Codeine phosphate hemihydrate EUROPEAN PHARMACOPOEIA 10.

DEFINITION
4,5α-Epoxy-3-methoxy-17-methyl-7,8-didehydromorphinan-
6α-ol phosphate hemihydrate.
Content : 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance : white or almost white, crystalline powder or
J. (17RS)-4,5α-epoxy-6α-hydroxy-3-methoxy-17-methyl-7,8- small, colourless crystals.
didehydromorphinan-17-oxide (codeine N-oxide), Solubility : freely soluble in water, slightly soluble or very
slightly soluble in ethanol (96 per cent).
IDENTIFICATION
First identification : A, D, E.
Second identification : B, C, D, E, F.
A. Infrared absorption spectrophotometry (2.2.24).
Preparation : dissolve 0.20 g in 4 mL of water R. Add 1 mL
of a mixture of equal volumes of strong sodium hydroxide
K. 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-7,8- solution R and water R and initiate crystallisation, if
didehydromorphinan-6-one (14-hydroxycodeinone), 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.
Comparaison : codeine CRS.
B. Dissolve 0.20 g in 4 mL of water R. 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. The precipitate, washed with water R and
L. 4,5α-epoxy-6-methoxy-17-methyl-6,7,8,14- dried at 100-105 °C, melts (2.2.14) at 155 °C to 159 °C.
tetradehydromorphinan-3-ol (oripavine), 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. Loss on drying (see Tests).
E. Solution S gives reaction (a) of phosphates (2.3.1).
F. It gives the reaction of alkaloids (2.3.1).
TESTS
Solution S. Dissolve 1.00 g in carbon dioxide-free water R
prepared from distilled water R and dilute to 25.0 mL with
M. 7,7′-oxybis(4,5α-epoxy-3-methoxy-17-methyl-6,7,8,14- the same solvent.
tetradehydromorphinan-6-ol) (7,7′-oxybis(6-O- pH (2.2.3): 4.0 to 5.0 for solution S.
demethylthebaine)).
Specific optical rotation (2.2.7): − 102 to − 98 (dried
substance).
Dilute 5.0 mL of solution S to 10.0 mL with water R.
01/2021:0074 Related substances. Liquid chromatography (2.2.29).
corrected 10.5
Solution A : 0.5 per cent V/V solution of phosphoric acid R.
Test solution. Dissolve 0.190 g of the substance to be examined
in solution A and dilute to 50.0 mL with solution A.
Reference solution (a). Dilute 2.0 mL of the test solution to
CODEINE PHOSPHATE 100.0 mL with solution A. Dilute 1.0 mL of this solution to
10.0 mL with solution A.
HEMIHYDRATE Reference solution (b). Dissolve 3 mg of codeine for system
suitability CRS (containing impurities A, B, C, D, E, F, G, H
Codeini phosphas hemihydricus and I) in 1 mL of solution A.
Column :
– size : l = 0.075 m, Ø = 3.0 mm ;
– stationary phase : end-capped octadecylsilyl multi-layered
organosilica polymer for chromatography R (1.9 μm).
– temperature : 40 °C.
Mobile phase :
– mobile phase A : mix 4 volumes of acetonitrile R and
96 volumes of a 20 g/L solution of glacial acetic acid R
previously adjusted to pH 4.5 with a 500 g/L solution of
C18H24NO7P,½H2O Mr 406.4 sodium hydroxide R ;
[41444-62-6] – mobile phase B : acetonitrile R ;

