Fentanyl citrate

EUROPEAN PHARMACOPOEIA 8.0

01/2013:1103 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
FENTANYL CITRATE
to impurities A, B, C and D.
Relative retention with reference to fentanyl (retention
Fentanyli citras
time = about 15 min) : impurity B = about 0.1 ;
impurity A = about 0.3 ; impurity C = about 0.9 ;
impurity D = about 1.1.
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 2.5 times
than the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.25 per cent) ;
C28H36N2O8
Mr 528.6
unspecified impurities : for each impurity, not more than the
[990-73-8]
area of the principal peak in the chromatogram obtained
with reference solution (b) (0.10 per cent) ;
DEFINITION
total : not more than 5 times the area of the principal peak
N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide
in the chromatogram obtained with reference solution (b)
dihydrogen 2-hydroxypropane-1,2,3-tricarboxylate.
(0.5 per cent) ;
Content : 99.0 per cent to 101.0 per cent (dried substance).
disregard limit : 0.5 times the area of the principal peak in
the chromatogram obtained with reference solution (b)
CHARACTERS
(0.05 per cent) ; disregard any peak with a relative retention
Appearance : white or almost white powder.
with reference to fentanyl of 0.05 or less.
Solubility : soluble in water, freely soluble in methanol,
Loss
on drying (2.2.32) : maximum 0.5 per cent, determined
sparingly soluble in ethanol (96 per cent).
on 1.000 g by drying in vacuo at 60 C.
mp : about 152 C, with decomposition.
ASSAY
IDENTIFICATION
Dissolve 0.300 g in 50 mL of a mixture of 1 volume of
Infrared absorption spectrophotometry (2.2.24).
anhydrous acetic acid R and 7 volumes of methyl ethyl
ketone R. Titrate with 0.1 M perchloric acid, using 0.2 mL of
Comparison : Ph. Eur. reference spectrum of fentanyl citrate.
naphtholbenzein solution R as indicator.
TESTS
1 mL of 0.1 M perchloric acid is equivalent to 52.86 mg
of C28H36N2O8.
Appearance of solution. The solution is clear (2.2.1) and
colourless (2.2.2, Method II).
STORAGE
Dissolve 0.2 g of the substance to be examined in water R and
Protected from light.
dilute to 20 mL with the same solvent.
Related substances. Liquid chromatography (2.2.29).
IMPURITIES
Test solution. Dissolve 0.100 g of the substance to be examined Specified impurities : A, B, C, D.
in methanol R and dilute to 10.0 mL with the same solvent.
Other detectable impurities (the following substances would,
if present at a sufcient level, be detected by one or other of
Reference solution (a). Dissolve 10 mg of fentanyl for system
the tests in the monograph. They are limited by the general
suitability CRS (containing impurities A, B, C and D) in
acceptance criterion for other/unspecied impurities and/or
1.0 mL of methanol R.
by the general monograph Substances for pharmaceutical
Reference solution (b). Dilute 1.0 mL of the test solution to
use (2034). It is therefore not necessary to identify these
100.0 mL with methanol R. Dilute 1.0 mL of this solution to
impurities for demonstration of compliance. See also 5.10.
10.0 mL with methanol R.
Control of impurities in substances for pharmaceutical use) : E.
Column :
size : l = 0.1 m, = 3.0 mm ;
stationary phase : end-capped octadecylsilyl silica gel for
chromatography R (3 m).
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 ;
A. N-phenyl-N-[cis,trans-1-oxido-1-(2-phenylethyl)piperidin-4-yl]propanamide,
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.
General Notices (1) apply to all monographs and other texts

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

2223

Fenticonazole nitrate

EUROPEAN PHARMACOPOEIA 8.0

C. Infrared absorption spectrophotometry (2.2.24).

Comparison : fenticonazole nitrate CRS.
D. It gives the reaction of nitrates (2.3.1).

