Cefadroxil monohydrate EUROPEAN PHARMACOPOEIA 5.0

C. (6R,7R)-7-[[(2S)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

D. (2R,6R,7R)- and (2S,6R,7R)-7-[[(2R)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid(delta-3-cefaclor),

E. 2-[[(2R)-2-amino-2-phenylacetyl]amino]-2-(5-chloro-4-oxo-3,4-dihydro-2H-1,3-thiazin-2-yl)acetic acid,

F. 3-phenylpyrazin-2-ol.

G. (2R,6R,7R)- and (2S,6R,7R)-7-[[(2R)-2-amino-2-phenylacetyl]amino]-3-methylene-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylic acid (isocefalexine),

H. (6R,7R)-7-[[(2R)-2-[[(2R)-2-amino-2-phenylacetyl]amino]-2-phenylacetyl]amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid(N-phenylglycyl cefaclor).

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CEFADROXIL MONOHYDRATE

Cefadroxilum monohydricum

C16H17N3O5S,H2O Mr 381.4

DEFINITION(6R,7R)-7-[[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid monohydrate.Content : 95.0 per cent to 102.0 per cent (anhydroussubstance).

CHARACTERSAppearance : white or almost white powder.Solubility : slightly soluble in water, very slightly solublein alcohol.

IDENTIFICATION

Infrared absorption spectrophotometry (2.2.24).

TESTS

pH (2.2.3) : 4.0 to 6.0.Suspend 1.0 g in carbon dioxide-free water R and dilute to20 ml with the same solvent.

Specific optical rotation (2.2.7) : + 165 to + 178 (anhydroussubstance).Dissolve 0.500 g in water R and dilute to 50.0 ml with thesame solvent.

Absorbance (2.2.25). Dissolve 20.0 mg in phosphatebuffer solution pH 6.0 R and dilute to 100.0 ml with thesame solvent. The absorbance of the solution determinedat 330 nm is not greater than 0.05. Dilute 10.0 ml ofthe solution to 100.0 ml with phosphate buffer solutionpH 6.0 R. Examined between 235 nm and 340 nm, thediluted solution shows an absorption maximum at 264 nm.The specific absorbance at this maximum is 225 to 250(anhydrous substance).

Related substances. Liquid chromatography (2.2.29).Test solution. Dissolve 50.0 mg of the substance to beexamined in mobile phase A and dilute to 50.0 ml withmobile phase A.Reference solution (a). Dissolve 10.0 mg ofD-α-(4-hydroxyphenyl)glycine CRS (impurity A) inmobile phase A and dilute to 10.0 ml with mobile phase A.Reference solution (b). Dissolve 10.0 mg of7-aminodesacetoxycephalosporanic acid CRS(impurity B) in phosphate buffer solution pH 7.0 R5 anddilute to 10.0 ml with the same buffer solution.Reference solution (c). Dilute 1.0 ml of reference solution (a)and 1.0 ml of reference solution (b) to 100.0 ml with mobilephase A.

1200 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 5.0 Cefadroxil monohydrate

Reference solution (d). Dissolve 10 mg ofdimethylformamide R and 10 mg of dimethylacetamide Rin mobile phase A and dilute to 10.0 ml with mobile phase A.Dilute 1.0 ml to 100.0 ml with mobile phase A.

Reference solution (e). Dilute 1.0 ml of reference solution (c)to 25.0 ml with mobile phase A.

Column :

— size : l = 0.10 m, Ø = 4.6 mm,

— stationary phase : spherical octadecylsilyl silica gel forchromatography R (5 µm).

Mobile phase :

— mobile phase A : phosphate buffer solution pH 5.0 R,

— mobile phase B : methanol R2,

Time(min)

Mobile phase A(per cent V/V)

Mobile phase B(per cent V/V)

0 - 1 98 2

1 - 20 98 → 70 2 → 30

20 - 23 70 → 98 30 → 2

23 - 30 98 2

Flow rate : 1.5 ml/min.

Detection : spectrophotometer at 220 nm.

Injection : 20 µl ; inject the test solution and referencesolutions (c), (d) and (e).

Relative retention with reference to cefadroxil (retentiontime = about 6 min) : dimethylformamide = about 0.4 ;dimethylacetamide = about 0.75.

System suitability :

— resolution : minimum 5.0 between the peaks due toimpurity A and to impurity B in the chromatogramobtained with reference solution (c),

— signal-to-noise ratio : minimum 10 for the second peak inthe chromatogram obtained with reference solution (e).

Limits :

— impurity A : not more than the area of the first peak inthe chromatogram obtained with reference solution (c)(1.0 per cent),

— any other impurity : not more than the area of the secondpeak in the chromatogram obtained with referencesolution (c) (1.0 per cent),

— total : not more than 3 times the area of the second peakin the chromatogram obtained with reference solution (c)(3.0 per cent),

— disregard limit : 0.05 times the area of the secondpeak in the chromatogram obtained with referencesolution (c) (0.05 per cent) ; disregard the peaks due todimethylformamide and dimethylacetamide.

N,N-Dimethylaniline (2.4.26, Method B) : maximum 20 ppm.

Water (2.5.12) : 4.0 per cent to 6.0 per cent, determined on0.200 g.

Sulphated ash (2.4.14) : maximum 0.5 per cent, determinedon 1.0 g.

ASSAY

Liquid chromatography (2.2.29).

Test solution. Dissolve 50.0 mg of the substance to beexamined in the mobile phase and dilute to 100.0 ml withthe mobile phase.

