Co-amoxiclav Tablets

General Notices

Amoxicillin and Potassium Clavulanate Tablets

Action and use

Penicillin antibacterial + beta-lactamase inhibitor.

Definition

Co-amoxiclav Tablets contain Amoxicillin Trihydrate and either Potassium Clavulanate or Diluted Potassium Clavulanate.

The tablets comply with the requirements stated under Tablets and with the following requirements.

Content of amoxicillin, C16H19N3O5S

90.0 to 105.0% of the stated amount.

Content of clavulanic acid, C8H9NO5

90.0 to 105.0% of the stated amount.

Identification

Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.

(1) Shake a quantity of the powdered tablets containing the equivalent of 0.4 g of clavulanic acid in 100 mL of a mixture of 4 volumes of methanol and 6 volumes of 0.1m mixed phosphate buffer pH 7.0 and filter.
(2) 0.4% w/v of lithium clavulanate EPCRS and 0.8% w/v of amoxicillin trihydrate BPCRS in a mixture of 4 volumes of methanol and 6 volumes of 0.1m mixed phosphate buffer pH 7.0.
chromatographic conditions
(a) Use a silica gel F254 precoated plate (Merck silica gel 60 F254 plates are suitable). Impregnate the plate by spraying it with a 0.1% w/v solution of disodium edetate in mixed phosphate buffer pH 4.0 and allow to dry overnight. Activate the plate by heating at 105° for 1 hour just prior to use.
(b) Use the mobile phase described below.
(c) Apply 1 µL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in air and examine under ultraviolet light (254 nm).
mobile phase

1 volume of butan-1-ol, 2 volumes of a 0.1% w/v solution of disodium edetate in mixed phosphate buffer pH 4.0, 6 volumes of glacial acetic acid and 10 volumes of butyl acetate.

confirmation

The principal spots in the chromatogram obtained with solution (1) correspond in position and colour to those 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 2, rotating the paddle at 75 revolutions per minute.
(b) Use 900 mL of water, at a temperature of 37°, as the medium.
procedure

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

(1) After 45 minutes withdraw 20 mL of the medium and filter through a 0.45-µm membrane filter, discarding the first 10 mL of filtrate. Use the filtered medium, diluted with water if necessary, to produce a solution containing the equivalent of 0.025% w/v of amoxicillin.
(2) 0.025% w/v of amoxicillin trihydrate BPCRS and 0.01% w/v of lithium clavulanate EPCRS in water.
chromatographic conditions

The chromatographic procedure described under Assay may be used.

determination of content

Calculate the total content of amoxicillin, C16H19N3O5S, and of clavulanic acid, C8H9NO5, in the medium from the chromatograms obtained and using the declared content of C16H19N3O5S in amoxicillin trihydrate BPCRS and the declared content of C8H8LiNO5 in lithium clavulanate EPCRS. Each mg of C8H8LiNO5 is equivalent to 0.9711 mg of C8H9NO5.

Clavulanate polymer and other fluorescent impurities

Carry out the method for fluorescence spectrophotometry, Appendix II E, using the following freshly prepared solutions.

(1) To a quantity of the finely powdered tablets containing the equivalent of 0.1 g of clavulanic acid add 50 mL of a 0.1m phosphate buffer solution pH 5.0, prepared as described below, stir until the sample is evenly dispersed and add sufficient of the buffer solution to produce 100 mL. Shake the solution vigorously for 1 minute, shake mechanically for 5 minutes and then with the aid of ultrasound for 5 minutes and filter through a 0.45-µm filter. To prepare the buffer solution dissolve 15.6 g of sodium dihydrogen orthophosphate in 800 mL of water, adjust the pH to 5.0 using 1m sodium hydroxide and add sufficient water to produce 1000 mL.
(2) Prepare a solution containing 0.42 µg per mL of quinine sulfate BPCRS in 0.5m sulfuric acid. [Note: The fluorescence of quinine sulfate is 118 times more intense than that of an equivalent concentration of clavulanate polymer.]
procedure

Measure the fluorescence of the solutions using an excitation wavelength of 360 nm and an emission wavelength of 440 nm, using the phosphate buffer solution in the reference cell.

limits

The fluorescence obtained with solution (1) is not more intense than that obtained with solution (2) (5% w/w, calculated with respect to the content of clavulanic acid).

