头孢拉定胶囊英国药典BP2013 UpdatedB

?British Pharmacopoeia Volume III

?Formulated Preparations: Specific Monographs

Cefradine Capsules

General Notices

Action and use

Cephalosporin antibacterial.

DEFINITION

Cefradine Capsules contain Cefradine.

The capsules comply with the requirements stated under Capsules and with the following requirements. Content of cephalosporins, calculated as the sum of cefradine (C16H19N3O4S), cefalexin

(C16H17N3O4S) and 4′,5′-dihydrocefradine (C16H21N3O4S)

90.0 to 105.0% of the stated amount of Cefradine.

IDENTIFICATION

CHROMATOGRAPHIC CONDITIONS

(a) Use a TLC silica gel plate (Analtech plates are suitable). Impregnate the plate by placing it in a tank

containing a shallow layer of a 5% v/v solution of n-tetradecane in n-hexane, allowing the impregnating solvent to ascend to the top, removing the plate from the tank and allowing the solvent to evaporate;

use with the flow of the mobile phase in the same direction that the impregnation was carried out.

(b) Use the mobile phase as described below.

(c) Apply 5 μL of each solution.

(d) Develop the plate to 15 cm.

(e) After removal of the plate, heat at 90° for 2 to 3 minutes and spray the hot plate with a 0.1% w/v

solution of ninhydrin in the mobile phase. Heat at 90° for 15 minutes in a circulating air oven with the plates parallel to the airflow, cool for 15 minutes protected from light and examine in daylight.

MOBILE PHASE

3 volume of acetone, 80 volumes of 0.2M anhydrous disodium hydrogen orthophosphate and

120 volumes of 0.1M citric acid.

CONFIRMATION

The principal spot in the chromatogram obtained with solution (1) corresponds to that in the chromatogram obtained with solution (2).

TESTS

Dissolution

Comply with the requirements for Monographs of the British Pharmacopoeia in the dissolution test for tablets and capsules, Appendix XII B1.

TEST CONDITIONS

(a) Use Apparatus 1, rotating the basket at 100 revolutions per minute.

(b) Use 900 mL of 0.12M hydrochloric acid, at a temperature of 37°, as the medium.

PROCEDURE

DETERMINATION OF CONTENT

Calculate the total content of cephalosporins, as the sum of the contents of C16H19N3O4S, C16H17N3O4S and C16H21N3O4S in the medium from the absorbance obtained and using the declared content of total cephalosporins in cefradine BPCRS.

Related substances

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Shake a quantity of the contents of the capsules containing 0.3 g of Cefradine in mobile phase A, add sufficient mobile phase A to produce 50 mL and filter through a 0.45-μm filter.

(2) Dilute 1 volume of solution (1) to 100 volumes with mobile phase A.

(3) 0.012% w/v of each of cefradine BPCRS and cefalexin BPCRS in mobile phase A.

(4) 0.003% w/v of cyclohexa-1,4-dienylglycine EPCRS (impurity B) in mobile phase A.

(5) Dissolve 6 mg of cefradine for peak identification EPCRS (containing impurities C, D and E) in 1 mL of mobile phase A.

(6) Dissolve the contents of a vial of cefradine impurity mixture EPCRS (containing impurities A and G) in 1 mL of mobile phase A.

CHROMATOGRAPHIC CONDITIONS

(a) Use a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Varian Chrompack Inertsil ODS-3 is suitable).

(b) Use gradient elution and the mobile phase described below.

(c) Use a flow rate of 1.0 mL per minute.

(d) Use a column temperature of 30°.

(e) Use a detection wavelength of 220 nm.

(f) Inject 25 μL of each solution.

MOBILE PHASE

Mobile phase A 0.272% w/v of potassium dihydrogen orthophosphate adjusted to pH 3.0 with dilute orthophosphoric acid.

Mobile phase B methanol R2.

