Co-dydramol Tablets

General Notices

Dihydrocodeine and Paracetamol Tablets

Action and use

Opioid analgesic + analgesic; antipyretic.

Definition

Co-dydramol Tablets contain Dihydrocodeine Tartrate and Paracetamol in the proportions, by weight, 1 part to 50 parts.

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

Content of dihydrocodeine tartrate, C18H23NO3,C4H6O6

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 the following solutions.
(1) Shake a quantity of the powdered tablets containing 30 mg of Dihydrocodeine Tartrate with 10 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).
(2) 0.1% w/v of dihydrocodeine tartrate BPCRS in methanol (50%).
(3) 0.1% w/v of codeine phosphate BPCRS in methanol (50%).
(4) A mixture of equal volumes of solutions (2) and (3).
chromatographic conditions
(a) Use as the coating silica gel F254 precoated plate (Merck silica gel 60 F254 plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 10 µL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in air, spray with ethanolic iron(iii) chloride solution and heat at 105° for 10 minutes.
mobile phase

1 volume of 13.5m ammonia, 10 volumes of methanol and 90 volumes of dichloromethane.

system suitability

The test is not valid unless the chromatogram obtained with solution (4) shows two clearly separated spots of different colours.

confirmation

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

C. In the Assay for dihydrocodeine tartrate, 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.

test conditions
(a) Use Apparatus 2, rotating the paddle at 50 revolutions per minute.
(b) Use 900 mL of phosphate buffer pH 5.8, at a temperature of 37°, as the medium.
procedure
(1) After 45 minutes withdraw a 20 mL sample of the medium and measure the absorbance of the filtered sample, suitably diluted with 0.1m sodium hydroxide to give a solution expected to contain about 0.00075% w/v of Paracetamol, at the maximum at 257 nm, Appendix II B using 0.1m sodium hydroxide in the reference cell.
determination of content

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.

(1) 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.
(2) 0.001% w/v of 4-aminophenol in the mobile phase.
chromatographic conditions
(a) Use a stainless steel column (20 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (10 µm) (Nucleosil C18 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 272 nm.
(f) Inject 20 µL of each solution.
mobile phase

0.01m sodium butanesulfonate in a mixture of 0.4 volume of formic acid, 15 volumes of methanol and 85 volumes of water.

limits

In the chromatogram obtained with solution (1):

the area of any peak corresponding to 4-aminophenol is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.1%).

In the chromatogram obtained with solution (1) 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 the following solutions.
(1) Shake a quantity of the powdered tablets containing 50 mg of Dihydrocodeine Tartrate with 0.5m hydrochloric acid, filter, make the filtrate alkaline with 5m sodium hydroxide and extract with four 25 mL quantities of chloroform. Wash each chloroform extract with 10 mL of each of 0.01m sodium hydroxide and water, filter the combined chloroform extracts, evaporate the filtrate to dryness at a temperature not exceeding 45° and dissolve the residue in 2 mL of chloroform.
(2) Dilute 1 volume of solution (1) to 100 volumes with chloroform.
(3) Dilute 1 volume of solution (1) to 200 volumes with chloroform.
chromatographic conditions
(a) Use as the coating silica gel GF254.
(b) Use the mobile phase as described below.
(c) Apply 20 µL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in air and spray with dilute potassium iodobismuthate solution.
mobile phase

1 volume of 13.5m ammonia, 10 volumes of methanol and 90 volumes of dichloromethane.

limits

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%) and not more than one such spot is more intense than the spot in the chromatogram obtained with solution (3) (0.5%).

B. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(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.
(2) Dilute 1 mL of solution (1) to 10 mL with ethanol (96%).
(3) 0.0050% w/v of 4′-chloroacetanilide in ethanol (96%).
(4) Dissolve 0.25 g of 4′-chloroacetanilide and 0.10 g of paracetamol in sufficient ethanol (96%) to produce 100 mL.
chromatographic conditions
(a) Use as the coating silica gel GF254.
(b) Use the mobile phase as described below.
(c) Apply 200 µL of solution (1). Apply 40 µL each of solutions (2), (3) and (4).
(d) Pour the mobile phase into an unlined tank, immediately place the prepared plate in the tank and close the tank. Develop the plate to 14 cm.
(e) After removal of the plate, dry in air and examine under ultraviolet light (254 nm).
mobile phase

10 volumes of toluene, 25 volumes of acetone and 65 volumes of chloroform.

system suitability

The test is not valid unless the chromatogram obtained with solution (4) shows two clearly separated spots, the spot corresponding to 4′-chloroacetanilide having the higher Rf value.

limits

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%).

Uniformity of content

Tablets containing less than 2 mg and/or less than 2% w/w of Dihydrocodeine Tartrate 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.

(1) Add 50 mL of methanol to one tablet and mix with the aid of ultrasound until completely dispersed. Add 100 mL of water, shake for 10 minutes, dilute to 200 mL with water, filter through glass-fibre paper (Whatman GF/C is suitable) and use the filtrate.
(2) 0.005% w/v of dihydrocodeine tartrate BPCRS in methanol (25%).
chromatographic conditions
(a) Use a stainless steel column (10 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Nucleosil C18 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 225 nm.
(f) Inject 20 µL of each solution.
mobile phase

0.01m sodium pentanesulfonate in a mixture of 22 volumes of methanol and 78 volumes of water, the pH of the solution being adjusted to 2.8 using 2m hydrochloric acid.

determination of content

Calculate the content of C18H23NO3,C4H6O6 in each tablet using the declared content of C18H23NO3,C4H6O6 in dihydrocodeine tartrate BPCRS.

Assay

For dihydrocodeine tartrate

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

(1) Shake a quantity of the powdered tablets containing 10 mg of Dihydrocodeine Tartrate with 50 mL of methanol for 1 minute, add 100 mL of water and shake for a further 10 minutes. Dilute to 200 mL with water, filter through glass-fibre paper (Whatman GF/C is suitable) and use the filtrate.
(2) 0.005% w/v of dihydrocodeine tartrate BPCRS in methanol (25%).
chromatographic conditions

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

mobile phase

0.01m sodium pentanesulfonate in a mixture of 22 volumes of methanol and 78 volumes of water, the pH of the solution being adjusted to 2.8 using 2m hydrochloric acid.

determination of content

Calculate the content of C18H23NO3,C4H6O6 in the tablets using the declared content of C18H23NO3,C4H6O6 in dihydrocodeine tartrate BPCRS.

For paracetamol

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

(1) Dilute 1 volume of solution (1) obtained in the Assay for dihydrocodeine tartrate to 50 volumes with water.
(2) 0.005% w/v of paracetamol BPCRS in water.
chromatographic conditions

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

mobile phase

0.01m sodium pentanesulfonate in a mixture of 22 volumes of methanol and 78 volumes of water, the pH of the solution being adjusted to 2.8 using 2m hydrochloric acid.

determination of content

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