Co-codamol Tablets

General Notices

Codeine Phosphate and Paracetamol Tablets

Action and use

Opioid analgesic + analgesic; antipyretic.

Definition

Co-codamol Tablets contain Codeine Phosphate and Paracetamol.

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

Content of codeine phosphate, C18H21NO3,H3PO4,½H2O

95.0 to 105.0% of the stated amount.

Content of paracetamol, C8H9NO2

95.0 to 105.0% of the stated amount.

Identification

A. Shake a quantity of the powdered tablets containing 0.5 g of Paracetamol with 20 mL of acetone, filter and evaporate the filtrate to dryness. The infrared absorption spectrum of the residue, Appendix II A, is concordant with the reference spectrum of paracetamol (RS 258).
B. Carry out the method for thin-layer chromatography, Appendix III A, using a silica gel F254 precoated plate (Merck silica gel 60 F254 plates are suitable) and a mixture of 1 volume of 13.5m ammonia, 10 volumes of methanol and 90 volumes of dichloromethane as the mobile phase. Apply separately to the plate 10 µL of each of the following solutions. For solution (1) shake a quantity of the powdered tablets containing 24 mg of Codeine Phosphate with 30 mL of water for 1 minute and centrifuge. Decant, add 10 mL of 1m sodium hydroxide and 30 mL of chloroform to the supernatant liquid, shake for 1 minute and filter the chloroform layer through glass-fibre paper (Whatman GF/C is suitable). Solution (2) contains 0.08% w/v of codeine phosphate BPCRS in methanol (50%). Solution (3) contains 0.08% w/v each of codeine phosphate BPCRS and dihydrocodeine tartrate BPCRS in methanol (50%). After removal of the plate, allow it to dry in air, spray with ethanolic iron(iii) chloride solution and heat at 105° for 10 minutes. The principal spot in the chromatogram obtained with solution (1) corresponds in position and colour to that in the chromatogram obtained with solution (2). The test is not valid unless the chromatogram obtained with solution (3) shows two clearly separated spots of different colours.
C. In the Assay for codeine phosphate, the chromatogram obtained with solution (2) shows a peak with the same retention time as the principal peak in the chromatogram obtained with solution (1).

TESTS

Dissolution

Comply with the requirements for Monographs of the British Pharmacopoeia in the dissolution test for tablets and capsules with respect to the content of Paracetamol, Appendix XII B1, using Apparatus 2. Use as the medium 900 mL of phosphate buffer pH 5.8 and rotate the paddle at 50 revolutions per minute. Withdraw a sample of 20 mL of the medium and filter. Dilute the filtrate with 0.1m sodium hydroxide to give a solution expected to contain about 0.00075% w/v of Paracetamol. Measure the absorbance of this solution, Appendix II B, at the maximum at 257 nm using 0.1m sodium hydroxide in the reference cell. Calculate the total content of paracetamol, C8H9NO2 in the medium taking 715 as the value of A(1%, 1 cm) at the maximum at 257 nm.

4-Aminophenol

Carry out the method for liquid chromatography, Appendix III D, using the following solutions. Solution (1) contains 0.001% w/v of 4-aminophenol in the mobile phase. For solution (2) shake a quantity of the powdered tablets containing 0.5 g of Paracetamol with 50 mL of the mobile phase for 10 minutes and filter.

The chromatographic procedure may be carried out using (a) a stainless steel column (20 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (10 µm) (Nucleosil C18 is suitable), (b) 0.01m sodium butanesulfonate in a mixture of 0.4 volume of formic acid, 15 volumes of methanol and 85 volumes of water as the mobile phase with a flow rate of 2 mL per minute and (c) a detection wavelength of 272 nm.

In the chromatogram obtained with solution (2) the area of any peak corresponding to 4-aminophenol is not greater than the area of the peak in the chromatogram obtained with solution (1) (0.1%). In the chromatogram obtained with solution (2) peaks with a long retention time may occur due to excipients.

