Dutasteride

EUROPEAN PHARMACOPOEIA 8.0

Content : 97.0 per cent to 102.0 per cent (anhydrous substance).

A. (3R)-N-methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2yl)propan-1-amine,

B. (1S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol,

CHARACTERS
Appearance : white or pale yellow powder.
Solubility : practically insoluble in water, freely soluble in
methylene chloride, soluble or sparingly soluble in anhydrous
ethanol.
IDENTIFICATION
A. Specic optical rotation (see Tests).
B. Infrared absorption spectrophotometry (2.2.24).
Comparison : dutasteride CRS.

TESTS
Specic optical rotation (2.2.7) : + 33.0 to + 39.0 (anhydrous
substance).
Dissolve 0.100 g in anhydrous ethanol R and dilute to 20.0 mL
with the same solvent.
Related substances
C. 4-[(1RS)-3-(methylamino)-1-(thiophen-2A. Liquid chromatography (2.2.29).
yl)propyl]naphthalen-1-ol,
Solvent mixture : water for chromatography R, acetonitrile R1
(40:60 V/V).
Test solution. Dissolve 50.0 mg of the substance to be
examined in the solvent mixture and dilute to 100.0 mL
with the solvent mixture.
D. naphthalen-1-ol,
Reference solution (a). 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 (b). Dissolve 5 mg of dutasteride for
system suitability CRS (containing impurities A, B, C, E,
F, G, H and I) in the solvent mixture and dilute to 10 mL
with the solvent mixture.
E. 2-[(1RS)-3-(methylamino)-1-(thiophen-2Reference solution (c). Dissolve 50.0 mg of dutasteride CRS
yl)propyl]naphthalen-1-ol,
in the solvent mixture and dilute to 100.0 mL with the
solvent mixture.
Column :
size : l = 0.25 m, = 4.6 mm ;
stationary phase : end-capped octadecylsilyl silica gel for
chromatography R (5 m) ;
F. (3S)-N-methyl-3-(naphthalen-1-yloxy)-3-(thiophen-3 temperature : 35 C.
yl)propan-1-amine,
Mobile phase : mix 0.25 volumes of trifluoroacetic
acid R, 480 volumes of water for chromatography R and
520 volumes of acetonitrile R1.
Flow rate : 1.0 mL/min.
Detection : spectrophotometer at 220 nm.
G. 1-uoronaphthalene.
Injection : 20 L of the test solution and reference
solutions (a) and (b).
01/2014:2641
Run time : 1.6 times the retention time of dutasteride.
Identification of impurities: use the chromatogram
DUTASTERIDE
supplied with dutasteride for system suitability CRS and
the chromatogram obtained with reference solution (b) to
identify the peaks due to impurities A, B, C, E, F and G.
Dutasteridum
Relative retention with reference to dutasteride (retention
time = about 36 min) : impurity A = about 0.10 ;
impurity B = about 0.11 ; impurity C = about 0.4 ;
impurity E = about 0.9 ; impurity F = about 1.1 ;
impurity G = about 1.2.
System suitability :
resolution : minimum 1.5 between the peaks due
to impurity E and dutasteride and minimum 1.5
C27H30F6N2O2
Mr 528.5
between the peaks due to impurities A and B in the
[164656-23-9]
chromatogram obtained with reference solution (b) ;
DEFINITION
signal-to-noise ratio : minimum 30 for the peak due
N-[2,5-Bis(triuoromethyl)phenyl]-3-oxo-4-aza-5-androstto dutasteride in the chromatogram obtained with
1-ene-17-carboxamide.
reference solution (a).

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EUROPEAN PHARMACOPOEIA 8.0

Calculation of percentage contents :

correction factors : multiply the peak areas of the
following impurities by the corresponding correction
factor : impurity B = 0.7 ; impurity F = 3.0 ;
for each impurity, use the concentration of dutasteride
in reference solution (a).
Limits :
impurity F : maximum 0.4 per cent ;
impurities E, G : for each impurity, maximum 0.3 per
cent ;
impurities A, C : for each impurity, maximum 0.2 per
cent ;
impurity B : maximum 0.15 per cent ;
unspecified impurities : for each impurity, maximum
0.10 per cent ;
reporting threshold : 0.05 per cent.
B. Liquid chromatography (2.2.29) as described in test A for
related substances with the following modications.
Column :
size : l = 0.15 m, = 4.6 mm ;
stationary phase : phenylsilyl silica gel for
chromatography R (5 m).
Mobile phase : water for chromatography R, acetonitrile R1
(20:80 V/V).
Injection : 10 L of the test solution and reference
solutions (a) and (b).
Run time : 5 times the retention time of dutasteride.
Identification of impurities : use the chromatogram
supplied with dutasteride for system suitability CRS and
the chromatogram obtained with reference solution (b) to
identify the peaks due to impurities H and I.
Relative retention with reference to dutasteride
(retention time = about 4 min) : impurity H = about 3.4 ;
impurity I = about 3.9.
System suitability : reference solution (b) :
resolution : minimum 2.0 between the peaks due to
impurities H and I.
Calculation of percentage contents :
for each impurity, use the concentration of dutasteride
in reference solution (a).
Limits :
impurity I : maximum 0.5 per cent ;
impurity H : maximum 0.3 per cent ;
unspecified impurities eluting after dutasteride : for each
impurity, maximum 0.10 per cent ;
reporting threshold : 0.05 per cent.
Limit :
total for tests A and B : maximum 1.5 per cent.
Water (2.5.32) : maximum 0.2 per cent, determined on 0.100 g
using the evaporation technique :
temperature : 180 C ;
heating time : 4 min.
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on
1.0 g in a platinum crucible.
ASSAY
Liquid chromatography (2.2.29) as described in test A for
related substances with the following modication.
Injection : 10 L of the test solution and reference solution (c).
Calculate the percentage content of C27H30F6N2O2 taking into
account the assigned content of dutasteride CRS.
General Notices (1) apply to all monographs and other texts

Dutasteride

IMPURITIES
Specified impurities : A, B, C, E, F, G, H, I.
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) : D.

