EUROPEAN PHARMACOPOEIA 5.

0 Nimesulide

Appearance. The substance to be examined, in liquid CHARACTERS

form or liquefied by slight heating, is clear (2.2.1) and not Appearance : yellowish crystalline powder.
more intensely coloured than reference solution Y5 (2.2.2, Solubility : practically insoluble in water, freely soluble in
Method II). acetone, slightly soluble in ethanol.
pH (2.2.3). The pH of solution S is 6.0 to 7.8. mp : about 149 °C.
Refractive index (2.2.6). 1.524 to 1.526. It shows polymorphism.
Related substances. Examine by thin-layer chromatography IDENTIFICATION
(2.2.27), using silica gel GF254 R as the coating substance.
Infrared absorption spectrophotometry (2.2.24).
Test solution. Dissolve 0.4 g of the substance to be examined
in methanol R and dilute to 10 ml with the same solvent. Preparation : discs.
Comparison : nimesulide CRS.
Reference solution (a). Dissolve 40 mg of
ethylnicotinamide CRS in methanol R and dilute to If the spectra obtained show differences, dissolve the
100 ml with the same solvent. substance to be examined and the reference substance
separately in acetone R, evaporate to dryness and record
Reference solution (b). Dilute 1 ml of reference solution (a) new spectra using the residues.
to 10 ml with methanol R.
Apply separately to the plate 10 µl of each solution. Develop TESTS
over a path of 15 cm using a mixture of 25 volumes of Absorbance (2.2.25) : maximum 0.50 at 450 nm.
propanol R and 75 volumes of chloroform R. Allow the Dissolve 1.0 g in acetone R and dilute to 10.0 ml with the
plate to dry in air and examine in ultraviolet light at 254 nm.
same solvent.
In the chromatogram obtained with the test solution,
any spot corresponding to ethylnicotinamide is not more Related substances. Liquid chromatography (2.2.29).
intense than the spot in the chromatogram obtained with Test solution. Dissolve 20 mg of the substance to be
reference solution (a) (1.0 per cent) and any spot, apart examined in 8 ml of acetonitrile R and dilute to 20.0 ml
from the principal spot and the spot corresponding to with water R.
ethylnicotinamide, is not more intense than the spot in the Reference solution (a). Dissolve 10 mg of nimesulide
chromatogram obtained with reference solution (b) (0.1 per impurity C CRS and 10 mg of nimesulide impurity D CRS
cent). in 20 ml of acetonitrile R and dilute to 50.0 ml with water R.
Heavy metals (2.4.8). Dilute 10 ml of solution S to 25 ml Dilute 1.0 ml of the solution to 50.0 ml with the mobile
phase.
with water R. 12 ml of this solution complies with limit test A
for heavy metals (10 ppm). Prepare the standard using lead Reference solution (b). Dilute 1.0 ml of the test solution to
standard solution (1 ppm Pb) R. 10.0 ml with the mobile phase. Dilute 1.0 ml of the solution
Water (2.5.12). Not more than 0.3 per cent, determined on to 100.0 ml with the mobile phase.
2.00 g by the semi-micro determination of water. Column :
Sulphated ash (2.4.14). Not more than 0.1 per cent, — dimensions : l = 0.125 m, Ø = 4.0 mm,
determined on 1.0 g. — stationary phase : octadecylsilyl silica gel for
chromatography R.
ASSAY Mobile phase : a mixture of 35 volumes of acetonitrile R and
Dissolve 0.150 g in a mixture of 5 ml of acetic anhydride R 65 volumes of a 1.15 g/l solution of ammonium dihydrogen
and 20 ml of anhydrous acetic acid R. Titrate with phosphate R adjusted to pH 7.0 with ammonia R.
0.1 M perchloric acid, determining the end-point Flow rate : 1.3 ml/min.
potentiometrically (2.2.20). Detection : spectrophotometer at 230 nm.
1 ml of 0.1 M perchloric acid is equivalent to 17.82 mg of Injection : 20 µl.
C10H14N2O.
Run time : 7 times the retention time of nimesulide.
System suitability :
01/2005:1548 — resolution : minimum of 2.0 between the 2 principal peaks
in the chromatogram obtained with reference solution (a).
NIMESULIDE Limits :
— any impurity : not more than the area of the principal
peak in the chromatogram obtained with reference
Nimesulidum solution (b) (0.1 per cent),
— total : not more than 5 times the area of the principal peak
in the chromatogram obtained with reference solution (b)
(0.5 per cent),
— disregard limit : 0.1 times the area of the principal peak
in the chromatogram obtained with reference solution (b)
(0.01 per cent).
Heavy metals (2.4.8) : maximum 20 ppm.
1.0 g complies with limit test D. Prepare the standard using
C13H12N2O5S Mr 308.3 2 ml of lead standard solution (10 ppm Pb) R.
Loss on drying (2.2.32) : maximum 0.5 per cent, determined
DEFINITION on 1.000 g by drying in an oven at 100-105 °C for 4 h.
N-(4-Nitro-2-phenoxyphenyl)methanesulphonamide. Sulphated ash (2.4.14) : maximum 0.1 per cent, determined
Content : 98.5 per cent to 101.5 per cent (dried substance). on 1.0 g.

