Codeine

(Ph. Eur. monograph 0076)

C₁₈H₂₁NO₃,H₂O    317.4    76-57-3

Opioid receptor agonist; analgesic.

Ph Eur

7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol monohydrate.

99.0 per cent to 101.0 per cent (dried substance).

White or almost white, crystalline powder or colourless crystals.

Soluble in boiling water, freely soluble in ethanol (96 per cent).

First identification   A, C.

Second identification   A, B, D, E.

A. Melting point (2.2.14): 155 °C to 159 °C.

B. Ultraviolet and visible absorption spectrophotometry (2.2.25).

Test solution  To 2.0 mL of solution S (see Tests) add 50 mL of water R then 10 mL of 1 M sodium hydroxide and dilute to 100.0 mL with water R.

Spectral range  250-350 nm.

Absorption maximum  At 284 nm.

Specific absorbance at the absorption maximum  About 50 (dried substance).

C. Infrared absorption spectrophotometry (2.2.24).

Preparation  Dried substance prepared as a disc of potassium bromide R.

Comparison   codeine CRS.

D. To about 10 mg add 1 mL of sulfuric acid R and 0.05 mL of ferric chloride solution R2 and heat on a water-bath. A blue colour develops. Add 0.05 mL of nitric acid R. The colour changes to red.

E. It gives the reaction of alkaloids (2.3.1).

Dissolve 50 mg in carbon dioxide-free water R and dilute to 10.0 mL with the same solvent.

Solution S is clear (2.2.1) and colourless (2.2.2, Method II).

- 142 to - 146 (dried substance).

Dissolve 0.50 g in ethanol (96 per cent) R and dilute to 25.0 mL with the same solvent.

Liquid chromatography (2.2.29).

Test solution  Dissolve 0.100 g of the substance to be examined and 0.100 g of sodium octanesulfonate R in the mobile phase and dilute to 10.0 mL with the mobile phase.

Reference solution (a)  Dissolve 5.0 mg of codeine impurity A CRS in the mobile phase and dilute to 5.0 mL with the mobile phase.

Reference solution (b)  Dilute 1.0 mL of reference solution (a) to 20.0 mL with the mobile phase.

Reference solution (c)  Dilute 1.0 mL of the test solution to 50.0 mL with the mobile phase. Dilute 5.0 mL of this solution to 100.0 mL with the mobile phase.

Reference solution (d)  To 0.25 mL of the test solution, add 2.5 mL of reference solution (a).

• — size: l = 0.25 m, Ø = 4.6 mm;

• — stationary phase: end-capped octylsilyl silica gel for chromatography R (5 µm).

Mobile phase  Dissolve 1.08 g of sodium octanesulfonate R in a mixture of 20 mL of glacial acetic acid R and 250 mL of acetonitrile R and dilute to 1000 mL with water R.

Flow rate  2 mL/min.

Detection  Spectrophotometer at 245 nm.

Injection  10 µL.

Run time  10 times the retention time of codeine.

Relative retention  With reference to codeine (retention time = about 6 min): impurity B = about 0.6; impurity E = about 0.7; impurity A = about 2.0; impurity C = about 2.3; impurity D = about 3.6.

System suitability  Reference solution (d):

• — resolution: minimum 3 between the peaks due to codeine and impurity A.

• — correction factor: for the calculation of content, multiply the peak area of impurity C by 0.25;

• — impurity A: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 per cent);

• — impurities B, C, D, E: for each impurity, not more than twice the area of the principal peak in the chromatogram obtained with reference solution (c) (0.2 per cent);

• — unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.10 per cent);

• — sum of impurities other than A: not more than 10 times the area of the principal peak in the chromatogram obtained with reference solution (c) (1.0 per cent);

• — disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.05 per cent).

4.0 per cent to 6.0 per cent, determined on 1.000 g by drying in an oven at 105 °C.

Maximum 0.1 per cent, determined on 1.0 g.

Dissolve 0.250 g in 10 mL of anhydrous acetic acid R. Add 20 mL of dioxan R. Titrate with 0.1 M perchloric acid, using 0.05 mL of crystal violet solution R as indicator.

1 mL of 0.1 M perchloric acid is equivalent to 29.94 mg of C₁₈H₂₁NO₃.

Protected from light.

Specified impurities   A, B, C, D, E.

Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use): F, G.

A. 7,8-didehydro-4,5α-epoxy-3,6α-dimethoxy-17-methylmorphinan (methylcodeine),

B. 7,8-didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol (morphine),

C. 7,7′,8,8′-tetradehydro-4,5α:4′,5′α-diepoxy-3,3′-dimethoxy-17,17′-dimethyl-2,2′-bimorphinanyl-6α,6′α-diol (codeine dimer),

D. 7,8-didehydro-2-[(7,8-didehydro-4,5α-epoxy-6α-hydroxy-17-methylmorphinan-3-yl)oxy]-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol (3-O-(codein-2-yl)morphine),

E. 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α,10-diol,

F. 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α,14-diol,

G. 6,7,8,14-tetradehydro-4,5α-epoxy-3,6-dimethoxy-17-methylmorphinan (thebaine).

Ph Eur