EUROPEAN PHARMACOPOEIA 5.
0 Cefixime
E. 5-methyl-1,3,4-thiadiazol-2-thiol (MMTD),
F. (1H-tetrazol-1-yl)acetic acid,
G. (5aR,6R)-6-[(1H-tetrazol-1-ylacetyl)amino]-5a,6-dihydro-
3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione,
H. (6R,7R)-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-ACA),
I. 2-[carboxy[(1H-tetrazol-1-ylacetyl)amino]methyl]-5-[[(5-
methyl-1,3,4-thiadiazol-2-yl)sulphanyl]methyl]-5,6-dihydro- and dilute to 10 ml with the same solvent. The pH of the
2H-1,3-thiazine-4-carboxylic acid (cefazoloic acid),
J. 2-[carboxy[(1H-tetrazol-1-ylacetyl)amino]methyl]-5-
(hydroxymethyl)-5,6-dihydro-2H-1,3-thiazine-4-carboxylic
acid (hydrolysed cefazoloic acid),
K. (6R,7R)-3-[[(5-methyl-1,3,4-thiadiazol-2-
yl)sulphanyl]methyl]-8-oxo-7-[(1H-tetrazol-1-
ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxamide (cefazolinamide).
General Notices (1) apply to all monographs and other texts
01/2005:1188
corrected
CEFIXIME
Cefiximum
C16H15N5O7S2,3H2O Mr 507.5
DEFINITION
Cefixime is (6R,7R)-7-[[(Z)-2-(2-aminothiazol-4-yl)-2-
[(carboxymethoxy)imino]acetyl]amino]-3-ethenyl-8-oxo-5-thia-
1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trihydrate. It
contains not less than 95.0 per cent and not more than the
equivalent of 101.0 per cent of C16H15N5O7S2, calculated with
reference to the anhydrous and ethanol-free substance.
CHARACTERS
A white or almost white powder, slightly hygroscopic, slightly
soluble in water, soluble in methanol, sparingly soluble in
ethanol, practically insoluble in ethyl acetate.
IDENTIFICATION
Examine by infrared absorption spectrophotometry (2.2.24),
comparing with the spectrum obtained with cefixime CRS. If
the spectra obtained show differences, dissolve the substance
to be examined and the reference substance separately in
methanol R, evaporate to dryness and record new spectra
using the residues.
TESTS
pH (2.2.3). Suspend 0.5 g in carbon dioxide-free water R
suspension is 2.6 to 4.1.
Related substances. Examine by liquid chromatography
(2.2.29) as described under Assay. Inject reference
solution (b). Adjust the sensitivity of the system so that the
height of the principal peak in the chromatogram obtained
is at least 50 per cent of the full scale of the recorder. Inject
the test solution and continue the chromatography for
3 times the retention time of the principal peak. In the
chromatogram obtained with the test solution : the area of
any peak, apart from the principal peak, is not greater than
half the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.5 per cent) ; the sum
of the areas of all the peaks, apart from the principal peak, is
not greater than 3 times the area of the principal peak in the
chromatogram obtained with reference solution (b) (3 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 (b).
Ethanol (2.4.24). Not more than 1.0 per cent m/m,
determined by head-space gas chromatography (2.2.28),
using the standard additions method.
Sample solution. Dissolve 0.250 g of the substance to be
examined in a mixture of 1 volume of dimethylacetamide R
and 4 volumes of water R and dilute to 25.0 ml with the
same mixture of solvents.
1211
Cefoperazone sodium EUROPEAN PHARMACOPOEIA 5.0

Water (2.5.12) : 9.0 per cent to 12.0 per cent, determined on

0.200 g by the semi-micro determination of water.
Sulphated ash (2.4.14). Not more than 0.2 per cent,
determined on 1.0 g.

