Droperidol

EUROPEAN PHARMACOPOEIA 8.0

stationary phase : poly(dimethyl)(diphenyl)siloxane R (lm

thickness 1.5 m).
Carrier gas : helium for chromatography R.
Flow rate : 7 mL/min.
Temperature :

Column

Time
(min)
0 - 12

Temperature
(C)
160 220

12 - 27

220

Injection port

250

Detector

250

Detection : ame ionisation.

Injection : 1 L.
Identification of impurities : use the chromatogram supplied
with doxylamine for system suitability CRS and the
chromatogram obtained with reference solution (b) to identify
the peak due to impurity C.
Relative retention with reference to doxylamine (retention
time = about 12 min) : impurity C = about 0.96.
System suitability : reference solution (b) :
resolution : minimum 1.5 between the peaks due to
impurity C and doxylamine.
Limits :
impurity C : not more than 5 times the area of the principal
peak in the chromatogram obtained with reference
solution (a) (0.5 per cent) ;
unspecified impurities : for each impurity, not more than the
area of the principal peak in the chromatogram obtained
with reference solution (a) (0.10 per cent) ;
total : not more than 7 times the area of the principal peak
in the chromatogram obtained with reference solution (a)
(0.7 per cent) ;
disregard limit : 0.5 times the area of the principal peak in
the chromatogram obtained with reference solution (a)
(0.05 per cent).
Water (2.5.12) : maximum 0.5 per cent, determined on 2.00 g.
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Dissolve 0.150 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 19.43 mg of
C21H28N2O5.
IMPURITIES
Specified impurities : C.
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
for demonstration of compliance. See also 5.10. Control of
impurities in substances for pharmaceutical use) : A, B, D.

A. N,N-dimethyl-2-[(1RS)-1-phenyl-1-(pyridin-4yl)ethoxy]ethanamine,
General Notices (1) apply to all monographs and other texts

B. (1RS)-1-phenyl-1-(pyridin-2-yl)ethanol,

C. N,N-dimethyl-2-[(1RS)-1-phenyl-1-(pyridin-2yl)methoxy]ethanamine,

D. phenyl(pyridin-2-yl)methanone (2-benzoylpyridine).
07/2011:1010

DROPERIDOL
Droperidolum

C22H22FN3O2
[548-73-2]

Mr 379.4

DEFINITION
1-[1-[4-(4-Fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridin4-yl]-1,3-dihydro-2H-benzimidazol-2-one.
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
dimethylformamide and in methylene chloride, sparingly
soluble in ethanol (96 per cent).
It shows polymorphism (5.9).
IDENTIFICATION
First identification : A.
Second identification : B, C, D.
A. Infrared absorption spectrophotometry (2.2.24).
Comparison : droperidol CRS.
If the spectra obtained show differences, dissolve the
substance to be examined and the reference substance
separately in the minimum volume of acetone R, evaporate
to dryness on a water-bath and record new spectra using
the residues.
B. Thin-layer chromatography (2.2.27).
Test solution. Dissolve 30 mg of the substance to be
examined in the mobile phase and dilute to 10 mL with
the mobile phase.
Reference solution (a). Dissolve 30 mg of droperidol CRS in
the mobile phase and dilute to 10 mL with the mobile phase.