Related substances

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

(1) Disperse a quantity of the powdered tablets containing the equivalent of 30 mg of amoxicillin in 15 mL of mobile phase A with the aid of ultrasound for 20 minutes, with occasional shaking. Add sufficient mobile phase A to produce 20 mL and filter through a 0.45-µm membrane filter.
(2) Dilute 1 volume of solution (1) to 100 volumes with mobile phase A.
(3) 0.0004% w/v of cefadroxil BPCRS and 0.003% w/v of amoxicillin trihydrate BPCRS in mobile phase A.
(4) 0.075% w/v of lithium clavulanate EPCRS in mobile phase A.
chromatographic conditions
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Hypersil ODS is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 254 nm.
(f) Inject 50 µL of each solution.
mobile phase
Mobile phase A1 volume of acetonitrile and 99 volumes of a pH 5.0 buffer solution prepared in the following manner. To 250 mL of 0.2m potassium dihydrogen orthophosphate add 2m sodium hydroxide until the pH reaches 5.0 and then add sufficient water to produce 1000 mL.
Mobile phase B20 volumes of acetonitrile and 80 volumes of the pH 5.0 buffer solution.

Use the following gradient conditions:

Equilibrate the column with the mobile phase ratio established during system suitability. Inject freshly prepared solution (1) and immediately after the elution of the amoxicillin peak start a linear gradient elution to reach a mobile phase ratio A:B of 0:100 over 25 minutes. Continue the chromatography with mobile phase B for a further 15 minutes. Equilibrate the column for 15 minutes with the starting mobile phase ratio established during system suitability before the next injection.

Inject mobile phase A using the same elution gradient to obtain a blank.

system suitability

Equilibrate the column with a mobile phase ratio A:B of 92:8. The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to amoxicillin and cefadroxil is at least 2.0. If necessary adjust the ratio A:B of the mobile phase.

limits

In the chromatogram obtained with solution (1):

the area of any peak with a retention time relative to amoxicillin of about 4.1 (amoxicillin dimer) is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (2%);

the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1%).

Disregard any peak corresponding to the principal peak in the chromatogram obtained with solution (4).

Assay

Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Dissolve, with shaking, a quantity of the powdered tablets containing the equivalent of 0.25 g of amoxicillin in 400 mL of water, add sufficient water to produce 500 mL, mix and filter.
(2) 0.05% w/v of amoxicillin trihydrate BPCRS and 0.02% w/v of lithium clavulanate EPCRS in water.
chromatographic conditions
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Hypersil ODS 5 µm is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 2 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 220 nm.
(f) Inject 20 µL of each solution.
mobile phase

5 volumes of methanol and 95 volumes of a 0.78% w/v solution of sodium dihydrogen orthophosphate monohydrate, adjusted to pH 4.4 with orthophosphoric acid.

system suitability

The assay is not valid unless, in the chromatogram obtained with solution (2), the resolution factor between the peaks due to amoxicillin and lithium clavulanate is at least 3.5 and the symmetry factor of the peak due to lithium clavulanate is at most 1.5.

determination of content

Calculate the content of C16H19N3O5S and of C8H9NO5 in the tablets using the declared content of C16H19N3O5S in amoxicillin trihydrate BPCRS and the declared content of C8H8LiNO5 in lithium clavulanate EPCRS. Each mg of C8H8LiNO5 is equivalent to 0.9711 mg of C8H9NO5.

Storage

Co-amoxiclav Tablets should be protected from light and stored in an airtight container.

Labelling

The quantity of Amoxicillin Trihydrate is stated in terms of the equivalent amount of amoxicillin, and the quantity of Potassium Clavulanate is stated in terms of the equivalent amount of clavulanic acid.

The label states that the preparation contains a penicillin.