General Notices (1) apply to all monographs and other texts 2101
Nimodipine EUROPEAN PHARMACOPOEIA 5.0

ASSAY It shows polymorphism.

Dissolve 0.240 g in 30 ml of previously neutralised acetone R Exposure to ultraviolet light leads to the formation of a
and add 20 ml of water R. Titrate with 0.1 M sodium nitrophenylpyridine derivative.
hydroxide, determining the end-point potentiometrically Prepare solutions immediately before use either protected
(2.2.20). from light or under long-wavelength light (> 420 nm).
1 ml of 0.1 M sodium hydroxide is equivalent to 30.83 mg
of C13H12N2O5S. IDENTIFICATION
Examine by infrared absorption spectrophotometry
IMPURITIES (2.2.24), comparing with the spectrum obtained with
nimodipine CRS. If the spectra obtained in the solid state
show differences, record further spectra using 20 g/l
solutions in methylene chloride R and a 0.2 mm cell.
TESTS
Solution S. Dissolve 1.0 g in acetone R and dilute to 20.0 ml
with acetone R.
Appearance of solution. Solution S is clear (2.2.1).
Optical rotation (2.2.7). The angle of optical rotation,
A. R1 = SO2-CH3, R2 = H, R3 = R4 = NO2 : determined on solution S, is − 0.10° to + 0.10°.
N-(2,4-dinitro-6-phenoxyphenyl)methanesulphonamide,
Related substances. Examine by liquid chromatography
B. R1 = SO2-CH3, R2 = R3 = R4 = H : N-(2- (2.2.29).
phenoxyphenyl)methanesulphonamide, Test solution. Dissolve 40.0 mg of the substance to be
C. R1 = R2 = R3 = R4 = H : 2-phenoxyaniline, examined in 2.5 ml of tetrahydrofuran R and dilute to
25.0 ml with the mobile phase.
D. R1 = R2 = R4 = H, R3 = NO2 : 4-nitro-2-phenoxyaniline,
Reference solution (a). Dilute 1.0 ml of the test solution to
E. R1 = R2 = SO2-CH3, R3 = R4 = H : N,N-bis(methylsulphonyl)- 100.0 ml with the mobile phase. Dilute 2.0 ml of the solution
2-phenoxyaniline, to 10.0 ml with the mobile phase.
F. R1 = R2 = SO2-CH3, R3 = NO2, R4 = H : Reference solution (b). Dissolve 20.0 mg of nimodipine
N,N-bis(methylsulphonyl)-4-nitro-2-phenoxyaniline, impurity A CRS in 2.5 ml of tetrahydrofuran R and dilute to
25.0 ml with the mobile phase. Dilute 1.0 ml of the solution
to 20.0 ml with the mobile phase.
Reference solution (c). Dilute 0.5 ml of the test solution to
20.0 ml with the mobile phase.
Reference solution (d). Mix 1.0 ml of reference solution (b)
and 1.0 ml of reference solution (c) and dilute to 25.0 ml
with the mobile phase.
The chromatographic procedure may be carried out using :
G. 4-nitro-2-phenoxyphenol. — a stainless steel column 0.125 m long and 4.6 mm in
internal diameter packed with octadecylsilyl silica gel for
01/2005:1245 chromatography R (5 µm),
— as mobile phase at a flow rate of 2.0 ml/min a
NIMODIPINE mixture of 20 volumes of methanol R, 20 volumes of
tetrahydrofuran R and 60 volumes of water R,
Nimodipinum — as detector a spectrophotometer set at 235 nm,
maintaining the temperature of the column at 40 °C.
Adjust the sensitivity of the system so that the height of the
peak corresponding to nimodipine in the chromatogram
obtained with 20 µl of reference solution (d) is at least 50 per
cent of the full scale of the recorder.
Inject 20 µl of reference solution (d). When the
chromatograms are recorded in the prescribed conditions,
the retention times are : impurity A about 7 min and
C21H26N2O7 Mr 418.4 nimodipine about 8 min. The test is not valid unless the
resolution between the peaks corresponding to impurity A
DEFINITION and nimodipine is at least 1.5.
Nimodipine contains not less than 98.5 per cent and not Inject separately 20 µl of the test solution and 20 µl of
more than the equivalent of 101.5 per cent of 2-methoxyethyl reference solution (a). Record the chromatogram of the test
1-methylethyl (4RS)-2,6-dimethyl-4-(3-nitrophenyl)-1,4- solution for four times the retention time of nimodipine.
dihydropyridine-3,5-dicarboxylate, calculated with reference In the chromatogram obtained with the test solution : the
to the dried substance. area of the peak due to impurity A is not greater than the
corresponding peak in the chromatogram obtained with
CHARACTERS reference solution (d) (0.1 per cent) ; none of the peaks, apart
A light yellow or yellow, crystalline powder, practically from the principal peak and the peak due to impurity A, has
insoluble in water, freely soluble in ethyl acetate, sparingly an area greater than the area of the principal peak in the
soluble in ethanol. chromatogram obtained with reference solution (a) (0.2 per

2102 See the information section on general monographs (cover pages)