Codeine Hydrochloride

(Codeine Hydrochloride Dihydrate, Ph Eur monograph 1412)

C₁₈H₂₁NO_3,HCl,2H₂O    371.9    1422-07-7

Opioid receptor agonist; analgesic.

Ph Eur

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

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

White or almost white, crystalline powder or small, colourless crystals.

Soluble in water, slightly soluble in ethanol (96 per cent), practically insoluble in cyclohexane.

First identification   A, D.

Second identification   B, C, D, E.

A. Infrared absorption spectrophotometry (2.2.24).

Comparison   Ph. Eur. reference spectrum of codeine hydrochloride dihydrate.

B. To 5 mL of solution S (see Tests) add 1 mL of a mixture of equal volumes of strong sodium hydroxide solution R and water R and initiate crystallisation, if necessary, by scratching the wall of the tube with a glass rod and cooling in iced water. Wash the precipitate with water R and dry at 100-105 °C. It melts (2.2.15) at 155 °C to 159 °C.

C. 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.

D. Solution S gives reaction (a) of chlorides (2.3.1).

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

Dissolve 2.00 g in carbon dioxide-free water R prepared from distilled water R and dilute to 50.0 mL with the same solvent.

Solution S is clear (2.2.1) and not more intensely coloured than reference solution Y₆ (2.2.2, Method II).

To 5 mL of solution S add 5 mL of carbon dioxide-free water R. Add 0.05 mL of methyl red solution R and 0.2 mL of 0.02 M hydrochloric acid; the solution is red. Add 0.4 mL of 0.02 M sodium hydroxide; the solution becomes yellow.

- 117 to - 121 (anhydrous substance).

Dilute 5.0 mL of solution S to 10.0 mL with water R.

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).

Maximum 0.1 per cent.

Dilute 5 mL of solution S to 20 mL with distilled water R.

8.0 per cent to 10.5 per cent, determined on 0.250 g.

Dissolve 0.300 g in a mixture of 5 mL of 0.01 M hydrochloric acid R and 30 mL of ethanol (96 per cent) R. Carry out a potentiometric titration (2.2.20), using 0.1 M sodium hydroxide. Read the volume added between the 2 points of inflexion.

1 mL of 0.1 M sodium hydroxide is equivalent to 33.59 mg of C₁₈H₂₂ClNO₃.

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