i ¡¢£i¤¥ PHARMACOPOEIA 7.0 Ambroxol hydrochloride
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AMBROXOL HYDROCHLORIDE
Ambroxoli hydrochloridum
g13H19Br2ClN2O Mr 414.6
[23828-92-4]
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. Ultraviolet and visible absorption spectrophotometry
(2.2.25).
Test solution. Dissolve 20.0 mg in 0.05 M sulfuric acid and
dilute to 100.0 mL with the same acid. Dilute 2.0 mL of the
solution to 10.0 mL with 0.05 M sulfuric acid.
Spectral range: 200-350 nm.
Absorption maxima: at 245 nm and 310 nm.
Absorbance ratio: A245/A310 = 3.2 to 3.4.
B. Infrared absorption spectrophotometry (2.2.24).
Comparison: ambroxol hydrochloride CRS.
C. 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, propanol R, ethyl
acetate R, hexane R (1:10:20:70 V/V/V/V).
Application: 10 L.
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 mg of the substance to be examined
in water R and dilute to 50.0 mL with the same solvent.
Reference solution (a). Dilute 1.0 mL of the test solution
to 100.0 mL with water R. Dilute 1.0 mL of this solution to
10.0 mL with the mobile phase.
Reference solution (b). In order to prepare impurity B in
situ, dissolve 5 mg of the substance to be examined in 0.2 mL
of methanol R, add 0.04 mL of a mixture of 1 volume of
formaldehyde solution R and 99 volumes of water R. Heat
at 60 °C for 5 min. Evaporate to dryness under a current of
nitrogen. Dissolve the residue in 5 mL of water R and dilute to
20.0 mL with the mobile phase.
Column:
— size: l = 0.25 m, Ø = 4.0 mm;
— stationary phase: octadecylsilyl silica gel for
chromatography R (5 m).
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 L.
Run time: 3 times the retention time of ambroxol.
Identification of impurities: use the chromatogram obtained
with reference solution (b) to identify the peak due to impurity B.
Relative retention with reference to ambroxol (retention
time = about 9 min): impurity B = about 0.6.
System suitability: reference solution (b):
— resolution: minimum 4.0 between the peaks due to
impurity B and ambroxol.
Limits:
— unspecified impurities: for each impurity, not more than the
area of the principal peak in the chromatogram obtained
with reference solution (a) (0.10 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: 0.5 times the area of the principal peak
in the chromatogram obtained with reference solution (a)
(0.05 per cent).
Heavy metals (2.4.8): maximum 20 ppm.
1.0 g complies with test C. Prepare the reference solution 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 105 °C.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Dissolve 0.300 g in 70 mL of ethanol (96 per cent) R and add
5 mL of 0.01 M hydrochloric acid. Carry out a potentiometric
titration (2.2.20), using 0.1 M sodium hydroxide. Read
the volume added between the 2 points of inflexion.
1 mL of 0.1 M sodium hydroxide is equivalent to 41.46 mg of
C13H19Br2ClN2O.
STORAGE
Protected from light.
General Notices (1) apply to all monographs and other texts 1365