Fentanyl

EUROPEAN PHARMACOPOEIA 8.0

Flow rate : 1 mL/min.

Detection : spectrophotometer at 215 nm.
Injection : 20 L.
Run time : 3 times the retention time of fenoterol.
Relative retention with reference to fenoterol (retention
time = about 7 min) : impurity A = about 1.3 ;
impurity B = about 2.0 ; impurity C = about 2.2.
System suitability :
resolution : minimum 3 between the peaks due to fenoterol
and impurity A in the chromatogram obtained with
reference solution (a) ; minimum 1.5 between the peaks
due to impurities B and C in the chromatogram obtained
with reference solution (b).
Limits :
correction factor : for the calculation of content, multiply
the peak area of impurity B by 0.6 ;
impurity A : maximum 4.0 per cent, calculated from the
area of the corresponding peak in the chromatogram
obtained with reference solution (a) and taking into
account the declared content of impurity A in fenoterol
hydrobromide CRS ;
impurity C : not more than 1.5 times the area of the
principal peak in the chromatogram obtained with
reference solution (c) (0.3 per cent) ;
impurity B : not more than 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
0.5 times 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 1.5 times the
area of the principal peak in the chromatogram obtained
with reference solution (c) (0.3 per cent) ;
disregard limit : 0.25 times the area of the principal peak
in the chromatogram obtained with reference solution (c)
(0.05 per cent).
Iron (2.4.9) : maximum 10 ppm.
Dissolve the residue obtained in the test for sulfated ash in
2.5 mL of dilute hydrochloric acid R and dilute to 10 mL with
water R.
Loss on drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 C.
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on
1.0 g.

B. 1-(3,5-dihydroxyphenyl)-2-[[(1RS)-2-(4-hydroxyphenyl)1-methylethyl]amino]ethanone,

C. (1RS)-1-(3,5-dihydroxyphenyl)-2-[[(1RS)-2-(4-hydroxy-3methylphenyl)-1-methylethyl]amino]ethanol.
01/2013:1210

FENTANYL
Fentanylum

C22H28N2O
[437-38-7]

Mr 336.5

DEFINITION
N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide.
Content : 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance : white or almost white powder.
Solubility : practically insoluble in water, freely soluble in
ethanol (96 per cent) and in methanol.
It shows polymorphism (5.9).

IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
ASSAY
Comparison : Ph. Eur. reference spectrum of fentanyl.
Dissolve 0.600 g in 50 mL of water R and add 5 mL of dilute
If the spectrum obtained in the solid state shows differences,
nitric acid R, 25.0 mL of 0.1 M silver nitrate and 2 mL of ferric dissolve the substance to be examined in the minimum volume
ammonium sulfate solution R2. Shake and titrate with 0.1 M
of anhydrous ethanol R, evaporate to dryness at room
ammonium thiocyanate until an orange colour is obtained.
temperature under an air-stream and record a new spectrum
Carry out a blank titration.
using the residue.
1 mL of 0.1 M silver nitrate is equivalent to 38.43 mg
TESTS
of C17H22BrNO4.
Related substances. Liquid chromatography (2.2.29).
STORAGE
Test solution. Dissolve 0.100 g of the substance to be examined
Protected from light.
in methanol R and dilute to 10.0 mL with the same solvent.
Reference solution (a). Dissolve 10 mg of fentanyl for system
IMPURITIES
suitability CRS (containing impurities A, B, C, D and H) in
Specified impurities : A, B, C.
1.0 mL of methanol R.
Reference solution (b). Dilute 1.0 mL of the test solution to
100.0 mL with methanol R. Dilute 1.0 mL of this solution to
10.0 mL with methanol R.
Column :
size : l = 0.1 m, = 3.0 mm ;
A. (1RS)-1-(3,5-dihydroxyphenyl)-2-[[(1SR)-2-(4 stationary phase : end-capped octadecylsilyl silica gel for
hydroxyphenyl)-1-methylethyl]amino]ethanol,
chromatography R (3 m).
General Notices (1) apply to all monographs and other texts

2221

Fentanyl

EUROPEAN PHARMACOPOEIA 8.0

Mobile phase :
mobile phase A : 5 g/L solution of ammonium carbonate R
in a mixture of 10 volumes of tetrahydrofuran R and
90 volumes of water R ;
mobile phase B : acetonitrile R1 ;
Time
(min)
0 - 15

Mobile phase A
(per cent V/V)
90 40

Mobile phase B
(per cent V/V)
10 60

15 - 20

40

60

Flow rate : 0.64 mL/min.

Detection : spectrophotometer at 220 nm.
Injection : 10 L.
Identification of impurities : use the chromatogram supplied
with fentanyl for system suitability CRS and the chromatogram
obtained with reference solution (a) to identify the peaks due
to impurities A, B, C, D and H.
Relative retention with reference to fentanyl (retention
time = about 15 min) : impurity B = about 0.1 ;
impurity A = about 0.3 ; impurity C = about 0.9 ;
impurity D = about 1.1 ; impurity H = about 1.2.
System suitability : reference solution (a) :
resolution : minimum 3.0 between the peaks due to fentanyl
and impurity D.
Limits :
impurities A, B, C, D : for each impurity, not more than
2.5 times the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.25 per cent) ;
impurity H : not more than 1.5 times the area of the
principal peak in the chromatogram obtained with
reference solution (b) (0.15 per cent) ;
unspecified impurities : for each impurity, not more than the
area of the principal peak in the chromatogram obtained
with reference solution (b) (0.10 per cent) ;
total : not more than 5 times the area of the principal peak
in the chromatogram obtained with reference solution (b)
(0.5 per cent) ;
disregard limit : 0.5 times the area of the principal peak in
the chromatogram obtained with reference solution (b)
(0.05 per cent).
Loss on drying (2.2.32): maximum 0.5 per cent, determined
on 1.000 g by drying in vacuo at 50 C.
ASSAY
Dissolve 0.200 g in 50 mL of a mixture of 1 volume of
anhydrous acetic acid R and 7 volumes of methyl ethyl
ketone R and titrate with 0.1 M perchloric acid, using 0.2 mL
of naphtholbenzein solution R as indicator.
1 mL of 0.1 M perchloric acid is equivalent to 33.65 mg
of C22H28N2O.
STORAGE
Protected from light.

A. N-phenyl-N-[cis,trans-1-oxido-1-(2-phenylethyl)piperidin-4-yl]propanamide,

B. N-phenyl-N-(piperidin-4-yl)propanamide,

C. N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]acetamide,

D. N-phenyl-1-(2-phenylethyl)piperidin-4-amine,

E. benzaldehyde,

F. aniline (phenylamine),

G. N-phenylpropanamide,

IMPURITIES
Specified impurities : A, B, C, D, H.
Other detectable impurities (the following substances would,
if present at a sufcient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecied impurities and/or
by the general monograph Substances for pharmaceutical use
(2034). It is therefore not necessary to identify these impurities
H. (2RS)-2-chloro-N-phenyl-N-[1-(2-phenylethyl)piperidinfor demonstration of compliance. See also 5.10. Control of
4-yl]propanamide.
impurities in substances for pharmaceutical use): E, F, G.

2222

See the information section on general monographs (cover pages)