Anastrozole
04/2013:2406
ANASTROZOLE
Anastrozolum
C17H19N5 Mr 293.4 time = about 29 min) : impurity E = about 1.05.
[120511-73-1]
DEFINITION
2,2′-[5-(1H-1,2,4-Triazol-1-ylmethyl)benzene-1,3-diyl]bis(2-
methylpropanenitrile).
Content : 98.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance : white or almost white powder.
Solubility : very slightly soluble in water, freely soluble in
anhydrous ethanol, practically insoluble in cyclohexane.
It shows polymorphism (5.9).
IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
Comparison : anastrozole CRS.
If the spectra obtained in the solid state show differences,
dissolve the substance to be examined and the reference
substance separately in acetone R, evaporate to dryness and
record new spectra using the residues.
TESTS
Related substances. Liquid chromatography (2.2.29).
Solvent mixture : acetonitrile R1, water for chromatography R
(50:50 V/V).
Test solution (a). Dissolve 25 mg of the substance to be
examined in the solvent mixture and dilute to 100.0 mL with
the solvent mixture.
Test solution (b). Dissolve 25.0 mg of the substance to be
examined in the solvent mixture and dilute to 200.0 mL with
the solvent mixture.
Reference solution (a). Dilute 1.0 mL of test solution (a) 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 2.5 mg of anastrozole
impurity E CRS in 20.0 mL of the solvent mixture. Dilute
1.0 mL of the solution to 50.0 mL with test solution (a).
Reference solution (c). Dissolve 25.0 mg of anastrozole CRS in
the solvent mixture and dilute to 200.0 mL with the solvent
mixture.
Column :
– size : l = 0.15 m, Ø = 4.6 mm ;
– stationary phase : end-capped polar-embedded octadecylsilyl
amorphous organosilica polymer R (3.5 μm).
Mobile phase :
– mobile phase A : phosphoric acid R, water for
chromatography R (0.1 :100 V/V) ;
– mobile phase B : phosphoric acid R, acetonitrile R1
(0.1 :100 V/V) ;
1570
EUROPEAN PHARMACOPOEIA 8.
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-2 95 5
2 - 54 95 → 35 5 → 65
Flow rate : 1.0 mL/min.
Detection : spectrophotometer at 215 nm.
Injection : 20 μL of test solution (a) and reference solutions (a)
and (b).
Identification of impurities: use the chromatogram obtained
with reference solution (b) to identify the peak due to
impurity E.
Relative retention with reference to anastrozole (retention
System suitability : reference solution (b) :
– resolution : minimum 3.5 between the peaks due to
anastrozole and impurity E.
Calculation of percentage contents :
– for each impurity, use the concentration of anastrozole in
reference solution (a).
Limits :
– unspecified impurities : for each impurity, maximum
0.10 per cent ;
– total : maximum 0.2 per cent ;
– reporting threshold : 0.05 per cent.
Water (2.5.32) : maximum 0.3 per cent, determined on
50.0 mg.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Liquid chromatography (2.2.29) as described in the test for
related substances with the following modification.
Injection : test solution (b) and reference solution (c).
Calculate the percentage content of C17H19N5 taking into
account the assigned content of anastrozole CRS.
IMPURITIES
Other detectable impurities (the following substances would,
if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified 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, C, D, E, F, G, H, I.
A. 2-[3-[(1RS)-1-cyanoethyl]-5-(1H-1,2,4-triazol-1-
ylmethyl)phenyl]-2-methylpropanenitrile,
B. (2RS)-2,3-bis[3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-
triazol-1-ylmethyl)phenyl]-2-methylpropanenitrile,
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 8.0
C. 2,2′-[5-(bromomethyl)benzene-1,3-diyl]bis(2-
methylpropanenitrile),
D. 2,2′-[5-(dibromomethyl)benzene-1,3-diyl]bis(2-
methylpropanenitrile),
E. 2,2′-[5-(hydroxymethyl)benzene-1,3-diyl]bis(2-
methylpropanenitrile),
F. 4-methylbenzenesulfonic acid,
G. 2,2′-[5-(4H-1,2,4-triazol-4-ylmethyl)benzene-1,3-
diyl]bis(2-methylpropanenitrile),
H. 2,2′-(5-methylbenzene-1,3-diyl)bis(2-methylpropaneni-
trile),
I. 2,2′-[5-(chloromethyl)benzene-1,3-diyl]bis(2-
methylpropanenitrile).
General Notices (1) apply to all monographs and other texts
Antazoline hydrochloride
01/2008:0972
corrected 6.0
ANTAZOLINE HYDROCHLORIDE
Antazolini hydrochloridum
C17H20ClN3 Mr 301.8
[2508-72-7]
DEFINITION
Antazoline hydrochloride contains not less than 99.0 per
cent and not more than the equivalent of 101.0 per cent of
N-benzyl-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]aniline
hydrochloride, calculated with reference to the dried
substance.
CHARACTERS
A white or almost white, crystalline powder, sparingly soluble
in water, soluble in alcohol, slightly soluble in methylene
chloride.
It melts at about 240 °C, with decomposition.
IDENTIFICATION
First identification : A, D.
Second identification : B, C, D.
A. Examine by infrared absorption spectrophotometry
(2.2.24), comparing with the spectrum obtained with
antazoline hydrochloride CRS. Examine the substances as
discs prepared using potassium chloride R.
B. Examine the chromatograms obtained in the test for related
substances in daylight after spraying. The principal spot in
the chromatogram obtained with test solution (b) is similar
in position, colour and size to the principal spot in the
chromatogram obtained with reference solution (b).
C. To 5 mL of solution S (see Tests) add, drop by drop, dilute
sodium hydroxide solution R until an alkaline reaction
is produced. Filter. The precipitate, washed with two
quantities, each of 10 mL, of water R and dried in a
desiccator under reduced pressure, melts (2.2.14) at 119 °C
to 123 °C.
D. It gives reaction (a) of chlorides (2.3.1).
TESTS
Solution S. Dissolve 2.0 g in carbon dioxide-free water R
prepared from distilled water R, heating at 60 °C if necessary.
Allow to cool and dilute to 100 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution Y7 (2.2.2,
Method II).
Acidity or alkalinity. To 10 mL of solution S add 0.2 mL
of methyl red solution R. Not more than 0.1 mL of 0.01 M
hydrochloric acid or 0.01 M sodium hydroxide is required to
change the colour of the indicator.
Related substances. Examine by thin-layer chromatography
(2.2.27), using silica gel GF254 R as the coating substance. Heat
the plate at 110 °C for 15 min before using.
Test solution (a). Dissolve 0.10 g of the substance to be
examined in methanol R and dilute to 5 mL with the same
solvent.
Test solution (b). Dilute 1 mL of test solution (a) to 5 mL with
methanol R.
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