A. 3-oxo-4-aza-5-androst-1-ene-17-carboxylic acid,

B. N,N-dimethyl-3-oxo-4-aza-5-androst-1-ene-17carboxamide,

C. ethyl 3-oxo-4-aza-5-androst-1-ene-17-carboxylate,

D. N-[2,5-bis(triuoromethyl)phenyl]-3-oxo-4-azaandrost1,5-diene-17-carboxamide,

E. N-[2,5-bis(triuoromethyl)phenyl]-3-oxo-4-aza-5androst-1-ene-17-carboxamide,

F. N-[2,5-bis(triuoromethyl)phenyl]-1-chloro-3-oxo-4-aza5-androstane-17-carboxamide,

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Dydrogesterone

EUROPEAN PHARMACOPOEIA 8.0

TESTS
Specic optical rotation (2.2.7): 469 to 485 (dried
substance), measured at 25 C.
Dissolve 0.100 g in methylene chloride R and dilute to 20.0 mL
with the same solvent.
Related substances. Liquid chromatography (2.2.29).
Test solution (a). Dissolve 50.0 mg of the substance to be
G. N-[2,5-bis(triuoromethyl)phenyl]-3-oxo-4-azaandrostexamined in the mobile phase and dilute to 100.0 mL with
1,5-diene-17-carboxamide,
the mobile phase.
Test solution (b). Dissolve 20.0 mg of the substance to be
examined in the mobile phase and dilute to 100.0 mL with
the mobile phase.
Reference solution (a). Dissolve 3.0 mg of dydrogesterone
impurity A CRS in the mobile phase and dilute to 20.0 mL with
the mobile phase. Dilute 1.0 mL of this solution to 100.0 mL
with the mobile phase.
Reference solution (b). Dilute 1.0 mL of test solution (a) to
100.0 mL with the mobile phase. Dilute 1.0 mL of this solution
to 10.0 mL with the mobile phase.
Reference solution (c). Dissolve 10 mg of the substance to be
examined in 10 mL of reference solution (a).
H. N-[2,5-bis(triuoromethyl)phenyl]-3-oxo-4-[3-oxo-4-aza- Reference solution (d). Dissolve 10 mg of the substance to be
5-androst-1-ene-17-carbonyl]-4-aza-5-androst-1-eneexamined in 30 mL of ethanol (96 per cent) R. Add 1 mL of a
17-carboxamide (dutasteride dimer 1),
8.4 g/L solution of sodium hydroxide R and heat at 85 C for
10 min. Cool to room temperature, add 1 mL of a 20.6 g/L
solution of hydrochloric acid R, add 20 mL of acetonitrile R,
2 mg of dydrogesterone impurity B CRS, dilute to 100 mL with
water R and mix. This solution contains dydrogesterone and
impurities B and C.
Reference solution (e). Dissolve 20.0 mg of dydrogesterone CRS
in the mobile phase and dilute to 100.0 mL with the mobile
phase.
Column :
size : l = 0.15 m, = 4.6 mm ;
stationary phase : spherical end-capped octadecylsilyl silica
gel for chromatography R (3 m) ;

temperature
: 40 C.
I. N-[2,5-bis(triuoromethyl)phenyl]-3-oxo-4-[3-oxo-4-azaMobile
phase
:
acetonitrile
R, ethanol (96 per cent) R, water R
5-androst-1-ene-17-carbonyl]-4-aza-5-androst-1-ene(21:25:54 V/V/V).
17-carboxamide (dutasteride dimer 2).
Flow rate : 1.0 mL/min.
Detection
: spectrophotometer at 280 nm and at 385 nm.
01/2009:2357
Injection : 10 L of test solution (a) and reference solutions (a),
(b), (c) and (d).
DYDROGESTERONE
Run time : twice the retention time of dydrogesterone.
Relative retention at 385 nm with reference to dydrogesterone
Dydrogesteronum
(retention time = about 13 min) : impurity A = about 0.9.
Relative retention at 280 nm with reference to dydrogesterone
(retention time = about 13 min): impurity B = about 1.1 ;
impurity C = about 1.2.
System suitability :
resolution at 385 nm : minimum 1.1 between the peaks due
to impurity A and dydrogesterone in the chromatogram
obtained with reference solution (c) ;
C21H28O2
Mr 312.5

resolution
at 280 nm : minimum 4.5 between the peaks
[152-62-5]
due to dydrogesterone and impurity B and minimum 1.5
between the peaks due to impurity B and impurity C in the
DEFINITION
chromatogram obtained with reference solution (d).
9,10-Pregna-4,6-diene-3,20-dione.
Limits
:
Content : 98.0 per cent to 102.0 per cent (dried substance).
impurity A at 385 nm : not more than the area of the
CHARACTERS
corresponding peak in the chromatogram obtained with
reference solution (a) (0.3 per cent) ;
Appearance : white or almost white, crystalline powder.

impurity
B at 280 nm : not more than 1.5 times the area
Solubility : practically insoluble in water, soluble in acetone,
of the principal peak in the chromatogram obtained with
sparingly soluble in ethanol (96 per cent).
reference solution (b) (0.15 per cent) ;
IDENTIFICATION
impurity C at 280 nm : not more than 3 times the area of
Infrared absorption spectrophotometry (2.2.24).
the principal peak in the chromatogram obtained with
reference solution (b) (0.3 per cent) ;
Comparison : dydrogesterone CRS.

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