Reference solution (a). Dissolve 50.0 mg of cefadroxil CRSin the mobile phase and dilute to 100.0 ml with the mobilephase.Reference solution (b). Dissolve 5 mg of cefadroxil CRS and50 mg of amoxicillin trihydrate CRS in the mobile phaseand dilute to 100 ml with the mobile phase.Column :— size : l = 0.25 m, Ø = 4.6 mm,— stationary phase : octadecylsilyl silica gel for

chromatography R (5 µm).Mobile phase : acetonitrile R, a 2.72 g/l solution ofpotassium dihydrogen phosphate R (4:96 V/V).Flow rate : 1 ml/min.Detection : spectrophotometer at 254 nm.Injection : 20 µl.System suitability : reference solution (b) :— resolution : minimum 5.0 between the peaks due to

cefadroxil and to amoxicillin.Calculate the percentage content of cefadroxil.

STORAGEProtected from light.

IMPURITIES

A. (2R)-2-amino-2-(4-hydroxyphenyl)acetic acid,

B. (6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-ADCA),

C. (2R,5RS)-2-[(R)-[[(2R)-2-amino-2-(4-hydroxy-phenyl)acetyl]amino]carboxymethyl]-5-methyl-5,6-dihy-dro-2H-1,3-thiazine-4-carboxylic acid,

D. (6R,7R)-7-[[(2S)-2-amino-2-(4-hydroxy-phenyl)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-ene-2-carboxylic acid (L-cefadroxil),

General Notices (1) apply to all monographs and other texts 1201

Cefalexin monohydrate EUROPEAN PHARMACOPOEIA 5.0

E. (6RS)-3-(aminomethylene)-6-(4-hydroxyphenyl)piperazine-2,5-dione,

F. (6R,7R)-7-[[(2R)-2-[[(2RS)-2-amino-2-(4-hydroxy-phenyl)acetyl]amino]-2-(4-hydroxyphenyl)acetyl]ami-no]-3-methyl-8-oxo-5-thia-1-azabicyc-lo[4.2.0]oct-2-ene-2-carboxylic acid,

G. 3-hydroxy-4-methylthiophen-2(5H)-one,

H. (6R,7R)-7-[(2,2-dimethylpropanoyl)amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid(7-ADCA pivalamide).

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CEFALEXIN MONOHYDRATE

Cefalexinum monohydricum

C16H17N3O4S,H2O Mr 365.4

DEFINITION(6R,7R)-7-[[(2R)-2-Amino-2-phenylacetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acidmonohydrate.Content : 95.0 per cent to 102.0 per cent (anhydroussubstance).

CHARACTERSAppearance : white or almost white, crystalline powder.Solubility : sparingly soluble in water, practically insolublein alcohol.

IDENTIFICATIONInfrared absorption spectrophotometry (2.2.24).Comparison : cefalexin monohydrate CRS.

TESTS

pH (2.2.3) : 4.0 to 5.5.Dissolve 50 mg in carbon dioxide-free water R and dilute to10 ml with the same solvent.

Specific optical rotation (2.2.7) : + 149 to + 158 (anhydroussubstance).Dissolve 0.125 g in phthalate buffer solution pH 4.4 R anddilute to 25.0 ml with the same solvent.

Absorbance (2.2.25). Dissolve 50 mg in water R and diluteto 100.0 ml with the same solvent. The absorbance of thesolution determined at 330 nm is not greater than 0.05.Dilute 2.0 ml of the solution to 50.0 ml with water R.Examined between 220 nm and 300 nm, the diluted solutionshows an absorption maximum at 262 nm. The specificabsorbance at this maximum is 220 to 245, calculated withreference to the anhydrous substance.

Related substances. Liquid chromatography (2.2.29).Test solution. Dissolve 50.0 mg of the substance to beexamined in mobile phase A and dilute to 50.0 ml withmobile phase A.Reference solution (a). Dissolve 10.0 mg ofD-phenylglycine R in mobile phase A and dilute to10.0 ml with mobile phase A.Reference solution (b). Dissolve 10.0 mg of7-aminodesacetoxycephalosporanic acid CRS inphosphate buffer solution pH 7.0 R5 and dilute to 10.0 mlwith mobile phase A.Reference solution (c). Dilute 1.0 ml of reference solution (a)and 1.0 ml of reference solution (b) to 100.0 ml with mobilephase A.Reference solution (d). Dissolve 10 mg ofdimethylformamide R and 10 mg of dimethylacetamide Rin mobile phase A and dilute to 10.0 ml with mobile phase A.Dilute 1.0 ml to 100.0 ml with mobile phase A.Reference solution (e). Dilute 1.0 ml of reference solution (c)to 20.0 ml with mobile phase A.Reference solution (f). Dissolve 10 mg of cefotaximesodium CRS in mobile phase A and dilute to 10.0 ml withmobile phase A. To 1.0 ml of the solution add 1.0 ml of thetest solution and dilute to 100 ml with mobile phase A.Column :— size : l = 0.10 m, Ø = 4.6 mm,— stationary phase : spherical octadecylsilyl silica gel for

chromatography R (5 µm).Mobile phase :— mobile phase A : phosphate buffer solution pH 5.0 R,— mobile phase B : methanol R2,

Time(min)

Mobile phase A(per cent V/V)

Mobile phase B(per cent V/V)

0 - 1 98 2

1 - 20 98 → 70 2 → 30

20 - 23 70 → 98 30 → 2

23 - 30 98 2

Flow rate : 1.5 ml/min.Detection : spectrophotometer at 220 nm.Injection : 20 µl ; inject the test solution and referencesolutions (c), (d), (e) and (f).

1202 See the information section on general monographs (cover pages)