg of salbutamol CRS, 2.0 mg of salbutamol impurity B CRS, 3.0 mg of salbutamol impurity D CRS, 3.0 mg of salbutamol impurity F CRS, 3.0 mg of salbutamol impurity G CRS and 3.0 mg of salbutamol impurity I CRS in the mobile phase and dilute to 10.0 ml with the mobile phase. Dilute 2.0 ml of the solution to 100.0 ml with the mobile phase.

Column:

size: l = 0.15 m, Ø = 3.9 mm,

stationary phase: spherical end-capped octylsilyl silica gel for chromatography R (5 mm) with a specific surface of 335 m²/g, a pore size of 10 nm and a carbon loading of 11.7 per cent.

Mobile phase

Mix 22 volumes of acetonitrile R and 78 volumes of a solution containing 2.87 g/l of sodium heptanesulphonate R and 2.5 g/l of potassium dihydrogen phosphate R ajusted to pH 3.65 with dilute phosphoric acid R.

Flow rate

1 ml/min.

Detection

Spectrophotometer at 220 nm.

Injection

20 ml.

Run time

25 times the retention time of salbutamol.

Relative retention

With reference to salbutamol (retention time = about 1.9 min): impurity B = about 1.3, impurity A = about 1.7, impurity C = about 2.0, impurity D = about 2.7, impurity H = about 3.0, impurity E = about 3.1, impurity G = about 4.1, impurity F = about 6.2, impurity I = about 23.2.

System suitability

Reference solution:

resolution: minimum of 3.0 between the peaks due to salbutamol and to impurity B.

Limits:

impurity D: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (0.3 per cent),

impurity F: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (0.3 per cent),

impurity G: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (0.3 per cent),

impurity I: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (0.3 per cent),

any other impurity: not more than 1.5 times the area of the peak due to salbutamol in the chromatogram obtained with reference solution (0.3 per cent),

total: maximum 1.0 per cent,

disregard limit: 0.05 per cent.

The following chromatogram is published for information.

Figure 0529.-1. C Chromatogram for the test for related substances

Impurity J

Maximum 0.2 per cent.

Dissolve 50.0 mg in a 1 g/l solution of hydrochloric acid R and dilute to 25.0 ml with the same solvent. The absorbance (2.2.25) of the solution measured at 310 nm is not greater than 0.10.

Boron

Maximum 50 ppm.

Test solution

To 50 mg of the substance to be examined add 5 ml of a solution containing 13 g/l of anhydrous sodium carbonate R and 17 g/l of potassium carbonate R. Evaporate to dryness on a water-bath and dry at 120C. Ignite the residue rapidly until the organic matter has been destroyed, allow to cool and add 0.5 ml of water  R and 3.0 ml of a freshly prepared 1.25 g/l solution of curcumin R in glacial acetic acid R. Warm gently to effect solution, allow to cool and add 3.0 ml of a mixture prepared by adding 5 ml of sulphuric acid R, slowly and with stirring, to 5 ml of glacial acetic acid R. Mix and allow to stand for 30 min. Dilute to 100.0 ml with alcohol  R, filter and use the filtrate.

Reference solution

Dissolve 0.572 g of boric acid R in 1000.0 ml of water  R. Dilute 1.0 ml to 100.0 ml with water  R. To 2.5 ml of the solution add 5 ml of a solution containing 13 g/l of anhydrous sodium carbonate R and 17 g/l of potassium carbonate R, and treat this mixture in the same manner as the test solution.

Measure the absorbance (2.2.25) of the test solution and of the reference solution at the maximum at about 555 nm. The absorbance of the test solution is not greater than that of the reference solution.

Loss on drying (2.2.32)

Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 100-105C.

Sulphated ash (2.4.14)

Maximum 0.1 per cent, determined on 1.0 g.

Assay

Dissolve 0.200 g in 30 ml of anhydrous acetic acid R. Titrate with 0.1M perchloric acid, determining the end-point potentiometrically (2.2.20).

1 ml of 0.1M perchloric acid is equivalent to 23.93 mg of C₁₃H₂₁NO₃.

Storage

Protected from light.

Impurities

A.    R1 = OCH₃, R2 = CH₂OH: [5-[(1RS)-2-[(1,1-dimethylethyl)amino]-1-methoxyethyl]-2-hydroxyphenyl]methanol,

B.    R1 = OH, R2 = H: (1RS)-2-[(1,1-dimethylethyl)amino]-1-(4-hydroxyphenyl)ethanol,

C.    R1 = OH, R2 = CH₃: (1RS)-2-[(1,1-dimethylethyl)amino]-1-(4-hydroxy-3-methylphenyl)ethanol,

D.    R1 = OH, R2 = CHO: 5-[(1RS)-2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzaldehyde,

E.    R1 = H, R2 = OH, R3 = CH₂-C₆H₅: (1RS)-2-[benzyl(1,1-dimethylethyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanol,

G.    R1+R2 = O, R3 = CH₂-C₆H₅: 2-[benzyl(1,1-dimethylethyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone,

J.     R1+R2 = O, R3 = H: 2-[(1,1-dimethylethyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (salbutamone),

F.    1,1¢-[oxybis[methylene(4-hydroxy-1,3-phenylene)]]bis[2-[(1,1-dimethylethyl)amino]ethanol],

H.    R1 = R2 = H: 4-[2-[(1,1-dimethylethyl)amino]ethyl]-2-methylphenol,

I.     R1 = OH, R2 = CH₂-C₆H₅: (1RS)-2-[(1,1-dimethylethyl)amino]-1-[3-(hydroxymethyl)-4-benzyloxyphenyl]ethanol.

Ph Eur

Action and use

Beta-adrenoceptor agonist.

Preparation

Salbutamol Pressurised Inhalation