EUROPEAN PHARMACOPOEIA 7.

0 Phenylephrine

Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on Second identification : A, C, D.
1.0 g. A. Specific optical rotation (see Tests).
ASSAY B. Infrared absorption spectrophotometry (2.2.24).
Dissolve 0.250 g in 25 mL of acetone R and add 0.5 mL of Comparison : phenylephrine CRS.
bromothymol blue solution R1. Titrate with 0.1 M sodium C. Thin-layer chromatography (2.2.27).
hydroxide until a blue colour is obtained which persists for Solvent mixture. A mixture of equal volumes of methylene
15 s. Carry out a blank titration. chloride R and methanolic hydrochloric acid (hydrochloric
1 mL of 0.1 M sodium hydroxide is equivalent to 30.84 mg of acid R diluted 10-fold with methanol R).
C19H20N2O2. Test solution. Dissolve 0.1 g of the substance to be examined
in the solvent mixture and dilute to 5 mL with the solvent
STORAGE mixture.
Protected from light. Reference solution. Dissolve 20 mg of phenylephrine CRS
in the solvent mixture and dilute to 1 mL with the solvent
IMPURITIES
mixture.
Plate: TLC silica gel F254 plate R.
Mobile phase : concentrated ammonia R, methanol R,
methylene chloride R (0.[Link] V/V/V).
Application : 10 μL.
Development : over a path of 15 cm.
Drying : in a current of cold air.
A. (2RS)-2-[(1,2-diphenyldiazanyl)carbonyl]hexanoic acid,
Detection : examine in ultraviolet light at 254 nm ; spray with
a 1 g/L solution of fast red B salt R in a 50 g/L solution of
sodium carbonate R and examine in daylight.
Results : the principal spot in the chromatogram obtained
with the test solution is similar in position, colour and size
to the principal spot in the chromatogram obtained with the
reference solution.
D. Dissolve about 10 mg in 1 mL of 1 M hydrochloric acid, add
B. 4-butyl-4-hydroxy-1,2-diphenylpyrazolidine-3,5-dione,
0.05 mL of copper sulfate solution R and 1 mL of a 200 g/L
C. C6H5-NH-NH-C6H5 : 1,2-diphenyldiazane, (1,2- solution of sodium hydroxide R. A violet colour develops.
diphenylhydrazine), Add 1 mL of ether R and shake. The upper layer remains
colourless.
D. C6H5-N=N-C6H5 : 1,2-diphenyldiazene,
TESTS
Appearance of solution. The solution is clear (2.2.1) and not
more intensely coloured than reference solution Y7 (2.2.2,
Method II).
E. biphenyl-4,4′-diamine (benzidine).
Dissolve 1 g in 1 M hydrochloric acid and dilute to 10 mL with
the same acid.
Specific optical rotation (2.2.7) : − 53 to − 57 (dried substance).
01/2008:1035
Dissolve 1.250 g in 1 M hydrochloric acid and dilute to 25.0 mL
corrected 7.0
with the same acid.
Related substances. Liquid chromatography (2.2.29).
PHENYLEPHRINE Solvent mixture : dilute hydrochloric acid R, mobile phase B,
mobile phase A ([Link] V/V/V).
Phenylephrinum Buffer solution pH 2.8. Dissolve 3.25 g of sodium
octanesulfonate monohydrate R in 1000 mL of water R by
stirring for 30 min and adjust to pH 2.8 with dilute phosphoric
acid R.
Test solution. Dissolve 41.0 mg of the substance to be examined
in the solvent mixture and dilute to 50.0 mL with the solvent
C9H13NO2 Mr 167.2 mixture.
[59-42-7] Reference solution (a). Dilute 5.0 mL of the test solution
DEFINITION to 100.0 mL with the solvent mixture. Dilute 2.0 mL of this
solution to 100.0 mL with the solvent mixture.
(1R)-1-(3-Hydroxyphenyl)-2-(methylamino)ethanol.
Reference solution (b). Dissolve the contents of a vial of
Content: 99.0 per cent to 100.5 per cent (dried substance). phenylephrine hydrochloride for peak identification CRS
(containing impurities C and E) in 2.0 mL of the solvent mixture.
CHARACTERS
Column :
Appearance : white or almost white, crystalline powder.
— size : l = 0.055 m, Ø = 4.0 mm ;
Solubility : slightly soluble in water, sparingly soluble in
methanol, slightly soluble in ethanol (96 per cent). It dissolves in — stationary phase : end-capped octadecylsilyl silica gel for
dilute mineral acids and in dilute solutions of alkali hydroxides. chromatography R (3 μm) ;
mp : about 174 °C. — temperature : 45 °C.
Mobile phase :
IDENTIFICATION — mobile phase A : acetonitrile R1, buffer solution pH 2.8
First identification : A, B. (10:90 V/V) ;

General Notices (1) apply to all monographs and other texts 2713
Phenylephrine hydrochloride EUROPEAN PHARMACOPOEIA 7.0

— mobile phase B : buffer solution pH 2.8, acetonitrile R1

(10:90 V/V) ;
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-3 93 7
A. R = R′ = H : (1R)-2-amino-1-(3-hydroxyphenyl)ethanol
(norphenylephrine),
3 - 13 93 → 70 7 → 30
D. R = CH2-C6H5, R′ = CH3 : (1R)-2-(benzylmethylamino)-1-(3-
13 - 14 70 → 93 30 → 7 hydroxyphenyl)ethanol (benzylphenylephrine),

Flow rate: 1.5 mL/min.

