EUROPEAN PHARMACOPOEIA 11.

0 Flurbiprofen

01/2022:1519 Reference solution (d). Dissolve 10 mg of flurbiprofen for peak

identification CRS (containing impurity B) in the solvent
mixture and dilute to 5 mL with the solvent mixture.
Column :
– size : l = 0.15 m, Ø = 3.9 mm ;
FLURBIPROFEN – stationary phase : octadecylsilyl silica gel for
chromatography R (5 μm).
Mobile phase : glacial acetic acid R, acetonitrile R, water for
Flurbiprofenum chromatography R (5:35:60 V/V/V).
Flow rate : 1 mL/min.
Detection : spectrophotometer at 254 nm.
Injection : 10 μL.
Run time : twice the retention time of flurbiprofen.
Identification of impurities : use the chromatogram supplied
with flurbiprofen for peak identification CRS and the
C15H13FO2 Mr 244.3 chromatogram obtained with reference solution (d) to
[5104-49-4] identify the peak due to impurity B ; use the chromatogram
obtained with reference solution (b) to identify the peak due
DEFINITION to impurity A.
(2RS)-2-(2-Fluoro[1,1′-biphenyl]-4-yl)propanoic acid. Relative retention with reference to flurbiprofen (retention
Content : 99.0 per cent to 101.0 per cent (dried substance). time = about 25 min) : impurity B = about 0.8 ; impurity A =
about 0.9.
CHARACTERS System suitability : reference solution (c) :
Appearance : white or almost white, crystalline powder. – resolution : minimum 1.5 between the peaks due to
Solubility : practically insoluble in water, freely soluble in impurity A and flurbiprofen.
ethanol (96 per cent) and in methylene chloride. It dissolves Calculation of percentage contents :
in dilute solutions of alkali hydroxides and carbonates. – for impurity A, use the concentration of impurity A in
IDENTIFICATION reference solution (b);
A. Infrared absorption spectrophotometry (2.2.24). – for impurities other than A, use the concentration of
flurbiprofen in reference solution (a).
Comparison : flurbiprofen CRS. Limits :
B. Mix about 5 mg with 45 mg of heavy magnesium oxide R – impurity A : maximum 0.5 per cent ;
and ignite in a crucible until an almost white residue is
obtained (usually less than 5 min). Allow to cool, add – impurity B : maximum 0.2 per cent ;
1 mL of water R, 0.05 mL of phenolphthalein solution R1 – unspecified impurities : for each impurity, maximum
and about 1 mL of dilute hydrochloric acid R to render the 0.10 per cent ;
solution colourless. Filter. To a freshly prepared mixture – total : maximum 0.7 per cent ;
of 0.1 mL of alizarin S solution R and 0.1 mL of zirconyl – reporting threshold : 0.05 per cent.
nitrate solution R, add 1.0 mL of the filtrate. Mix, allow to
stand for 5 min and compare the colour of the solution Loss on drying (2.2.32) : maximum 0.5 per cent, determined
with that of a blank prepared in the same manner. The test on 1.000 g by drying at 60 °C at a pressure not exceeding
solution is yellow and the blank is red. 0.7 kPa for 3 h.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
TESTS 1.0 g in a platinum crucible.
Appearance of solution. The solution is clear (2.2.1) and ASSAY
colourless (2.2.2, Method I).
Dissolve 0.200 g in 50 mL of ethanol (96 per cent) R. Titrate
Dissolve 1.0 g in methanol R and dilute to 10 mL with the with 0.1 M sodium hydroxide, determining the end-point
same solvent. potentiometrically (2.2.20).
Optical rotation (2.2.7): − 0.1° to + 0.1°. 1 mL of 0.1 M sodium hydroxide is equivalent to 24.43 mg of
Dissolve 0.50 g in methanol R and dilute to 20.0 mL with the C15H13FO2.
same solvent.
IMPURITIES
Related substances. Liquid chromatography (2.2.29). Specified impurities : A, B.
Solvent mixture : acetonitrile R, water R (45:55 V/V). Other detectable impurities (the following substances would,
Test solution. Dissolve 0.20 g of the substance to be examined if present at a sufficient level, be detected by one or other of
in the solvent mixture and dilute to 100.0 mL with the solvent the tests in the monograph. They are limited by the general
mixture. acceptance criterion for other/unspecified impurities and/or
Reference solution (a). Dilute 1.0 mL of the test solution to by the general monograph Substances for pharmaceutical use
100.0 mL with the solvent mixture. Dilute 1.0 mL of this (2034). It is therefore not necessary to identify these impurities
solution to 10.0 mL with the solvent mixture. for demonstration of compliance. See also 5.10. Control of
impurities in substances for pharmaceutical use): C, D, E.
Reference solution (b). Dissolve 10.0 mg of flurbiprofen
impurity A CRS in the solvent mixture and dilute to 100.0 mL
with the solvent mixture. Dilute 10.0 mL of the solution to
100.0 mL with the solvent mixture.
Reference solution (c). Dissolve 10 mg of the substance to be
examined in the solvent mixture and dilute to 100 mL with
the solvent mixture. Dilute 1 mL of the solution to 10 mL with
reference solution (b). A. (2RS)-2-([1,1′-biphenyl]-4-yl)propanoic acid,