Related substances

A. Carry out the method for thin-layer chromatography, Appendix III A, using silica gel G as the coating substance and a mixture of 6 volumes of 13.5m ammonia, 30 volumes of cyclohexane and 72 volumes of absolute ethanol as the mobile phase. Apply separately to the plate 20 µL of each of the following solutions. For solution (1) shake a quantity of the powdered tablets containing 50 mg of Codeine Phosphate with 50 mL of 0.1m hydrochloric acid for 10 minutes and filter. Make the filtrate alkaline with 5m sodium hydroxide and extract with two 40 mL quantities of chloroform. Wash the combined extracts with 10 mL of water, filter through a layer of anhydrous sodium sulfate on an absorbent cotton plug moistened with chloroform, evaporate the filtrate to dryness at a temperature not exceeding 45° using a rotary evaporator and dissolve the residue in 2 mL of chloroform. For solution (2) dilute 1.5 volumes of solution (1) to 100 volumes with chloroform. For solution (3) dilute 1 volume of solution (1) to 100 volumes with chloroform. After removal of the plate, allow it to dry in air and spray with dilute potassium iodobismuthate solution. Any secondary spot in the chromatogram obtained with solution (1) is not more intense than the spot in the chromatogram obtained with solution (2) (1.5%) and not more than one such spot with an Rf value higher than that of the principal spot is more intense than the spot in the chromatogram obtained with solution (3) (1%).
B. Carry out the method for thin-layer chromatography, Appendix III A, using silica gel GF254 as the coating substance and a mixture of 10 volumes of toluene, 25 volumes of acetone and 65 volumes of chloroform as the mobile phase. Pour the mobile phase into an unlined tank, immediately place the prepared plate in the tank, close the tank and allow the solvent front to ascend 14 cm above the line of application. Apply separately to the plate 200 µL of solution (1) and 40 µL of each of solutions (2), (3) and (4). For solution (1) transfer a quantity of the finely-powdered tablets containing 1.0 g of Paracetamol to a ground-glass-stoppered 15 mL centrifuge tube, add 5 mL of peroxide-free ether, shake mechanically for 30 minutes, centrifuge at 1000 revolutions per minute for 15 minutes or until a clear supernatant liquid is obtained and use the supernatant liquid. For solution (2) dilute 1 mL of solution (1) to 10 mL with ethanol (96%). Solution (3) contains 0.0050% w/v of 4′-chloroacetanilide in ethanol (96%). For solution (4) dissolve 0.25 g of 4′-chloroacetanilide and 0.10 g of paracetamol in sufficient ethanol (96%) to produce 100 mL. After removal of the plate, dry it in a current of warm air and examine under ultraviolet light (254 nm). Any spot corresponding to 4′-chloroacetanilide in the chromatogram obtained with solution (1) is not more intense than the spot in the chromatogram obtained with solution (3) (0.005%). Any secondary spot in the chromatogram obtained with solution (2) with an Rf value lower than that of 4′-chloroacetanilide is not more intense than the spot in the chromatogram obtained with solution (3) (0.25%). The test is not valid unless the chromatogram obtained with solution (4) shows two clearly separated principal spots, the spot corresponding to 4′-chloroacetanilide having the higher Rf value.

Uniformity of content

Tablets containing less than 2 mg and/or less than 2% w/w of Codeine Phosphate comply with the requirements stated under Tablets using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. Solution (1) contains 0.004% w/v of codeine phosphate BPCRS in the mobile phase. For solution (2) add 100 mL of the mobile phase to one tablet and mix with the aid of ultrasound until completely dispersed. Shake for 10 minutes, dilute to 200 mL with the mobile phase, filter through a glass-fibre filter (Whatman GF/C is suitable) and use the filtrate.

The chromatographic procedure may be carried out using (a) a stainless steel column (10 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Nucleosil C18 is suitable), (b) as the mobile phase with a flow rate of 1.5 mL per minute 0.01m sodium pentanesulfonate in a mixture of 78 volumes of water and 22 volumes of methanol, the pH of the solution being adjusted to 2.8 using 2m hydrochloric acid, and (c) a detection wavelength of 220 nm.

Calculate the content of C18H21NO3,H3PO4,½H2O in each tablet using the declared content of C18H21NO3,H3PO4,½H2O in codeine phosphate BPCRS.

Assay

For codeine phosphate

Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. Solution (1) contains 0.004% w/v of codeine phosphate BPCRS in the mobile phase. For solution (2) shake a quantity of the powdered tablets containing 8 mg of Codeine Phosphate with 100 mL of the mobile phase for 10 minutes, dilute to 200 mL with the same solvent, filter through a glass-fibre filter (Whatman GF/C is suitable) and use the filtrate.

The chromatographic conditions described under Uniformity of content may be used.

Calculate the content of C18H21NO3,H3PO4,½H2O using the declared content of C18H21NO3,H3PO4,½H2O in codeine phosphate BPCRS.

For paracetamol

Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. Solution (1) contains 0.005% w/v of paracetamol BPCRS in the mobile phase. For solution (2) shake a quantity of the powdered tablets containing 500 mg of Paracetamol with 100 mL of the mobile phase for 10 minutes, dilute to 200 mL with the same solvent, filter through a glass-fibre filter (Whatman GF/C is suitable) and dilute 5 mL of the filtrate to 250 mL with the mobile phase.

The chromatographic conditions described under Uniformity of content may be used but with a detection wavelength of 243 nm.

Calculate the content of C8H9NO2 using the declared content of C8H9NO2 in paracetamol BPCRS.

Labelling

The label states the quantities of Codeine Phosphate and of Paracetamol in each tablet.

When Co-codamol Tablets are prescribed or demanded no strength being stated, tablets containing 8 mg of Codeine Phosphate and 500 mg of Paracetamol shall be dispensed or supplied.