Detection : spectrophotometer at 215 nm.
Injection : 10 μL.
Relative retention with reference to phenylephrine C. R = H : 1-(3-hydroxyphenyl)-2-(methylamino)ethanone
(retention time = about 2.8 min) : impurity C = about 1.3 ; (phenylephrone),
impurity E = about 3.6. E. R = CH2-C6H5 : 2-(benzylmethylamino)-1-(3-
System suitability : hydroxyphenyl)ethanone (benzylphenylephrone).
— symmetry factor : maximum 1.9 for the principal peak in the
chromatogram obtained with the test solution ; 01/2008:0632
— peak-to-valley ratio : minimum 5, where Hp = height above corrected 7.0
the baseline of the peak due to impurity C and Hv = height
above the baseline of the lowest point of the curve separating PHENYLEPHRINE HYDROCHLORIDE
this peak from the peak due to phenylephrine in the
chromatogram obtained with reference solution (b). Phenylephrini hydrochloridum
Limits :
— correction factors : for the calculation of content, multiply the
peak areas of the following impurities by the corresponding
correction factor : impurity C = 0.5 ; impurity E = 0.5 ;
— impurities C, E : for each impurity, not more than the area C9H14ClNO2 Mr 203.7
of the principal peak in the chromatogram obtained with [61-76-7]
reference solution (a) (0.1 per cent) ;
— unspecified impurities : for each impurity, not more than the DEFINITION
area of the principal peak in the chromatogram obtained (1R)-1-(3-Hydroxyphenyl)-2-(methylamino)ethanol
with reference solution (a) (0.10 per cent) ; hydrochloride.
— total : not more than twice the area of the principal peak Content : 98.5 per cent to 101.0 per cent (dried substance).
in the chromatogram obtained with reference solution (a) CHARACTERS
(0.2 per cent) ;
Appearance: white or almost white, crystalline powder.
— disregard limit : 0.5 times the area of the principal peak Solubility : freely soluble in water and in ethanol (96 per cent).
in the chromatogram obtained with reference solution (a)
(0.05 per cent). mp : about 143 °C.
Loss on drying (2.2.32) : maximum 0.5 per cent, determined on IDENTIFICATION
1.000 g by drying in an oven at 105 °C. First identification : A, C, E.
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on Second identification : A, B, D, E.
1.0 g. A. Specific optical rotation (see Tests).
B. Melting point (2.2.14) : 171 °C to 176 °C.
ASSAY
Dissolve 0.3 g in 3 mL of water R, add 1 mL of dilute
Dissolve 0.150 g in 60 mL of anhydrous acetic acid R. ammonia R1 and initiate crystallisation by scratching the
Titrate with 0.1 M perchloric acid determining the end-point wall of the tube with a glass rod. Wash the crystals with iced
potentiometrically (2.2.20). water R and dry at 105 °C for 2 h.
1 mL of 0.1 M perchloric acid is equivalent to 16.72 mg C. Infrared absorption spectrophotometry (2.2.24).
of C9H13NO2. Preparation : discs.
Comparison : phenylephrine hydrochloride CRS.
STORAGE D. Dissolve about 10 mg in 1 mL of water R and add 0.05 mL
In an airtight container, protected from light. of a 125 g/L solution of copper sulfate R and 1 mL of a
200 g/L solution of sodium hydroxide R. A violet colour is
IMPURITIES produced. Add 1 mL of ether R and shake ; the upper layer
remains colourless.
Specified impurities : C, E.
Other detectable impurities (the following substances would, E. It gives reaction (a) of chlorides (2.3.1).
if present at a sufficient level, be detected by one or other of TESTS
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities and/or Solution S. Dissolve 2.00 g in carbon dioxide-free water R
by the general monograph Substances for pharmaceutical use prepared from distilled water R and dilute to 100.0 mL with
(2034). It is therefore not necessary to identify these impurities the same solvent.
for demonstration of compliance. See also 5.10. Control of Appearance of solution. Solution S is clear (2.2.1) and
impurities in substances for pharmaceutical use) : A, D. colourless (2.2.2, Method II).

