BP 2025 (Ph. Eur. 11.6 update)
Action and use
Opioid receptor agonist; analgesic.
DEFINITION
Dihydrocodeine Oral Solution is a solution of Dihydrocodeine Tartrate in a suitable flavoured vehicle.
The oral solution complies with the requirements stated under Oral Liquids and with the following requirements.
Content of dihydrocodeine tartrate, C18H23NO3, C4H6O6
95.0 to 105.0% of the stated amount.
IDENTIFICATION
Carry out the following procedure protected from light. To a volume of the oral solution containing 20 mg of Dihydrocodeine Tartrate add 10 mL of water and extract with two 25-mL quantities of cyclohexane. Discard the cyclohexane extracts, add 3 mL of 5M sodium hydroxide to the aqueous layer, mix and extract with 25 mL of cyclohexane. Wash the cyclohexane layer with 10 mL of water, shake with anhydrous sodium sulfate and filter. Wash the filter with cyclohexane and evaporate the combined filtrate and washings to dryness. Dissolve the residue in 1 mL of dichloromethane and apply 0.2 mL dropwise on to the surface of a disc prepared using 0.3 g of potassium bromide, allowing the solvent to evaporate between applications, and dry the disc at 50° for 2 minutes. The infrared absorption spectrum, Appendix II A, is concordant with the reference spectrum of dihydrocodeine (RS 102).
TESTS
Related substances
Carry out the following test protected from light. Carry out the method for liquid chromatography, Appendix III D, using the following solutions in the mobile phase.
(1) Dilute a quantity of the oral solution to produce a solution containing 0.1% w/v of Dihydrocodeine Tartrate.
(2) Dilute 1 volume of solution (1) to 200 volumes.
(3) 0.04% w/v each of dihydrocodeine tartrate BPCRS and codeine phosphate BPCRS.
(4) Dilute 1 volume of solution (2) to 5 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octylsilyl silica gel for chromatography (5 μm) (Hypersil Gold C8 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 284 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
Mobile phase A To 1.0 g of sodium heptanesulfonate, add 10 mL of glacial acetic acid and 4 mL of a solution containing 5 mL of triethylamine diluted to 25 mL with a mixture of equal volumes of acetonitrile and water. Add 170 mL of acetonitrile and dilute to 1000 mL with water.
Mobile phase B acetonitrile
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-20 | 100 | 0 | isocratic |
| 20-25 | 100→20 | 0→30 | linear gradient |
| 25-40 | 20 | 80 | isocratic |
| 40-45 | 20→100 | 80→0 | linear gradient |
| 45-50 | 100 | 0 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the retention relative to dihydrocodeine (retention time about 11 minutes) of codeine is about 1.1.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to dihydrocodeine and codeine is at least 2.0.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to codeine is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);
the area of any other secondary peak is not greater than 0.6 times the area of the principal peak in the chromatogram obtained with solution (2) (0.3%).
the sum of the areas of any secondary peaks is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (1.0%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (4) (0.1%).
ASSAY
Carry out the following procedure protected from light. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Disperse a weighed quantity of the oral solution containing 25 mg of Dihydrocodeine Tartrate in 25 mL of mobile phase A and filter. Dilute 1 volume to 10 volumes with mobile phase A.
(2) 0.01% w/v of dihydrocodeine tartrate BPCRS in water.
(3) 0.04% w/v each of dihydrocodeine tartrate BPCRS and codeine phosphate BPCRS in mobile phase A.
CHROMATOGRAPHIC CONDITIONS
Use the conditions described under Related substances.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to dihydrocodeine and codeine is at least 2.0.
DETERMINATION OF CONTENT
Determine the weight per mL of the oral solution, Appendix V G, and calculate the content of C18H23NO3, C4H6O6, weight in volume, using the declared content of C18H23NO3, C4H6O6 in dihydrocodeine tartrate BPCRS.
STORAGE
Dihydrocodeine Oral Solution should be protected from light.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Dihydrocodeine Tartrate.
