EUROPEAN PHARMACOPOEIA 11.
0 Fenofibrate
IMPURITIES
A. 3-(4-chlorophenyl)-3-oxopropanoic acid,
B. 4-(biphenyl-4-yl)-4-oxobut-2-enoic acid,
C. biphenyl,
D. 4-(4′-hydroxybiphenyl-4-yl)-4-oxobutanoic acid.
01/2017:1322 Run time : twice the retention time of fenofibrate.
FENOFIBRATE
Fenofibratum
C20H21ClO4 Mr 360.8 – impurity G : not more than the area of the corresponding
[49562-28-9]
DEFINITION
1-Methylethyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-
methylpropanoate.
Content : 98.0 per cent to 102.0 per cent (dried substance).
CHARACTERS
Appearance : white or almost white, crystalline powder.
Solubility : practically insoluble in water, very soluble in
methylene chloride, slightly soluble in ethanol (96 per cent).
IDENTIFICATION
A. Melting point (2.2.14): 79 °C to 82 °C.
B. Infrared absorption spectrophotometry (2.2.24).
Comparison : fenofibrate CRS.
TESTS
Solution S. To 5.0 g, add 25 mL of distilled water R and heat
at 50 °C for 10 min. Cool and dilute to 50.0 mL with distilled Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
water R. Filter. Use the filtrate as solution S.
General Notices (1) apply to all monographs and other texts
Appearance of solution. The solution is clear (2.2.1) and
not more intensely coloured than reference solution BY6
(2.2.2, Method II).
Dissolve 0.50 g in acetone R and dilute to 10.0 mL with the
same solvent.
Acidity. Dissolve 1.0 g in 50 mL of ethanol (96 per cent) R
previously neutralised using 0.2 mL of phenolphthalein
solution R1. Not more than 0.2 mL of 0.1 M sodium hydroxide
is required to change the colour of the indicator to pink.
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 100.0 mL with the mobile
phase.
Reference solution (a). Dissolve 25.0 mg of fenofibrate CRS in
the mobile phase and dilute to 25.0 mL with the mobile phase.
Reference solution (b). Dissolve 5.0 mg of fenofibrate CRS,
5.0 mg of fenofibrate impurity A CRS, 5.0 mg of fenofibrate
impurity B CRS and 10.0 mg of fenofibrate impurity G CRS
in the mobile phase and dilute to 100.0 mL with the mobile
phase. Dilute 1.0 mL of the solution to 50.0 mL with the
mobile phase.
Column :
– size : l = 0.25 m, Ø = 4.0 mm ;
– stationary phase : octadecylsilyl silica gel for
chromatography R (5 μm).
Mobile phase : mix 30 volumes of water R acidified to pH 2.5
with phosphoric acid R and 70 volumes of acetonitrile R.
Flow rate : 1 mL/min.
Detection : spectrophotometer at 286 nm.
Injection : 20 μL of the test solution and reference solution (b).
Identification of impurities: use the chromatogram obtained
with reference solution (b) to identify the peaks due to
impurities A, B and G.
Relative retention with reference to fenofibrate (retention
time = about 10 min) : impurity A = about 0.34 ;
impurity B = about 0.36 ; impurity G = about 1.35.
System suitability : reference solution (b) :
– resolution : minimum 1.5 between the peaks due to
impurities A and B.
Limits :
– impurities A, B : for each impurity, not more than 1.5 times
the area of the corresponding peak in the chromatogram
obtained with reference solution (b) (0.15 per cent) ;
peak in the chromatogram obtained with reference
solution (b) (0.2 per cent);
– unspecified impurities : for each impurity, not more than the
area of the peak due to fenofibrate in the chromatogram
obtained with reference solution (b) (0.10 per cent) ;
– total : not more than 5 times the area of the peak due to
fenofibrate in the chromatogram obtained with reference
solution (b) (0.5 per cent);
– disregard limit : 0.5 times the area of the peak due to
fenofibrate in the chromatogram obtained with reference
solution (b) (0.05 per cent).
Halides expressed as chlorides (2.4.4) : maximum 100 ppm.
To 5 mL of solution S add 10 mL of distilled water R.
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 vacuo at 60 °C.
1.0 g.
2751
Fenoterol hydrobromide
ASSAY
Liquid chromatography (2.2.29) as described in the test for
related substances with the following modifications.
Injection : 5 μL of the test solution and reference solution (a).
System suitability : reference solution (a) :
– repeatability : maximum relative standard deviation of
1.0 per cent determined on 6 injections.
STORAGE
Protected from light.
IMPURITIES
Specified impurities : A, B, G.
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) : C, D, E, F.
A. (4-chlorophenyl)(4-hydroxyphenyl)methanone,
B. 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid
(fenofibric acid),
C. (3RS)-3-[4-(4-chlorobenzoyl)phenoxy]butan-2-one,
D. methyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-
methylpropanoate,
E. ethyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-
methylpropanoate,
F. (4-chlorophenyl)[4-(1-methylethoxy)phenyl]methanone,
2752
EUROPEAN PHARMACOPOEIA 11.0
G. 1-methylethyl 2-[[2-[4-(4-chlorobenzoyl)phenoxy]-2-
methylpropanoyl]oxy]-2-methylpropanoate.
01/2020:0901
FENOTEROL HYDROBROMIDE
Fenoteroli hydrobromidum
C17H22BrNO4 Mr 384.3
[1944-12-3]
DEFINITION
5-[(1RS)-2-[(1RS)-2-(4-Hydroxyphenyl)-1-methylethyl]-
amino-1-hydroxyethyl]benzene-1,3-diol hydrobromide.
Content : 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance : white or almost white, crystalline powder.
Solubility : soluble in water and in ethanol (96 per cent).
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
Comparison : fenoterol hydrobromide CRS.
B. It gives reaction (a) of bromides (2.3.1).
TESTS
Solution S. Dissolve 2.00 g in carbon dioxide-free water R and
dilute to 50.0 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution Y7 (2.2.2,
Method II).
pH (2.2.3): 4.2 to 5.2 for solution S.
Related substances. Liquid chromatography (2.2.29). Prepare
the solutions immediately before use.
Test solution. Dissolve 6.0 mg of the substance to be examined
in water R and dilute to 5.0 mL with the same solvent.
Reference solution (a). Dilute 1.0 mL of the test solution to
25.0 mL with water R.
Reference solution (b). Dilute 2.5 mL of reference solution (a)
to 100.0 mL with water R.
Reference solution (c). Dissolve the contents of a vial of
fenoterol for system suitability CRS (containing impurities A,
B and C) in 1 mL of water R.
Column :
– size : l = 0.15 m, Ø = 4.6 mm ;
– stationary phase : end-capped octadecylsilyl silica gel for
chromatography R (5 μm).
Mobile phase. Dissolve 24 g of anhydrous disodium hydrogen
phosphate R in 1000 mL of water for chromatography R. Mix
69 volumes of the solution and 1 volume of a 9 g/L solution
of potassium dihydrogen phosphate R, adjust to pH 8.5 with
phosphoric acid R and add 35 volumes of methanol R2.
Flow rate : 1.0 mL/min.
See the information section on general monographs (cover pages)