2714 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 7.0 Phenylmercuric acetate

Acidity or alkalinity. To 10 mL of solution S add 0.1 mL of — disregard limit : 0.5 times the area of the principal peak
methyl red solution R and 0.2 mL of 0.01 M sodium hydroxide. in the chromatogram obtained with reference solution (a)
The solution is yellow. Not more than 0.4 mL of 0.01 M (0.05 per cent).
hydrochloric acid is required to change the colour of the Sulfates (2.4.13) : maximum 500 ppm, determined on solution S.
indicator to red.
Loss on drying (2.2.32): maximum 1.0 per cent, determined on
Specific optical rotation (2.2.7) : − 43 to − 47 (dried substance), 1.000 g by drying in an oven at 105 °C.
determined on solution S.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
Related substances. Liquid chromatography (2.2.29). 1.0 g.
Solvent mixture : mobile phase B, mobile phase A (20:80 V/V).
ASSAY
Buffer solution pH 2.8. Dissolve 3.25 g of sodium
octanesulfonate monohydrate R in 1000 mL of water R by Dissolve 0.150 g in a mixture of 0.5 mL of 0.1 M hydrochloric
stirring for 30 min and adjust to pH 2.8 with dilute phosphoric acid and 80 mL of ethanol (96 per cent) R. Carry out a
acid R. potentiometric titration (2.2.20) using 0.1 M ethanolic sodium
hydroxide. Read the volume added between the 2 points of
Test solution. Dissolve 50.0 mg of the substance to be examined inflexion.
in the solvent mixture and dilute to 50.0 mL with the solvent
mixture. 1 mL of 0.1 M ethanolic sodium hydroxide is equivalent to
20.37 mg of C9H14ClNO2.
Reference solution (a). Dilute 5.0 mL of the test solution
to 100.0 mL with the solvent mixture. Dilute 2.0 mL of this IMPURITIES
solution to 100.0 mL with the solvent mixture. Specified impurities : C, E.
Reference solution (b). Dissolve the contents of a vial of Other detectable impurities (the following substances would,
phenylephrine hydrochloride for peak identification CRS if present at a sufficient level, be detected by one or other of
(containing impurities C and E) in 2.0 mL of the solvent mixture. the tests in the monograph. They are limited by the general
Column : acceptance criterion for other/unspecified impurities and/or
— size : l = 0.055 m, Ø = 4.0 mm ; by the general monograph Substances for pharmaceutical use
(2034). It is therefore not necessary to identify these impurities
— stationary phase : end-capped octadecylsilyl silica gel for for demonstration of compliance. See also 5.10. Control of
chromatography R (3 μm) ; impurities in substances for pharmaceutical use) : A, D.
— temperature : 45 °C.
Mobile phase:
— mobile phase A : acetonitrile R1, buffer solution pH 2.8
(10:90 V/V) ;
— mobile phase B : buffer solution pH 2.8, acetonitrile R1 A. R = R′ = H : (1R)-2-amino-1-(3-hydroxyphenyl)ethanol
(10:90 V/V) ; (norphenylephrine),
Time Mobile phase A Mobile phase B D. R = CH2-C6H5, R′ = CH3 : (1R)-2-(benzylmethylamino)-1-(3-
(min) (per cent V/V) (per cent V/V) hydroxyphenyl)ethanol (benzylphenylephrine),
0-3 93 7

3 - 13 93 → 70 7 → 30

13 - 14 70 → 93 30 → 7

Flow rate: 1.5 mL/min. C. R = H : 1-(3-hydroxyphenyl)-2-(methylamino)ethanone

Detection : spectrophotometer at 215 nm. (phenylephrone),
Injection : 10 μL. E. R = CH2-C6H5 : 2-(benzylmethylamino)-1-(3-
Relative retention with reference to phenylephrine (retention hydroxyphenyl)ethanone (benzylphenylephrone).
time = about 2.8 min) : impurity C = about 1.3 ; impurity E = about
3.6. 01/2008:2042
System suitability :
PHENYLMERCURIC ACETATE
— symmetry factor : maximum 1.9 for the principal peak in the
chromatogram obtained with the test solution ;
Phenylhydrargyri acetas
— peak-to-valley ratio : minimum 5, where Hp = height above
the baseline of the peak due to impurity C and Hv = height
above the baseline of the lowest point of the curve separating
this peak from the peak due to phenylephrine in the
chromatogram obtained with reference solution (b).
Limits : C8H8HgO2 Mr 336.7
— correction factors : for the calculation of content, multiply the [62-38-4]
peak areas of the following impurities by the corresponding
correction factor : impurity C = 0.5 ; impurity E = 0.5 ; DEFINITION
— impurities C, E : for each impurity, not more than the area Content : 98.0 per cent to 100.5 per cent (dried substance).
of the principal peak in the chromatogram obtained with CHARACTERS
reference solution (a) (0.1 per cent) ; Appearance: white or yellowish, crystalline powder or small,
— unspecified impurities : for each impurity, not more than the colourless crystals.
area of the principal peak in the chromatogram obtained Solubility : slightly soluble in water, soluble in acetone and in
with reference solution (a) (0.10 per cent) ; alcohol.
— total : not more than twice the area of the principal peak
in the chromatogram obtained with reference solution (a) IDENTIFICATION
(0.2 per cent) ; First identification : A.

General Notices (1) apply to all monographs and other texts 2715