FLURBIPROFEN Flurbiprofenum

EUROPEAN PHARMACOPOEIA 5.0 Flurbiprofen
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
Comparison: Ph. Eur. reference spectrum of flurazepam
monohydrochloride.
B. It gives reaction (a) of chlorides (2.3.1).
ASSAY
Dissolve 0.350 g in a mixture of 1.0 ml of 0.1 M hydrochloric
acid and 50 ml of alcohol R. Carry out a potentiometric
titration (2.2.20), using 0.1 M sodium hydroxide. Readthe
volume added between the 2 points of inflexion.
1mlof0.1 M sodium hydroxide is equivalent to 42.43 mg
of C21H24Cl2FN3O. STORAGE
Protected from light.
IMPURITIES
TESTS
pH (2.2.3): 5.0to6.0. Dissolve 0.50 g in carbon dioxide-free water R and dilute to
10mlwiththesamesolvent.
Related substances. Liquid chromatography (2.2.29).
Prepare the solutions immediately before use.
Test solution. Dissolve50.0mgofthesubstancetobe
examined in the mobile phase and dilute to 50.0 ml with the
mobile phase.
Reference solution (a). Dilute 1.0 ml of the test solution
to 100.0 ml with the mobile phase. Dilute 5.0 ml of this
solution to 50.0 ml with the mobile phase.
Reference solution (b). Dissolve 5 mg of the substance to be A. [5-chloro-2-[[2-(diethylamino)ethyl]amino]phenyl](2-
examined and 5 mg of oxazepam R in 10 ml of acetonitrile R
and dilute to 50.0 ml with the mobile phase.
Column:
— size: l =0.15m,Ø=4.6mm,
— stationary phase: base-deactivated octylsilyl silica gel
for chromatography R (5 µm).
Mobile phase: mix 350 volumes of acetonitrile R and
650 volumes of a 10.5 g/l solution of potassium dihydrogen
phosphate R and ajust to pH 6.1 with a 40 g/l solution of
fluorophenyl)methanone,
sodium hydroxide R.
Flow rate: 1.0ml/min.
B. R = H: 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4benzodiazepin-2-one,
Detection: spectrophotometer at 239 nm.
Injection: 20µl.
C. R = CHOH-CH3: 7-chloro-5-(2-fluorophenyl)-1-[(1RS)-1hydroxyethyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one.
Run time: 6 times the retention time of flurazepam.
Relative retention with reference to flurazepam
01/2005:1519
(retention time = about 7 min): impurity C = about 1.5;
impurity B = about 1.9; impurity A = about 2.4.
FLURBIPROFEN
System suitability: reference solution (b):
— resolution: minimum of 4.5 between the peaks due to
flurazepam and to oxazepam.
Limits:
— correction factors: for the calculation of contents,
multiply the peak areas of the following impurities by
the corresponding correction factor: impurity B = 0.61;
impurity C = 0.65,
Flurbiprofenum
— any impurity: not more than the area of the principal
peak in the chromatogram obtained with reference
C15H13FO2 Mr 244.3
solution (a) (0.1 per cent),
DEFINITION
— total: not more than 3 times the area of the principal peak Flurbiprofen contains not less than 99.0 per cent and
in the chromatogram obtained with reference solution (a) not more than the equivalent of 101.0 per cent of
(0.3 per cent),
(2RS)-2-(2-fluorobiphenyl-4-yl)propanoic acid, calculated
— disregard limit: 0.5 times the area of the principal peak
with reference to the dried substance.
in the chromatogram obtained with reference solution (a)
(0.05 per cent).
CHARACTERS
A white or almost white, crystalline powder, practically
Fluorides (2.4.5): maximum 500 ppm.
insoluble in water, freely soluble in alcohol and in methylene
0.10 g complies with the limit test for fluorides.
Loss on drying (2.2.32): maximum 0.5 per cent, determined
chloride. It dissolves in aqueous solutions of alkali
hydroxides and carbonates.
on 1.000 g by drying in an oven at 100-105 °C for 4 h. IDENTIFICATION
Sulphated ash (2.4.14): maximum 0.1 per cent, determined First identification: C, D.
on 1.0 g.
Second identification: A, B, D.
GeneralNotices(1)applytoallmonographsandothertexts 1623

Flurbiprofen EUROPEAN PHARMACOPOEIA 5.0
A. Melting point (2.2.14) : 114 °C to 117 °C.
B. Dissolve 0.10 g in 0.1 M sodium hydroxide and dilute to
100.0 ml with the same alkaline solution. Dilute 1.0 ml of
the solution to 100.0 ml with 0.1 M sodium hydroxide.
Examined between 230 nm and 350 nm (2.2.25), the
solution shows an absorption maximum at 247 nm. The
specific absorbance at the maximum is 780 to 820.
