(Ph. Eur. monograph 1072)
C18H30ClNO3 343.9 63659-19-8
Action and use
Beta-adrenoceptor antagonist.
Preparations
Betaxolol Eye Drops, Solution
Betaxolol Eye Drops, Suspension
DEFINITION
(2RS)-1-[4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]-3-[(1-methylethyl)amino]propan-2-ol hydrochloride.
Content
98.5 per cent to 101.5 per cent (dried substance).
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Very soluble in water, freely soluble in ethanol (96 per cent), soluble in methylene chloride.
IDENTIFICATION
First identification: B, D.
Second identification: A, C, D.
A. Melting point (2.2.14): 113 °C to 117 °C.
B. Infrared absorption spectrophotometry (2.2.24).
Comparison betaxolol hydrochloride CRS.
C. Thin-layer chromatography (2.2.27).
Test solution: Dissolve 10 mg of the substance to be examined in 1 mL of methanol R.
Reference solution (a): Dissolve 20 mg of betaxolol hydrochloride CRS in 2 mL of methanol R.
Reference solution (b): Dissolve 10 mg of oxprenolol hydrochloride CRS in 1 mL of reference solution (a).
Plate: TLC octadecylsilyl silica gel F254 plate R.
Mobile phase: perchloric acid R, methanol R, water R (0.5:50:50 V/V/V).
Application: 2 μL.
Development: Over a path of 10 cm.
Drying: In air.
System suitability: Reference solution (b):
— the chromatogram shows 2 clearly separated spots.
Detection A: Examine in ultraviolet light at 254 nm.
Results A: 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 reference solution (a).
Detection B: Spray with a 50 g/L solution of vanillin R in a mixture of 5 volumes of sulfuric acid R, 10 volumes of glacial acetic acid R and 85 volumes of methanol R, heat at 100-105 °C until the colour of the spots reaches maximum intensity (10-15 min), and examine in daylight.
Results B: 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 reference solution (a).
D. It gives reaction (a) of chlorides (2.3.1).
TESTS
Appearance of solution
The solution is clear (2.2.1) and colourless (2.2.2, Method II).
Dissolve 0.5 g in water R and dilute to 25 mL with the same solvent.
Acidity or alkalinity
Dissolve 0.20 g in carbon dioxide-free water R and dilute to 20 mL with the same solvent. Add 0.2 mL of methyl red solution R and 0.2 mL of 0.01 M hydrochloric acid. The solution is red. Add 0.4 mL of 0.01 M sodium hydroxide. The solution is yellow.
Related substances: Liquid chromatography (2.2.29). Prepare reference solutions (c) and (d) immediately before use.
Test solution: Dissolve 10 mg of the substance to be examined in the mobile phase and dilute to 5.0 mL with the mobile phase.
Reference solution (a): Dissolve 8 mg of the substance to be examined and 4 mg of betaxolol impurity A CRS in 20.0 mL of the mobile phase.
Reference solution (b): Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase.
Reference solution (c): Dissolve 2 mg of betaxolol impurity C CRS in 50 mL of the mobile phase. Dilute 5 mL of the solution to 20 mL with the mobile phase.
Reference solution (d): Dissolve 10 mg of betaxolol for peak identification CRS (containing impurities B, D and E) in 5 m of reference solution (c).
Column:
— size: l = 0.25 m, Ø = 4 mm;
— stationary phase: octylsilyl silica gel for chromatography R (5 μm).
Mobile phase: Mix 175 mL of acetonitrile R and 175 mL of methanol R and dilute to 1 L with a 3.4 g/L solution of potassium dihydrogen phosphate R, previously adjusted to pH 3.0 with phosphoric acid R.
Flow rate: 1.5 mL/min.
Detection: Spectrophotometer at 273 nm.
Injection: 20 μL of the test solution and reference solutions (a), (b) and (d).
Run time: 4.5 the retention time of betaxolol.
Identification of impurities: Use the chromatogram obtained with reference solution (a) to identify the peak due to impurity A; use the chromatogram supplied with betaxolol for peak identification CRS and the chromatogram obtained with reference solution (d) to identify the peaks due to impurities B, C, D and E.
Relative retention: With reference to betaxolol (retention time = about 8 min): impurity B = about 0.3; impurity A = about 0.8; impurity D = about 1.5; impurity E = about 2.2; impurity C = about 4.1.
System suitability: Reference solution (a):
— resolution: minimum 2.0 between the peaks due to impurity A and betaxolol.
Limits:
— impurities A, B, C, D, E: for each impurity, not more than 0.3 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.3 per cent);
— unspecified impurities: for each impurity, not more than 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);
— total: not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 per cent);
— disregard limit: 0.05 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).
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 a mixture of 10.0 mL of 0.01 M hydrochloric acid and 50 mL of ethanol (96 per cent) R. 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 34.39 mg of C18H30ClNO3.
STORAGE
Protected from light.
IMPURITIES
Specified impurities A, B, C, D, E.
A. (2RS)-1-(4-ethylphenoxy)-3-[(1-methylethyl)amino]propan-2-ol,
B. (2RS)-1-[4-(2-hydroxyethyl)phenoxy]-3-[(1-methylethyl)amino]propan-2-ol,
C. (2RS)-2-[[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]methyl]oxirane,
D. 4-[2-(cyclopropylmethoxy)ethyl]phenol,
E. (2RS)-1-[4-(2-butoxyethyl)phenoxy]-3-[(1-methylethyl)amino]propan-2-ol.
