Ambroxol Hydrochloride

(Ph Eur monograph 1489)

C₁₃H₁₈Br₂N₂O,HCl 414.6 23828-92-4

Ph Eur

Definition

trans-4-[(2-Amino-3,5-dibromobenzyl)amino]cyclohexanol hydrochloride.

Content

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

Characters

Appearance

White or yellowish crystalline powder.

Solubility

Sparingly soluble in water, soluble in methanol, practically insoluble in methylene chloride.

Identification

First identification

B, D.

Second identification

A, C, D.

A.    Dissolve 20.0 mg in 0.05M sulphuric acid and dilute to 100.0 ml with the same acid. Dilute 2.0 ml of the solution to 10.0 ml with 0.05M sulphuric acid. Examined between 200 nm and 350 nm (2.2.25), the solution shows two absorption maxima at 245 nm and 310 nm. The ratio of the absorbance measured at 245 nm to that measured at 310 nm is 3.2 to 3.4.

B.    Infrared absorption spectrophotometry (2.2.24).

Comparison: ambroxol hydrochloride CRS.

C.    Examine by thin-layer chromatography (2.2.27).

Test solution

Dissolve 50 mg of the substance to be examined in methanol  R and dilute to 5 ml with the same solvent.

Reference solution

Dissolve 50 mg of ambroxol hydrochloride CRS in methanol  R and dilute to 5 ml with the same solvent.

Plate

TLC silica gel F₂₅₄ plate R.

Mobile phase

Concentrated ammonia R, 1-propanol  R, ethyl acetate R, hexane R (1:10:20:70 V/V/V/V).

Application

10 ml.

Development

Over 2/3 of the plate.

Drying

In air.

Detection

Examine in ultraviolet light at 254 nm.

Results

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

D.    Dissolve 25 mg in 2.5 ml of water  R, mix with 1.0 ml of dilute ammonia R1 and allow to stand for 5 min. Filter and acidify the filtrate with dilute nitric acid R. The filtrate gives reaction (a) of chlorides (2.3.1).

Tests

Solution S

Dissolve 0.75 g in methanol  R and dilute to 15 ml with the same solvent.

Appearance of solution

Solution S is clear  (2.2.1) and not more intensely coloured than reference solution Y₆ (2.2.2, Method II).

pH (2.2.3)

4.5 to 6.0.

Dissolve 0.2 g in carbon dioxide-free water  R and dilute to 20 ml with the same solvent.

Related substances

Liquid chromatography (2.2.29).

Prepare the solutions immediately before use.

Test solution

Dissolve 50.0 mg of the substance to be examined in water  R and dilute to 50.0 ml with the same solvent.

Reference solution (a)

Dilute 5.0 ml of the test solution to 250.0 ml with water  R. Dilute 1.0 ml of this solution to 20.0 ml with the mobile phase.

Reference solution (b)

Dissolve 5 mg of the substance to be examined in 0.2 ml of methanol  R and add 0.04 ml of a mixture of 1 volume of formaldehyde solution R and 99 volumes of water  R. Heat at 60C for 5 min. Evaporate to dryness under a current of nitrogen. Dissolve the residue in 5 ml of water  R and dilute to 20 ml with the mobile phase.

Column:

size: l = 0.25 m, Ø = 4.0 mm,

stationary phase: octadecylsilyl silica gel for chromatography R (5 mm).

Mobile phase

A mixture of equal volumes of acetonitrile R and a solution prepared as follows: dissolve 1.32 g of ammonium phosphate R in 900 ml of water  R, adjust to pH 7.0 with phosphoric acid R and dilute to 1000 ml with water  R.

Flow rate

1 ml/min.

Detection

Spectrophotometer at 248 nm.

Injection

20 ml.

Sensitivity

Reference solution (a).

Run time

3 times the retention time of the principal peak in the chromatogram obtained with the test solution.

System suitability:

resolution: minimum of 4.0 between the peaks due to impurity B and ambroxol in the chromatogram obtained with reference solution (b).

Limits:

any impurity: not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent),

total: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent),

disregard limit: 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (a).

Heavy metals (2.4.8)

Maximum 20 ppm.

1.0 g complies with limit test C. Prepare the standard using 2 ml of lead standard solution (10 ppm Pb) R.

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 0.300 g in 70 ml of alcohol  R and add 5 ml of 0.01M hydrochloric acid. Carry out a potentiometric titration (2.2.20), using 0.1M sodium hydroxide. Read the volume added between the two points of inflexion.

1 ml of 0.1M sodium hydroxide is equivalent to 41.46 mg of C₁₃H₁₉Br₂ClN₂O.

Storage

Store protected from light.

Impurities

A.    Ar-CH₂OH: (2-amino-3,5-dibromophenyl)methanol,

B.    trans-4-(6,8-dibromo-1,4-dihydroquinazolin-3(2H)-yl)cyclohexanol,

C.    trans-4-[[(E)-2-amino-3,5-dibromobenzyliden]amino]cyclohexanol,

D.    cis-4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol,

E.    Ar-CH=O: 2-amino-3,5-dibromobenzaldehyde.

Ph Eur

Action and use

Expectorant.