5790 See the information section on general monographs (cover pages)

Time Mobile phase A Mobile phase B

5 - 7.33 100 → 93 0→7

7.33 - 10.33 93 → 67 7 → 33

10.33 - 12 67 33
A. 4,5α-epoxy-3,6α-dimethoxy-17-methyl-7,8-
Flow rate : 1.0 mL/min. didehydromorphinan (methylcodeine),
Detection : spectrophotometer at 280 nm.
Injection : 3 μL.
Identification of impurities : use the chromatogram supplied
with codeine for system suitability CRS and the chromatogram
obtained with reference solution (b) to identify the peaks due
to impurities A, B, C, D, E, F, G, H and I.
Relative retention with reference to codeine (retention
time = about 6 min) : impurity B = about 0.3 ;
impurity E = about 0.4 ; impurity F = about 0.8 ; B. 4,5α-epoxy-17-methyl-7,8-didehydromorphinan-3,6α-diol
impurity H = about 0.9 ; impurity C = about 1.2 ; (morphine),
impurity I = about 1.4 ; impurity D = about 1.45 ;
impurity A = about 1.5 ; impurity G = about 1.6.
System suitability : reference solution (b) :
– resolution : minimum 2.5 between the peaks due to
impurities F and H ; minimum 1.5 between the peaks due
to impurities D and A.
Calculation of percentage contents :
– correction factors : multiply the peak areas of the following
impurities by the corresponding correction factor :
impurity C = 0.7 ; impurity G = 0.2 ; impurity I = 1.3 ;
– for each impurity, use the concentration of codeine C. 4,5α:4′,5′α-diepoxy-3,3′-dimethoxy-17,17′-dimethyl-
phosphate hemihydrate in reference solution (a). 7,7′,8,8′-tetradehydro-2,2′-bimorphinan-6α,6′α-diol
Limits : (codeine dimer),
– impurity A : maximum 1.0 per cent ;
– impurity H : maximum 0.25 per cent ;
– impurities C, D, E : for each impurity, maximum 0.2 per
cent ;
– impurities B, F, G, I : for each impurity, maximum 0.15 per
cent ;
– unspecified impurities : for each impurity, maximum
0.10 per cent ;
– total : maximum 1.5 per cent ;
– reporting threshold : 0.05 per cent.
Sulfates (2.4.13) : maximum 0.1 per cent.
Dilute 5 mL of solution S to 20 mL with distilled water R. D. 4,5α-epoxy-2-[(4,5α-epoxy-6α-hydroxy-17-methyl-7,8-
didehydromorphinan-3-yl)oxy]-3-methoxy-17-methyl-7,8-
Loss on drying (2.2.32): 1.5 per cent to 3.0 per cent, didehydromorphinan-6α-ol (3-O-(codein-2-yl)morphine),
determined on 1.000 g by drying in an oven at 105 °C.
ASSAY
Dissolve 0.350 g in 50 mL of anhydrous acetic acid R. Titrate
with 0.1 M perchloric acid, determining the end-point
potentiometrically (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 39.74 mg
of C18H24NO7P.
STORAGE E. 4,5α-epoxy-3-methoxy-17-methyl-7,8-didehydro-
Protected from light. morphinan-6α,10ξ-diol,
IMPURITIES
Specified impurities : A, B, C, D, E, F, G, H, I.
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 F. 4,5α-epoxy-3-methoxy-17-methyl-7,8-didehydro-
impurities in substances for pharmaceutical use) : J, K, L, M. morphinan-6α,14-diol,

General Notices (1) apply to all monographs and other texts 5791
Codeine phosphate sesquihydrate EUROPEAN PHARMACOPOEIA 10.5

G. 4,5α-epoxy-3,6-dimethoxy-17-methyl-6,7,8,14-
tetradehydromorphinan (thebaine),
M. 7,7′-oxybis(4,5α-epoxy-3-methoxy-17-methyl-6,7,8,14-
tetradehydromorphinan-6-ol) (7,7′-oxybis(6-O-
demethylthebaine)).

07/2021:0075

CODEINE PHOSPHATE
H. 4,5α-epoxy-3-methoxy-7,8-didehydromorphinan-6α-ol SESQUIHYDRATE
(norcodeine),
Codeini phosphas sesquihydricus

C18H24NO7P,1½H2O Mr 424.4
I. 4,5α-epoxy-3-methoxy-17-methyl-7,8-didehydro- [5913-76-8]
morphinan-6-one (codeinone),
DEFINITION
4,5α-Epoxy-3-methoxy-17-methyl-7,8-didehydromorphinan-
6α-ol phosphate sesquihydrate.
Content : 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance : white or almost white, crystalline powder or
small, colourless crystals.
Solubility : freely soluble in water, slightly soluble in ethanol
(96 per cent).
J. (17RS)-4,5α-epoxy-6α-hydroxy-3-methoxy-17-methyl-7,8-
IDENTIFICATION
didehydromorphinan-17-oxide (codeine N-oxide),
First identification : A, D, E.
Second identification : B, C, D, E, F.
A. Infrared absorption spectrophotometry (2.2.24).
Preparation : dissolve 0.20 g in 4 mL of water R. 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. Examine the dried
precipitate prepared as discs using potassium bromide R.
K. 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-7,8- Comparison : codeine CRS dried at 105 °C.
didehydromorphinan-6-one (14-hydroxycodeinone), B. Dissolve 0.20 g in 4 mL of water R. 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. The precipitate, washed with water R and
dried at 100-105 °C, melts (2.2.14) 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. Loss on drying (see Tests).
L. 4,5α-epoxy-6-methoxy-17-methyl-6,7,8,14- E. Solution S gives reaction (a) of phosphates (2.3.1).
tetradehydromorphinan-3-ol (oripavine), F. It gives the reaction of alkaloids (2.3.1).

5792 See the information section on general monographs (cover pages)