Cefixime

(Ph Eur monograph 1188)

 

C16H15N5O7S2,3H2O 507.5      79350-37-1

 

Ph Eur


 

 

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

 

First identification

 

A.

 

Second identification

 

B, C.

 

A.    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.

 

B.    Examine by thin-layer chromatography (2.2.27), using a TLC silanised silica gel F254 plate R.

 

Test solution. Dissolve 20 mg of the substance to be examined in 5 ml of a mixture of equal volumes of methanol  R and 0.067 M phosphate buffer solution pH 7.0 R.

 

Reference solution (a). Dissolve 20 mg of cefixime CRS in 5 ml of a mixture of equal volumes of methanol  R and 0.067 M phosphate buffer solution pH 7.0 R.

 

Reference solution (b). Dissolve 20 mg of cefixime CRS and 20 mg of ceftriaxone sodium CRS in 5 ml of a mixture of equal volumes of methanol  R and 0.067 M phosphate buffer solution pH 7.0 R.

 

Apply to the plate 1 ml of each solution. Develop over a path of 15 cm using a mixture of 10 volumes of methyl acetate R and 90 volumes of a 154 g/l solution of ammonium acetate R previously adjusted to pH 6.2 with acetic acid R. Allow the plate to dry and examine in ultraviolet light at 254 nm. The principal spot in the chromatogram obtained with the test solution is similar in position and size to the principal spot in the chromatogram obtained with reference solution (a). The test is not valid unless the chromatogram obtained with reference solution (b) shows 2 clearly separated spots.

 

C.    Place about 2 mg in a test-tube about 150 mm long and 15 mm in diameter. Moisten with 0.05 ml of water  R and add 2 ml of sulphuric acid-formaldehyde reagent R. Mix the contents of the tube by swirling; the solution is yellow. Place the test-tube in a water-bath for 1 min; an orange colour develops.

 

TESTS

 

pH (2.2.3)

 

Suspend 0.5 g in carbon dioxide-free water  R and dilute to 10 ml with the same solvent. The pH of the 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.

 

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).

 

Test solution

 

Dissolve 25.0 mg of the substance to be examined in the mobile phase and dilute to 25.0 ml with the mobile phase.

 

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:

 

a column 0.125 m long and 4 mm in internal diameter packed with octadecylsilyl silica gel for chromatography R (5 mm),

 

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 ml loop injector,

 

maintaining the temperature of the column at 40 C.

 

Inject reference solution (c). Adjust the sensitivity of the system so that the heights of the principal peaks are at least 20 per cent of the full scale of the recorder. The test is not valid unless the resolution between the 2 principal peaks (cefixime and E-isomer) is at least 2.0. If necessary, adjust the concentration of acetonitrile in the mobile phase. Inject reference solution (a) 6 times. The test is not valid unless the 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).

 

STORAGE

 

Store in an airtight container , protected from light.

 

IMPURITIES

 

A.    R = CO2H: 2-[[(Z)-2-(2-aminothiazol-4-yl)-2-[(carboxymethoxy)imino]acetyl]amino]-2-[(2R)-5-methyl-7-oxo-1,2,5,7-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]acetic acid,

 

B.    R = H: 2-[[[(Z)-1-(2-aminothiazol-4-yl)-2-[[[(2R,5RS)-5-methyl-7-oxo-1,2,5,7-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]methyl]amino]-2-oxoethylidene]amino]oxy]acetic acid,

 

C.       (6R,7S)-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 (cefixime 7-epimer),

 

D.       (6R,7R)-7-[[(E)-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 (cefixime E-isomer),

 

E.    R = H, R¢ = CH3: (6R,7R)-7-[[(Z)-2-(2-aminothiazol-4-yl)-2-[(carboxymethoxy)imino]acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

 

F.    R = C2H5, R¢ = CH=CH2: (6R,7R)-7-[[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-ethoxy-2-oxoethoxy)imino]acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

 

 


 Ph Eur

 

Action and use

 

Antibacterial.