When the chromatograms are recorded under the prescribed conditions the retention times relative to Cefradine (retention time = about 15 minutes) are: impurity A = about 0.27; impurity B = about 0.32; impurity C = about 0.53; impurity D = about 0.63; impurity E = about 0.80; impurity F = about 0.92; cefalexin = about 0.95; 4′,5′-dihydrocefradine = about 1.06; impurity G = about 1.32.

SYSTEM SUITABILITY

The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to cefalexin and cefradine is at least 4.0.

LIMITS

Identify any peaks in the chromatogram obtained with solution (1) due to impurities C, D and E using the chromatogram obtained with solution (5) and the chromatogram supplied with cefradine for peak identification EPCRS. Identify any peaks in the chromatogram obtained with solution (1) due to impurities A and G using the chromatogram obtained with solution (6) and the chromatogram supplied with cefradine impurity mixture EPCRS.

In the chromatogram obtained with solution (1):

the area of any peak corresponding to impurity B is not greater than 0.5 times the area of the principal peak in the chromatogram obtained with solution (4) (0.25%);

the area of any peak corresponding to impurity A, D, F or G is not greater than 0.25 times the area of the principal peak in the chromatogram obtained with solution (2) (0.25% for each);

the area of any peak corresponding to impurity C is not greater than 0.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);

the area of any peak corresponding to impurity E is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1%);

the area of any other secondary peak is not greater than 0.25 times the area of the principal peak in the chromatogram obtained with solution (2) (0.25%);

the sum of the areas of all the peaks is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (2%).

Disregard the peaks due to cefalexin, and 4′,5′-dihydrocefradine and any peak with an area less than 0.05 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%). Cefalexin

Not more than 10.0%, calculated as the percentage of C16H17N3O4S in the sum of C16H19N3O4S,

C16H17N3O4S and C16H21N3O4S determined in the Assay.

4′,5′-Dihydrocefradine

Not more than 2.0%, calculated as the percentage of C16H21N3O4S in the sum of C16H19N3O4S,

C16H17N3O4S and C16H21N3O4S determined in the Assay.

Loss on drying

The contents of the capsules, when dried at 60° at a pressure not exceeding 0.7 kPa for 3 hours, lose not more than 7.0% of their weight. Use 1 g.

ASSAY

Carry out the method for liquid chromatography, Appendix III D, using the following solutions in a mixture of 3 volumes of 0.7M glacial acetic acid, 15 volumes of 0.5M sodium acetate, 200 volumes of methanol and 782 volumes of water (solution A).

(1) Dissolve a quantity of the powdered mixed contents of 20 capsules to produce a solution containing 0.05% w/v of Cefradine.

(2) 0.05% w/v of cefradine BPCRS.

(3) 0.005% w/v of cefalexin BPCRS.

(4) Dilute 1 volume of solution (2) to 10 volumes with solution A. Mix equal volumes of this solution and solution (3).

CHROMATOGRAPHIC CONDITIONS

(a) Use a stainless steel column (10 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Hypersil ODS is suitable).

(b) Use isocratic elution and the mobile phase described below.

(c) Use a flow rate of 1.5 mL per minute.

(d) Use an ambient column temperature.

(e) Use a detection wavelength of 254 nm.

(f) Inject 5 μL of each solution.

MOBILE PHASE

25 volumes of methanol and 75 volumes of phosphate buffer solution pH 5.0.

SYSTEM SUITABILITY

The Assay is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks corresponding to cefradine and cefalexin is at least 4.0.

DETERMINATION OF CONTENT

Calculate the content of cephalosporins in the capsules by determining the sum of the contents of

C16H19N3O4S, C16H17N3O4S and C16H21N3O4S. Calculate the content of C16H19N3O4S (cefradine) using the declared content of C16H19N3O4S in cefradine BPCRS. Calculate the content of C16H17N3O4S (cefalexin) using the declared content of C16H17N3O4S in cefalexin BPCRS. Calculate the content of

C16H21N3O4S (4′,5′-dihydrocefradine) using the declared content of C16H17N3O4S in cefalexin BPCRS and multiplying the area of the peak due to 4′,5′-dihydrocefradine by a correction factor of 1.6.