(Ph. Eur. monograph 0487)
C10H16ClNO 201.7 50-98-6
Action and use
Adrenoceptor agonist.
Preparations
Ephedrine Nasal Drops
Ephedrine Hydrochloride Tablets
Ephedrine Injection
DEFINITION
(1R,2S)-2-(Methylamino)-1-phenylpropan-1-ol hydrochloride.
Content
99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or almost white, crystalline powder or colourless crystals.
Solubility
Freely soluble in water, soluble in ethanol (96 per cent).
mp
About 219 °C.
IDENTIFICATION
First identification: B, E.
Second identification: A, C, D, E.
A. Specific optical rotation (see Tests).
B. Infrared absorption spectrophotometry (2.2.24).
Comparison ephedrine hydrochloride CRS.
C. Thin-layer chromatography (2.2.27).
Test solution Dissolve 20 mg of the substance to be examined in methanol R and dilute to 10 mL with the same solvent.
Reference solution Dissolve 10 mg of ephedrine hydrochloride CRS in methanol R and dilute to 5 mL with the same solvent.
Plate TLC silica gel plate R.
Mobile phase methylene chloride R, concentrated ammonia R, 2-propanol R (5:15:80 V/V/V).
Application 10 μL.
Development Over 2/3 of the plate.
Drying In air.
Detection Spray with ninhydrin solution R; heat at 110 °C for 5 min.
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. To 0.1 mL of solution S (see Tests) add 1 mL of water R, 0.2 mL of copper sulfate solution R and 1 mL of strong sodium hydroxide solution R. A violet colour is produced. Add 2 mL of methylene chloride R and shake. The lower (organic) layer is dark grey and the upper (aqueous) layer is blue.
E. To 5 mL of solution S (see Tests) add 5 mL of water R. The solution gives reaction (a) of chlorides (2.3.1).
TESTS
Solution S
Dissolve 5.00 g in distilled water R and dilute to 50.0 mL with the same solvent.
Appearance of solution
Solution S is clear (2.2.1) and colourless (2.2.2, Method II).
Acidity or alkalinity
To 10 mL of solution S add 0.1 mL of methyl red solution R and 0.2 mL of 0.01 M sodium hydroxide. The solution is yellow.
Add 0.4 mL of 0.01 M hydrochloric acid. The solution is red.
Specific optical rotation (2.2.7)
-33.5 to -35.5 (dried substance).
Dilute 12.5 mL of solution S to 25.0 mL with water R.
Related substances
Liquid chromatography (2.2.29).
Test solution Dissolve 75 mg of the substance to be examined in the mobile phase and dilute to 10 mL with the mobile phase.
Reference solution (a) Dilute 2.0 mL of the test solution to 100.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase.
Reference solution (b) Dissolve 5 mg of the substance to be examined and 5 mg of pseudoephedrine hydrochloride CRS in the mobile phase and dilute to 50 mL with the mobile phase.
Column:
— size: l = 0.15 m, Ø = 4.6 mm;
— stationary phase: spherical phenylsilyl silica gel for chromatography R (3 μm).
Mobile phase Mix 6 volumes of methanol R and 94 volumes of a 11.6 g/L solution of ammonium acetate R adjusted to pH 4.0 with glacial acetic acid R.
Flow rate 1.0 mL/min.
Detection Spectrophotometer at 257 nm.
Injection 20 μL.
Run time 2.5 times the retention time of ephedrine.
Relative retention With reference to ephedrine (retention time = about 8 min): impurity B = about 1.1;
impurity A = about 1.4.
System suitability Reference solution (b):
— resolution: minimum 2.0 between the peaks due to ephedrine and impurity B.
Limits:
— correction factor: for the calculation of content, multiply the peak area of impurity A by 0.4;
— impurity A: not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);
— unspecified impurities: for each impurity, not more than 0.5 times the area of the principal peak in the
chromatogram obtained with reference solution (a) (0.1 per cent);
— sum of impurities other than A: not more than 2.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5 per cent);
— disregard limit: 0.25 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent).
Sulfates (2.4.13)
Maximum 100 ppm, determined on solution S.
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 0.150 g in 50 mL of ethanol (96 per cent) R and add 5.0 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 20.17 mg of C10H16ClNO.
STORAGE
Protected from light.
IMPURITIES
Specified impurities A.
Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use) B.
A. (–)-(1R)-1-hydroxy-1-phenylpropan-2-one.
B. (1S,2S)-2-(methylamino)-1-phenylpropan-1-ol (pseudoephedrine).