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

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

E. benzaldehyde.
01/2008:1211
corrected 6.0

FENTICONAZOLE NITRATE
Fenticonazoli nitras

C24H21Cl2N3O4S
[73151-29-8]

Mr 518.4

DEFINITION
1-[(2RS)-2-(2,4-Dichlorophenyl)-2-[[4-(phenylsulfanyl)benzyl]oxy]ethyl]-1H-imidazole nitrate.
Content : 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance : white or almost white, crystalline powder.
Solubility : practically insoluble in water, freely soluble in
dimethylformamide and in methanol, sparingly soluble in
anhydrous ethanol.
IDENTIFICATION
First identification : C, D.
Second identification : A, B, D.
A. Melting point (2.2.14) : 134 C to 137 C.
B. Ultraviolet and visible absorption spectrophotometry
(2.2.25).
Test solution. Dissolve 20.0 mg in anhydrous ethanol R and
dilute to 100.0 mL with the same solvent. Dilute 1.0 mL of
this solution to 10.0 mL with anhydrous ethanol R.
Spectral range : 230-350 nm.
Absorption maximum : at 252 nm.
Shoulder : at about 270 nm.
Absorption minimum : at 236 nm.
Specific absorbance at the absorption maximum : 260 to 280.

2224

TESTS
Optical rotation (2.2.7) : 0.10 to + 0.10.
Dissolve 0.10 g in methanol R and dilute to 10.0 mL with the
same solvent.
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 25.0 mg of the substance to be
examined in the mobile phase and dilute to 25.0 mL with the
mobile phase.
Reference solution (a). Dilute 1.0 mL of the test solution to
200.0 mL with the mobile phase.
Reference solution (b). Dilute 10.0 mL of reference solution (a)
to 25.0 mL with the mobile phase.
Reference solution (c). Dilute 1.0 mL of reference solution (a)
to 10.0 mL with the mobile phase.
Reference solution (d). To 5 mL of the test solution add 5.0 mg
of fenticonazole impurity D CRS, dissolve in the mobile phase
and dilute to 100.0 mL with the mobile phase. Dilute 2.0 mL
of this solution to 10.0 mL with the mobile phase.
Column :
size : l = 0.25 m, = 4 mm ;
stationary phase : octadecylsilyl silica gel for
chromatography R (5-10 m).
Mobile phase : mix 70 volumes of acetonitrile R1 and
30 volumes of a phosphate buffer solution prepared by
dissolving 3.4 g of potassium dihydrogen phosphate R in
900 mL of water R, adjusting to pH 3.0 with phosphoric acid R
and diluting to 1000 mL with water R.
Flow rate : 1.0 mL/min.
Detection : spectrophotometer at 229 nm.
Injection : 10 L.
Run time : 5.5 times the retention time of fenticonazole.
System suitability :
resolution : minimum 2.0 between the peaks due to
impurity D and fenticonazole in the chromatogram
obtained with reference solution (d) ;
signal-to-noise ratio : minimum 5 for the principal peak in
the chromatogram obtained with reference solution (c).
Limits :
impurities A, B, C, D, E : for each impurity, not more
than the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.2 per cent) ;
total : not more than the area of the principal peak in the
chromatogram obtained with reference solution (a) (0.5 per
cent) ;
disregard limit : the area of the principal peak in the
chromatogram obtained with reference solution (c)
(0.05 per cent) ; disregard the peak due to the nitric ion
(which corresponds to the dead volume of the column).
Toluene. Head-space gas chromatography (2.2.28) : use the
standard additions method.
Test solution. Disperse 0.2 g of the substance to be examined
in a 10 mL vial with 5 mL of water R.
Reference solution. Mix 4 mg of toluene R with water R and
dilute to 1000 mL with the same solvent. Place 5 mL of this
solution in a 10 mL vial.
Column :
size : l = 25 m, = 0.32 mm ;
stationary phase : poly(cyanopropyl)(7)(phenyl)(7)(methyl)(86)siloxane R (lm thickness 1.2 m).
Carrier gas : helium for chromatography R.
Split ratio : 1:25.
Column head pressure : 40 kPa.
See the information section on general monographs (cover pages)