C. Examine by infrared absorption spectrophotometry
(2.2.24), comparing with the spectrum obtained with
flurbiprofenCRS. D.Mixabout5mgwith45mgofheavy magnesium oxide R
and ignite in a crucible until an almost white residue is
obtained (usually less than 5 min). Allow to cool, add 1 ml
of water R, 0.05mlofphenolphthalein solution R1 and
about 1 ml of dilute hydrochloric acid R to render the
solution colourless. Filter. To a freshly prepared mixture
of 0.1 ml of alizarin S solution R and 0.1 ml of zirconyl
nitrate solution R add 1.0 ml of the filtrate. Mix, allow to
stand for 5 min and compare the colour of the solution
with that of a blank prepared in the same manner. The
test solution is yellow and the blank is red.
TESTS
Appearance of solution. Dissolve1.0ginmethanol R and
dilute to 10 ml with the same solvent. The solution is clear
(2.2.1) and colourless (2.2.2, Method I).
Optical rotation (2.2.7). Dissolve 0.50 g in methanol R and
dilute to 20.0 ml with the same solvent. The angle of optical
rotation is −0.1° to + 0.1°.
Related substances. Examine by liquid chromatography
(2.2.29).
Test solution. Dissolve 0.20 g of the substance to be
examined in a mixture of 45 volumes of acetonitrile R and
55 volumes of water R and dilute to 100.0 ml with the same
mixture of solvents.
Reference solution (a). Dilute 1.0 ml of the test solution
to50.0mlwithamixtureof45volumesofacetonitrile R
and 55 volumes of water R. Dilute1.0mlofthesolutionto
10.0 ml with a mixture of 45 volumes of acetonitrile R and
55 volumes of water R.
Reference solution (b). Dissolve 10.0 mg of flurbiprofen
impurity A CRS in a mixture of 45 volumes of acetonitrile R
and 55 volumes of water R and dilute to100.0 ml with the
same mixture of solvents. Dilute 10.0 ml of this solution to
100.0mlwithamixtureof45volumesofacetonitrile R and
55 volumes of water R.
Reference solution (c). Dissolve 10 mg of the substance to
be examined in a mixture of 45 volumes of acetonitrile R
and 55 volumes of water R and dilute to 100.0 ml with the
same mixture of solvents. Dilute 1.0 ml of the solution to
10.0 ml with reference solution (b).
The chromatographic procedure may be carried out using:
— a stainless steel column 0.15 m long and 3.9 mm in
internal diameter packed with octadecylsilyl silica gel for
chromatography R (5 µm),
— as mobile phase at a flow rate of 1 ml/min a mixture
of 5 volumes of glacial acetic acid R, 35 volumes of
acetonitrile R and 60 volumes of water R,
— as detector a spectrophotometer set at 254 nm.
Inject 10 µl of reference solution (c). Adjust the sensitivity
of the system so that the heights of the two principal peaks
in the chromatogram obtained are at least 40 per cent of
the full scale of the recorder. The test is not valid unless the
resolution between the peak corresponding to impurity A
and the peak corresponding to flurbiprofen is at least 1.5.
Inject 10 µl of the test solution and of reference solutions (a)
and (b). Continue the chromatography for twice the retention
time of flurbiprofen. In the chromatogram obtained with
the test solution the area of any peak corresponding to
impurity A is not greater than the area of the peak in the
chromatogram obtained with reference solution (b) (0.5 per
cent); the area of any peak, apart from the principal peak
and the peak due to impurity A, is not greater than the area
of the principal peak in the chromatogram obtained with
reference solution (a) (0.2 per cent) and the sum of the areas
of any such peaks is not greater than five times the area
of the principal peak in the chromatogram obtained with
reference solution (a) (1.0 per cent). Disregard any peak with
an area less than 0.1 times that of the principal peak in the
chromatogram obtained with reference solution (a) (0.02 per
cent).
Heavy metals (2.4.8). Dissolve 2.0 g in a mixture of
10 volumes of water R and 90 volumes of methanol R and
dilute to 20 ml with the same mixture of solvents. 12 ml
of the solution complies with limit test B for heavy metals
(10 ppm). Prepare the standard using lead standard solution
(1 ppm Pb) obtained by diluting lead standard solution
(100 ppm Pb) R with a mixture of 10 volumes of water R and
90 volumes of methanol R.
Loss on drying (2.2.32). Not more than 0.5 per cent,
determined on 1.000 g by drying at 60 °C at a pressure not
exceeding 0.7 kPa for 3 h.
Sulphated ash (2.4.14). Not more than 0.1 per cent,
determined on 1.0 g in a platinum crucible.
ASSAY
Dissolve 0.200 g in 50 ml of alcohol R. Titratewith
0.1 M sodium hydroxide, determining the end-point
potentiometrically (2.2.20).
1mlof0.1 M sodium hydroxide is equivalent to 24.43 mg
of C 15H 13FO 2.
IMPURITIES
A. R = R′ =H:(2RS)-2-(biphenyl-4-yl)propanoic acid,
B. R = CH(CH 3)-CO 2H: 2-(2-fluorobiphenyl-4-yl)-2,3dimethylbutanedioic
acid,
C. C. R = OH, R′ =F:(2RS)-2-(2-fluorobiphenyl-4-yl)-2hydroxypropanoic
acid,
D. R = CO-CH 3:1-(2-fluorobiphenyl-4-yl)ethanone,
E. R = CO 2H: 2-fluorobiphenyl-4-carboxylic acid.
1624 See the information section on general monographs (cover pages)