General Notices (1) apply to all monographs and other texts 2815
Fluspirilene EUROPEAN PHARMACOPOEIA 11.0

TESTS
Appearance of solution. The solution is clear (2.2.1) and
colourless (2.2.2, Method II).
Dissolve 0.25 g in 25 mL of methylene chloride R.
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 0.100 g of the substance to be examined
B. (2Ξ,3Ξ)-2-(2-fluoro[1,1′-biphenyl]-4-yl)-2,3- in dimethylformamide R and dilute to 10.0 mL with the same
dimethylbutanedioic acid, solvent.
Reference solution (a). Dissolve 5.0 mg of fluspirilene
impurity C CRS in dimethylformamide R, add 0.5 mL of the
test solution and dilute to 100.0 mL with dimethylformamide R.
Reference solution (b). Dilute 1.0 mL of the test solution to
20.0 mL with dimethylformamide R. Dilute 1.0 mL of this
solution to 25.0 mL with dimethylformamide R.
C. (2RS)-2-(2-fluoro[1,1′-biphenyl]-4-yl)-2- Column :
hydroxypropanoic acid, – size : l = 0.15 m, Ø = 4.6 mm,
– stationary phase : octadecylsilyl silica gel for
chromatography R (3 μm).
Mobile phase :
– mobile phase A : 13.6 g/L solution of tetrabutylammonium
hydrogen sulfate R,
– mobile phase B : acetonitrile R,
D. 1-(2-fluoro[1,1′-biphenyl]-4-yl)ethan-1-one,
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0 - 15 75 → 70 25 → 30

15 - 20 70 30

20 - 22 70 → 0 30 → 100
E. 2-fluoro[1,1′-biphenyl]-4-carboxylic acid. 22 - 30 0 100

01/2011:1723 Flow rate : 1.2 mL/min.

Detection : spectrophotometer at 250 nm.
Injection : 10 μL.
Identification of impurities: use the chromatogram obtained
with reference solution (a) to identify the peak due to
FLUSPIRILENE impurity C.
Relative retention with reference to fluspirilene
Fluspirilenum (retention time = about 15 min) : impurity A = about 0.8 ;
impurity B = about 0.93 ; impurity C = about 0.97.
System suitability : reference solution (a) :
– resolution : minimum 2.2 between the peaks due to
impurity C and fluspirilene.
Limits :
– impurities A, B, C : for each impurity, not more than
1.5 times the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.3 per cent),
C29H31F2N3O Mr 475.6
[1841-19-6] – unspecified impurities : for each impurity, not more than
0.5 times the area of the principal peak in the chromatogram
DEFINITION obtained with reference solution (b) (0.10 per cent),
8-[4,4-bis(4-Fluorophenyl)butyl]-1-phenyl-1,3,8- – total : not more than 3 times the area of the principal peak
triazaspiro[4.5]decan-4-one. in the chromatogram obtained with reference solution (b)
Content : 99.0 per cent to 101.0 per cent (dried substance). (0.6 per cent),
– disregard limit : 0.25 times the area of the principal peak
CHARACTERS in the chromatogram obtained with reference solution (b)
Appearance : white or almost white powder. (0.05 per cent).
Solubility : practically insoluble in water, soluble in methylene Loss on drying (2.2.32) : maximum 0.5 per cent, determined
chloride, slightly soluble in ethanol (96 per cent). on 1.000 g by drying in an oven at 105 °C for 4 h.
It shows polymorphism (5.9). Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
IDENTIFICATION 1.0 g in a platinum crucible.
Infrared absorption spectrophotometry (2.2.24). ASSAY
Comparison : fluspirilene CRS. Dissolve 0.350 g in 50 mL of a mixture of 1 volume of
If the spectra obtained show differences, dissolve the substance anhydrous acetic acid R and 7 volumes of methyl ethyl
to be examined and the reference substance separately in ketone R. Titrate with 0.1 M perchloric acid, determining the
methylene chloride R, gently evaporate to dryness and record end-point potentiometrically (2.2.20). Carry out a blank
new spectra using the residues. titration.

2816 See the information section on general monographs (cover pages)