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Droperidol

EUROPEAN PHARMACOPOEIA 8.0

Reference solution (b). Dissolve 30 mg of droperidol CRS

and 30 mg of benperidol CRS in the mobile phase and dilute
to 10 mL with the mobile phase.
Plate : TLC silica gel GF254 plate R.
Mobile phase : acetone R, methanol R (10:90 V/V).
Application : 10 L.
Development : over 3/4 of the plate.
Drying : in air.
Detection : examine in ultraviolet light at 254 nm.
System suitability : reference solution (b) :
the chromatogram shows 2 clearly separated spots.
Results : the principal spot in the chromatogram obtained
with the test solution is similar in position and size to
the principal spot in the chromatogram obtained with
reference solution (a).
C. Dissolve about 10 mg in 5 mL of anhydrous ethanol R.
Add 0.5 mL of dinitrobenzene solution R and 0.5 mL of
2 M alcoholic potassium hydroxide R. A violet colour is
produced and becomes brownish-red after 20 min.
D. Mix about 5 mg with 45 mg of heavy magnesium oxide R
and ignite in a crucible until an almost white residue is
obtained (usually less than 5 min). Allow to cool, add
1 mL of water R, 0.05 mL of phenolphthalein solution R1
and about 1 mL of dilute hydrochloric acid R to render the
solution colourless. Filter. To a freshly prepared mixture
of 0.1 mL of alizarin S solution R and 0.1 mL of zirconyl
nitrate solution R, add 1.0 mL of the ltrate. Mix, allow
to stand for 5 min and compare the colour of the solution
with that of a blank prepared in the same manner. The test
solution is yellow and the blank is red.
TESTS
Appearance of solution. The solution is clear (2.2.1) and not
more intensely coloured than reference solution BY5 (2.2.2,
Method II).
Dissolve 0.20 g in methylene chloride R and dilute to 20.0 mL
with the same solvent.
Related substances. Liquid chromatography (2.2.29). Prepare
the solutions immediately before use.
Test solution. Dissolve 0.10 g of the substance to be examined
in dimethylformamide R and dilute to 10.0 mL with the same
solvent.
Reference solution (a). Dissolve 2.5 mg of droperidol CRS and
2.5 mg of benperidol CRS in dimethylformamide R and dilute
to 100.0 mL with the same solvent.
Reference solution (b). Dilute 1.0 mL of the test solution to
100.0 mL with dimethylformamide R. Dilute 5.0 mL of this
solution to 20.0 mL with dimethylformamide R.
Column :
size : l = 0.10 m, = 4.6 mm ;
stationary phase : base-deactivated octadecylsilyl silica gel for
chromatography R (3 m).
Mobile phase :
mobile phase A : acetonitrile R ;
mobile phase B : 10 g/L solution of tetrabutylammonium
hydrogen sulfate R1 ;
Time
(min)
0 - 15

Mobile phase A
(per cent V/V)
0 40

15 - 20

40

60

20 - 25

40 0

60 100

Flow rate : 1.5 mL/min.

Detection : spectrophotometer at 275 nm.
Injection : 10 L.

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Mobile phase B
(per cent V/V)
100 60

Relative retention with reference to droperidol

(retention time = about 7 min) : impurity A = about 0.2 ;
impurity B = about 0.85 ; benperidol = about 0.9 ;
impurity C = about 0.95 ; impurity D = about 1.2 ;
impurity E = about 1.5.
System suitability : reference solution (a) :
resolution : minimum 2.0 between the peaks due to
benperidol and droperidol.
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) (0.25 per cent) ;
unspecified impurities : for each impurity, not more than
0.4 times the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.10 per cent) ;
total : not more than twice the area of the principal peak
in the chromatogram obtained with reference solution (b)
(0.5 per cent) ;
disregard limit : 0.2 times the area of the principal peak in
the chromatogram obtained with reference solution (b)
(0.05 per cent).
Heavy metals (2.4.8): maximum 20 ppm.
1.0 g complies with test D. Prepare the reference solution
using 2 mL of lead standard solution (10 ppm Pb) 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.
ASSAY
Dissolve 0.300 g in 50 mL of a mixture of 1 volume of
anhydrous acetic acid R and 7 volumes of methyl ethyl
ketone R. Using 0.2 mL of naphtholbenzein solution R as
indicator, titrate with 0.1 M perchloric acid until the colour
changes from orange-yellow to green.
1 mL of 0.1 M perchloric acid is equivalent to 37.94 mg
of C22H22FN3O2.
STORAGE
Protected from light.
IMPURITIES
Specified impurities : A, B, C, D, E.

