Edition: BP 2025 (Ph. Eur. 11.6 update)
General Notices
Dihydrocodeine and Paracetamol Tablets
Action and use
Opioid analgesic + analgesic; antipyretic.
DEFINITION
Co-dydramol Tablets contain Dihydrocodeine Tartrate and Paracetamol.
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 and centrifuge. Decant, add 10 mL of 1M sodium hydroxide and 30 mL of dichloromethane to the supernatant liquid, shake, and filter the dichloromethane layer (Whatman GF/C is suitable).
(2) 0.1% w/v of dihydrocodeine tartrate BPCRS in methanol (50%).
(3) 0.1% w/v each of dihydrocodeine tartrate BPCRS and codeine phosphate BPCRS in methanol (50%).
CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel F254 (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 (3) 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 dissolution test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 50 revolutions per minute.
(b) Use as the medium 900 mL of a phosphate buffer (pH 5.8), at a temperature of 37°, prepared in the following manner. Mix 250 mL of 0.2M potassium dihydrogen phosphate and 18 mL of 0.2M sodium hydroxide, and dilute to 1000 mL with water.
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) After 45 minutes withdraw a sample of the medium and filter through a glass-fibre filter (Whatman GF/C is suitable). Dilute the filtrate with the medium, if necessary, to produce a solution expected to contain 0.0056% w/v of Paracetamol.
(2) 0.0056% w/v of paracetamol BPCRS in the mobile phase.
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 243 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, adjusted to pH 2.8 using 2M hydrochloric acid.
DETERMINATION OF CONTENT
Calculate the content of C8H9NO2 in the medium using the declared content of C8H9NO2 in paracetamol BPCRS.
LIMITS
The amount of Paracetamol released is not less than 75% (Q) of the stated amount.
Related substances
Carry out the method for liquid chromatography, Appendix III D using the following solutions prepared in a mixture of 22 volumes of methanol and 78 volumes of solution A.
Solution A: 0.223% w/v of sodium pentanesulfonate in water, adjusted to pH 2.8 with 2M hydrochloric acid.
(1) Mix with the aid of ultrasound a quantity of the powdered tablets containing 0.5 g of Paracetamol in 40 mL. Dilute to 50 mL with the same diluent and filter (a regenerated cellulose membrane is suitable).
(2) Dilute 1 volume of solution (1) to 100 volumes.
(3) 0.0005% w/v each of dihydrodeine tartrate BPCRS and codeine phosphate BPCRS (dihydrocodeine tartrate impurity A).
(4) 0.0001% w/v of 4-aminophenol (paracetamol impurity K)
(5) 0.00001% w/v of 4′-chloroacetanilide (paracetamol impurity J)
(6) Dilute 1 volume of solution (2) to 10 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (3 μm) (Waters Atlantis T3 C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 45°.
(e) Use an autosampler temperature of 4°.
(e) Use detection wavelengths of 220 nm and 246 nm.
(f) Inject 50 μL of each solution.
MOBILE PHASE
Mobile phase A 2 volumes of acetonitrile R1 and 98 volumes of solution A.
Mobile phase B acetonitrile R1.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-6 | 100 | 0 | isocratic |
| 6-18 | 100→93.9 | 0→6.1 | linear gradient |
| 18-30 | 93.9 | 6.1 | isocratic |
| 30-42 | 93.9→85.7 | 6.1→14.3 | linear gradient |
| 42-50 | 85.7→66.3 | 14.3→33.7 | linear gradient |
| 50-52 | 66.3→0 | 33.7→100 | linear gradient |
| 52-54.5 | 0 | 100 | isocratic |
| 54.5-55 | 0→100 | 100→0 | linear gradient |
| 55-65 | 100 | 0 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to paracetamol (retention time about 9 minutes) are: paracetamol impurity K, about 0.7; dihydrocodeine impurity B, about 2.3; dihydrocodeine, about 4.0; dihydrocodeine impurity A, about 4.1; dihydrocodeine impurity C, about 4.7; paracetamol impurity J, about 5.2; dihydrocodeine impurity D, about 5.3.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to dihydrocodeine and dihydrocodeine impurity A is at least 1.5 at 220 nm.
LIMITS
For paracetamol impurity J at 246 nm
In the chromatogram obtained with solution (1):
the area of any peak corresponding to paracetamol impurity J is not greater than the area of the principal peak in the chromatogram obtained with solution (5) (10 ppm).
For all other impurities at 220 nm
Identify any peak corresponding to dihydrocodeine impurity A and multiply the area of this peak by a correction factor of 0.7.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to dihydrocodeine impurity A is not greater than half the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);
the area of any peak corresponding to dihydrocodeine impurities B, C, or D is not greater than 3 times the area of the principal peak in the chromatogram obtained with solution (6) (0.3% of each);
the area of any peak corresponding to paracetamol impurity K is not greater than the area of the corresponding peak in the chromatogram obtained with solution (4) (100 ppm);
the area of any other secondary peak is not greater than the area of the peak due to paracetamol in the chromatogram obtained with solution (6) (0.1%).
The total impurity content, excluding dihydrocodeine impurities A to D, is not greater than 0.75%.
Disregard any peak, excluding paracetamol impurities J and K, with an area less than half the area of the peak due to paracetamol in the chromatogram obtained with solution (6) (0.05%)
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 and dilute with sufficient water to produce a solution expected to contain 0.005% w/v of Dihydrocodeine Tartrate, 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 Dissolution may be used, but with a detection wavelength of 225 nm.
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 tablets containing the equivalent of less than 2 mg and/or less than 2% w/w of dihydrocodeine tartrate
Use the average of the individual results determined in the test for Uniformity of content.
For tablets containing the equivalent of 2 mg or more and 2% w/w or more than of 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, dilute with sufficient water to produce a solution containing 0.005% w/v of Dihydrocodeine Tartrate, shake for a further 10 minutes and filter through glass-fibre paper (Whatman GF/C is suitable) and use the filtrate.
(2) 0.005% w/v of dihydrocodeine tartrate BPCRS in water.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Dissolution may be used, but with a detection wavelength of 225 nm.
DETERMINATION OF CONTENT
Calculate the content of dihydrocodeine tartrate, 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) Shake a quantity of the powdered tablets containing 0.5 g of Paracetamol with 50 mL of methanol for 1 minute, dilute with sufficient water to produce a solution containing 0.005% w/v of Paracetamol, shake a further 10 minutes and filter through a glass-fibre paper (Whatman GF/C is suitable) and use the filtrate.
(2) 0.005% w/v of paracetamol BPCRS in water.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Dissolution may be used.
DETERMINATION OF CONTENT
Calculate the content of paracetamol, C8H9NO2, in the tablets using the declared content of C8H9NO2 in paracetamol BPCRS.
LABELLING
The label states the quantities of Dihydrocodeine Tartrate and of Paracetamol in each tablet.
Co-dydramol Tablets should be prescribed and dispensed by strength to minimise dispensing errors and the risk of accidental opioid overdose.
IMPURITIES
The impurities limited by the requirements
