Edition: BP 2025 (Ph. Eur. 11.6 update)
General Notices
Effervescent Codeine Phosphate and Paracetamol Tablets
Codeine Phosphate and Paracetamol Effervescent Tablets
Effervescent Co-codamol Tablets
Action and use
Opioid analgesic + analgesic; antipyretic.
DEFINITION
Co-codamol Effervescent Tablets contain Codeine Phosphate and Paracetamol in a suitable soluble, effervescent basis.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of codeine phosphate, C18H21NO3,H3PO4, 1⁄2H2O
92.5 to 107.5% 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 10 mL of water, filter (Whatman GF/C is suitable) and discard the filtrate. Dissolve the residue in 10 mL of acetone 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) Mix a quantity of the powdered tablets containing 24 mg of Codeine Phosphate in 30 mL of water until effervescence ceases, add 10 mL of 1M sodium hydroxide and 30 mL of dichloromethane and shake for 1 minute. Filter the dichloromethane layer through a glass-fibre filter (Whatman GF/C is suitable).
(2) 0.08% w/v of codeine phosphate BPCRS in methanol (50%).
(3) 0.08% w/v of codeine phosphate BPCRS and dihydrocodeine tartrate 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 which are different in colour.
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 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
Related substances
Carry out the method for liquid chromatography, Appendix III D using the following solutions prepared in solution A.
Solution A: 0.23% w/v of sodium chloride in a mixture of 30 volumes of mobile phase B and 70 volumes of mobile phase A.
(1) Shake with the aid of ultrasound a quantity of the powdered tablets containing 0.5 g of Paracetamol with 50 mL of solution A and filter (a regenerated cellulose membrane is suitable).
(2) Dilute 1 volume of solution (1) to 100 volumes.
(3) 0.0005% w/v of codeine phosphate BPCRS and 0.0001% w/v of 4′-chloroacetanilide (paracetamol impurity J).
(4) 0.0001% w/v of 4-aminophenol (paracetamol impurity K).
(5) 0.00001% w/v of 4′-chloroacetanilide (paracetamol impurity J).
(6) 0.0005% w/v of methylcodeine (codeine impurity A).
(7) Dilute 1 volume of solution (2) to 10 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (2.6 μm) (Kinetex C18 100A is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 0.8 mL per minute.
(d) Use a column temperature of 35°.
(e) Use detection wavelengths of 212 nm and 246 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
Mobile phase A 5 mM sodium octanesulfonate, adjusted to pH 2.2 with orthophosphoric acid.
Mobile phase B methanol R1.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-2.5 | 80→70 | 20→30 | linear gradient |
| 2.5-20 | 70 | 30 | isocratic |
| 20-30 | 70→20 | 30→80 | linear gradient |
| 30-32 | 20→80 | 80→20 | linear gradient |
| 32-37 | 80 | 20 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to paracetamol (retention time about 3 minutes) are: paracetamol impurity K, about 2.3; codeine impurity B, about 3.0; codeine, about 5.1; paracetamol impurity J, about 5.7; codeine impurity A, about 7.7 and codeine impurity C, about 8.1.
SYSTEM SUITABILITY
The test is not valid unless:
in the chromatogram obtained with solution (3) at 246 nm, the resolution between the peaks due to codeine and paracetamol impurity J is at least 2.2;
in the chromatogram obtained with solution (4) at 212 nm, the signal-to-noise ratio of the peak due to paracetamol impurity K is at least 10;
in the chromatogram obtained with solution (5) at 246 nm, the signal-to-noise ratio of the peak due to paracetamol impurity J is at least 10.
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 212 nm
In the chromatogram obtained with solution (1):
the area of any peak corresponding to codeine impurity A is not greater than the area of the peak due to codeine in the chromatogram obtained with solution (2) (1%);
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 with a relative retention of 2.7 or less (with reference to paracetamol) is not greater than the area of the peak due to paracetamol in the chromatogram obtained with solution (7) (0.1%);
the area of any other secondary peak with a relative retention greater than 2.7 (with reference to paracetamol) is not greater than twice the area of the peak due to codeine in the chromatogram obtained with solution (7) (0.2%);
The total impurity content, excluding codeine impurity A, is not greater than 0.75%.
Disregard (excluding the peaks due to paracetamol impurities J and K):
any peak with a relative retention of 2.7 or less (with reference to paracetamol) and with an area less than half the area of the peak due to paracetamol in the chromatogram obtained with solution (7) (0.05%);
any peak with a relative retention greater than 2.7 (with reference to paracetamol) and with an area less than the area of the peak due to codeine in the chromatogram obtained with solution (7) (0.1%).
Uniformity of content
Capsules containing less than 2 mg and/or less than 2% w/w of Codeine Phosphate comply with the requirements stated under Capsules using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D,
using the following solutions.
(1) Add mobile phase to the contents of one capsule and mix with the aid of ultrasound until completely dispersed. Shake for 10 minutes, dilute with sufficient mobile phase to produce a solution containing 0.004% w/v of Codeine Phosphate, filter through a glass-fibre filter (Whatman GF/C is suitable) and use the filtrate.
(2) 0.004% w/v of codeine phosphate BPCRS in the mobile phase.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Dissolution may be used, but with a detection wavelength of 220 nm.
DETERMINATION OF CONTENT
Calculate the content of C18H21NO3 ,H3PO4 ,1⁄2H2O in each capsule using the declared content of C18H21NO3 ,H3PO4 ,1⁄2H2O in codeine phosphate BPCRS.
ASSAY
For codeine phosphate
For capsules containing the equivalent of less than 2 mg and/or less than 2% w/w of codeine phosphate
Use the average of the individual results determined in the test for Uniformity of content.
For capsules containing the equivalent of 2 mg or more and 2% w/w or more than of codeine phosphate
Weigh the contents of 20 capsules. Mix and powder if necessary. 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 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.
(2) 0.004% w/v of codeine phosphate BPCRS in the mobile phase.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Dissolution may be used, but with a detection wavelength of 220 nm.
DETERMINATION OF CONTENT
Calculate the content of C18H21NO3 ,H3PO4 ,1⁄2H2O in the capsules using the declared content of C18H21NO3 ,H3PO4 ,1⁄2H2O in codeine phosphate BPCRS.
For paracetamol
Weigh the contents of 20 capsules. Mix and powder if necessary. 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 0.5 g 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.
(2) 0.005% w/v of paracetamol BPCRS in the mobile phase.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Dissolution may be used.
DETERMINATION OF CONTENT
Calculate the content of paracetamol, C8H9NO2, in the capsules using the declared content of C8H9NO2 in paracetamol BPCRS.
LABELLING
The label states the quantities of Codeine Phosphate and of Paracetamol in each capsule.
When Co-codamol Capsules are prescribed or demanded no strength being stated, capsules containing 8 mg of Codeine Phosphate and 500 mg of Paracetamol shall be dispensed or supplied.
IMPURITIES
The impurities limited by the requirements of this monograph include impurities A, B, C, H, I, and J listed under Codeine Phosphate, and impurities J and K listed under Paracetamol.