A. 1-(1,2,3,6-tetrahydropyridin-4-yl)-1,3-dihydro-2Hbenzimidazol-2-one,

B. 1-[1-[4-(2-uorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

C. 1-[4-(4-uorophenyl)-4-oxobutyl]-4-(2-oxo-2,3-dihydro1H-benzimidazol-1-yl)pyridinium chloride,
See the information section on general monographs (cover pages)

Drospirenone

EUROPEAN PHARMACOPOEIA 8.0

D. (1RS)-1-[4-(4-uorophenyl)-4-oxobutyl]-4-(2-oxo-2,3dihydro-1H-benzimidazol-1-yl)-1,2,3,6-tetrahydropyridine
1-oxide,

E. 1-[1-[4-[4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)3,6-dihydropyridin-1(2H)-yl]-1-oxobutyl]phenyl]-1,2,3,6tetrahydropyridin-4-yl]-1,3-dihydro-2H-benzimidazol-2one.
07/2009:2404

DROSPIRENONE

Reference solution (a). Dilute 1.0 mL of the test solution

to 10.0 mL with the solvent mixture. Use 1.0 mL of this
solution to dissolve the contents of a vial of drospirenone
impurity E CRS.
Reference solution (b). Dilute 1.0 mL of the test solution to
100.0 mL with the solvent mixture. Dilute 1.0 mL of this
solution to 10.0 mL with the solvent mixture.
Reference solution (c). Dissolve 30.0 mg of drospirenone CRS
in the solvent mixture and dilute to 50.0 mL with the solvent
mixture.
Column :
size : l = 0.25 m, = 4.6 mm ;
stationary phase : spherical end-capped octadecylsilyl silica
gel for chromatography R (3 m) ;
temperature : 35 C.
Mobile phase :
mobile phase A : water R ;
mobile phase B : acetonitrile R ;
Time
(min)
0-2

Mobile phase A
(per cent V/V)
63

Mobile phase B
(per cent V/V)
37

2 - 16

63 52

37 48

16 - 23

52

48

23 - 31

52 20

48 80

31 - 39

20

80

Flow rate : 1.0 mL/min.

Detection : spectrophotometer at 245 nm.
Injection : 10 L of the test solution and reference solutions (a)
and (b).
Relative retention with reference to drospirenone (retention
time = about 22 min) : impurity E = about 1.1.
System suitability : reference solution (a) :
resolution : minimum 5.0 between the peaks due to
drospirenone and impurity E.
Limits :
C24H30O3
Mr 366.5
unspecified impurities : for each impurity, not more than the
[67392-87-4]
area of the principal peak in the chromatogram obtained
with reference solution (b) (0.10 per cent) ;
DEFINITION
total : not more than 3 times the area of the principal peak
3-Oxo-6,7,15,16-tetrahydro-3H,3H-dicyclopropain the chromatogram obtained with reference solution (b)
[6,7:15,16]-17-pregn-4-en-21,17-carbolactone.
(0.3 per cent) ;
Content : 98.0 per cent to 102.0 per cent (dried substance).
disregard limit : 0.5 times the area of the principal peak in
CHARACTERS
the chromatogram obtained with reference solution (b)
Appearance : white or almost white powder.
(0.05 per cent).
Solubility : practically insoluble in water, freely soluble in
Loss on drying (2.2.32) : maximum 0.5 per cent, determined
methylene chloride, soluble in methanol, sparingly soluble in on 1.000 g by drying in an oven at 105 C for 3 h.
ethanol (96 per cent).
ASSAY
IDENTIFICATION
Liquid chromatography (2.2.29) as described in the test for
A. Specic optical rotation (see Tests).
related substances with the following modication.
B. Infrared absorption spectrophotometry (2.2.24).
Injection : 10 L of the test solution and reference solution (c).
Comparison : drospirenone CRS.
Calculate the percentage content of C24H30O3 from the
declared content of drospirenone CRS.
TESTS
IMPURITIES
Specic optical rotation (2.2.7) : 187 to 193 (dried
substance).
Other detectable impurities (the following substances would,
if present at a sufcient level, be detected by one or other of
Dissolve 0.100 g in methanol R and dilute to 10.0 mL with
the tests in the monograph. They are limited by the general
the same solvent.
acceptance criterion for other/unspecied impurities and/or
Related substances. Liquid chromatography (2.2.29).
by the general monograph Substances for pharmaceutical
Solvent mixture : acetonitrile R, water R (50:50 V/V).
use (2034). It is therefore not necessary to identify these
Test solution. Dissolve 30.0 mg of the substance to be
impurities for demonstration of compliance. See also 5.10.
examined in the solvent mixture and dilute to 50.0 mL with
Control of impurities in substances for pharmaceutical use) : A,
the solvent mixture.
B, C, D, E, F, G, H, I, K.

Drospirenonum

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

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