ASSAY
Examine by liquid chromatography (2.2.29).
C. (6R,7S)-7-[[(Z)-2-(2-aminothiazol-4-yl)-2-
Test solution. Dissolve 25.0 mg of the substance to be
[(carboxymethoxy)imino]acetyl]amino]-3-ethenyl-
examined in the mobile phase and dilute to 25.0 ml with the
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
mobile phase.
(cefixime 7-epimer),
Reference solution (a). Dissolve 25.0 mg of cefixime CRS in
the mobile phase and dilute to 25.0 ml with the mobile phase.
Reference solution (b). Dilute 1.0 ml of reference solution (a)
to 100.0 ml with the mobile phase.
Reference solution (c). Dissolve 10 mg of cefixime CRS in
10 ml of water R. Heat on a water-bath for 45 min. Cool and
inject immediately.
The chromatographic procedure may be carried out using : D. (6R,7R)-7-[[(E)-2-(2-aminothiazol-4-yl)-2-
a column 0.125 m long and 4 mm in internal [(carboxymethoxy)imino]acetyl]amino]-3-ethenyl-
diameter packed with octadecylsilyl silica gel for 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
chromatography R (5 m), (cefixime E-isomer),
as mobile phase at a flow rate of 1.0 ml/min a mixture
of 250 volumes of acetonitrile R and 750 volumes of
a tetrabutylammonium hydroxide solution prepared
as follows : dissolve 8.2 g of tetrabutylammonium
hydroxide R in water R and dilute to 800 ml with the
same solvent ; adjust to pH 6.5 with dilute phosphoric
acid R and dilute to 1000 ml with water R,
as detector a spectrophotometer set at 254 nm,
a 10 l loop injector,
E. R = H, R = CH3 : (6R,7R)-7-[[(Z)-2-(2-aminothiazol-4-yl)-2-
maintaining the temperature of the column at 40 C. [(carboxymethoxy)imino]acetyl]amino]-3-methyl-8-oxo-5-
Inject reference solution (c). Adjust the sensitivity of the thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
system so that the heights of the principal peaks are at least F. R = C2H5, R = CH=CH2 : (6R,7R)-7-[[(Z)-2-(2-aminothiazol-
20 per cent of the full scale of the recorder. The test is not 4-yl)-2-[(2-ethoxy-2-oxoethoxy)imino]acetyl]amino]-
valid unless the resolution between the 2 principal peaks 3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
(cefixime and E-isomer) is at least 2.0. If necessary, adjust carboxylic acid.
the concentration of acetonitrile in the mobile phase. Inject
reference solution (a) 6 times. The test is not valid unless the 01/2005:1404
relative standard deviation of the peak area for cefixime is
at most 1.0 per cent. Inject alternately the test solution and
reference solution (a). CEFOPERAZONE SODIUM
STORAGE Cefoperazonum natricum
Store in an airtight container, protected from light.

IMPURITIES

C25H26N9NaO8S2 Mr 668
A. R = CO2H : 2-[[(Z)-2-(2-aminothiazol-4-yl)-2- DEFINITION
[(carboxymethoxy)imino]acetyl]amino]-2-[(2R)-5- Cefoperazone sodium contains not less than 95.0 per cent
methyl-7-oxo-1,2,5,7-tetrahydro-4H-furo[3,4-d][1,3]thiazin- and not more than the equivalent of 102.0 per cent of
2-yl]acetic acid, sodium (6R,7R)-7-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-
yl)carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3-[[(1-
B. R = H : 2-[[[(Z)-1-(2-aminothiazol-4-yl)-2-[[[(2R,5RS)-5- methyl-1H-tetrazol-5-yl)sulphanyl]methyl]-8-oxo-5-thia-1-
methyl-7-oxo-1,2,5,7-tetrahydro-4H-furo[3,4-d][1,3]thiazin- azabicyclo[4.2.0]oct-2-ene-2-carboxylate, calculated with
2-yl]methyl]amino]-2-oxoethylidene]amino]oxy]acetic acid, reference to the anhydrous and acetone-free substance.

1212 See the information section on general monographs (cover pages)