Docetaxel trihydrate

EUROPEAN PHARMACOPOEIA 8.0

07/2012:2449

DOCETAXEL TRIHYDRATE
Docetaxelum trihydricum

C. 5,20-epoxy-1,7,10-trihydroxy-9-oxotax11-ene-2,4,13-triyl 4-acetate 2-benzoate

13-[(2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2hydroxy-3-phenylpropanoate] (7-epi-docetaxel),

C43H53NO14,3H2O
[148408-66-6]

D. 5,20-epoxy-1,7-dihydroxy-9,10-dioxotax-11-ene2,4,13-triyl 4-acetate 2-benzoate 13-[(2R,3S)-3[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-3phenylpropanoate] (10-deoxy-10-oxo-7-epi-docetaxel),

Mr 862

DEFINITION
5,20-epoxy-1,7,10-Trihydroxy-9-oxotax-11-ene2,4,13-triyl 4-acetate 2-benzoate 13-[(2R,3S)-3[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-3phenylpropanoate] trihydrate.
Content : 97.5 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance : white or almost white, crystalline powder.
Solubility : practically insoluble in water, freely soluble in
anhydrous ethanol, soluble in methylene chloride.
IDENTIFICATION
A. Specic optical rotation (see Tests).
B. Infrared absorption spectrophotometry (2.2.24).
Comparison : docetaxel trihydrate CRS.

TESTS
Appearance of solution. The solution is not more opalescent
than reference suspension II (2.2.1) and not more intensely
E. 5,20-epoxy-4-(acetyloxy)-1,7,10,13-tetrahydroxy-9coloured than reference solution B5 (2.2.2, Method I).
oxotax-11-en-2-yl benzoate (10-desacetyl-baccatin III),
Dissolve 1.0 g in anhydrous ethanol R and dilute to 20 mL
with the same solvent.
Specic optical rotation (2.2.7) : 41.5 to 38.5 (anhydrous
substance).
Dissolve 0.250 g in methanol R and dilute to 25.0 mL with
the same solvent.
Related substances. Liquid chromatography (2.2.29).
Solvent mixture : acetic acid R, acetonitrile R1, water R
(0.05:50:50 V/V/V).
Test solution. Dissolve 50.0 mg of the substance to be
examined in 2.5 mL of anhydrous ethanol R and dilute to
F. 5,20-epoxy-1,7-dihydroxy-9-oxotax-11-ene50.0 mL with the solvent mixture.
2,4,10,13-tetrayl 4,10-diacetate 2-benzoate 13-[(2R,3S)- Reference solution (a). Dissolve 50.0 mg of docetaxel
3-(benzoylamino)-2-hydroxy-3-phenylpropanoate]
trihydrate CRS in 2.5 mL of anhydrous ethanol R and dilute to
(paclitaxel),
50.0 mL with the solvent mixture.
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 5 mg of docetaxel for system
suitability CRS (containing impurities A, B and C) in 0.25 mL
of anhydrous ethanol R and dilute to 5.0 mL with the solvent
mixture.
Column :
size : l = 0.15 m, = 4.6 mm ;
stationary phase : end-capped octadecylsilyl silica gel for
chromatography R (3.5 m) ;
G. 5,20-epoxy-1,7-dihydroxy-9-oxotax-11-ene
temperature
: 45 C.
2,4,10,13-tetrayl 4,10-diacetate 2-benzoate
Mobile
phase
:
13-[(2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2hydroxy-3-phenylpropanoate] (10-acetyldocetaxel).
mobile phase A : water R ;

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See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 8.0

Docetaxel trihydrate

mobile phase B : acetonitrile R1 ;

IMPURITIES
Specified impurities : A, B, C.
Mobile phase A
Mobile phase B
(per cent V/V)
(per cent V/V)
Other detectable impurities (the following substances would,
if present at a sufcient level, be detected by one or other of
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28
the tests in the monograph. They are limited by the general
9 - 39
72 28
28 72
acceptance criterion for other/unspecied impurities and/or
by the general monograph Substances for pharmaceutical
Flow rate : 1.2 mL/min.
use (2034). It is therefore not necessary to identify these
Detection : spectrophotometer at 232 nm.
impurities for demonstration of compliance. See also 5.10.
Injection : 10 L of the test solution and reference solutions (b) Control of impurities in substances for pharmaceutical use) : D.
and (c).
Identification of impurities : use the chromatogram
supplied with docetaxel for system suitability CRS and the
chromatogram obtained with reference solution (c) to identify
the peaks due to impurities A, B and C.
Relative retention with reference to docetaxel (retention
time = about 27 min) : impurity A = about 0.97 ;
impurity B = about 1.08 ; impurity C = about 1.13.
System suitability : reference solution (c) :
resolution : minimum 3.0 between the peaks due to
A. 5,20-epoxy-1,7,10-trihydroxy-9-oxotax-11impurity A and docetaxel.
ene-2,4,13-triyl 4-acetate 13-[(2R,3S)-3-[[(1,1Limits :
dimethylethoxy)carbonyl]amino]-2-hydroxy-3 correction factor : for the calculation of content, multiply
phenylpropanoate] 2-[(2E)-2-methylbut-2-enoate]
the peak area of impurity A by 1.6 ;
(2-O-desbenzoyl-2-O-tiglyldocetaxel),
impurity A : not more than 5 times the area of the principal
peak in the chromatogram obtained with reference
solution (b) (0.5 per cent) ;
impurities B, C : for each impurity, not more than 3 times
the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.3 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 10 times the area of the principal peak
in the chromatogram obtained with reference solution (b) B. 5,20-epoxy-1,7-dihydroxy-9,10-dioxotax(1.0 per cent) ;
11-ene-2,4,13-triyl 4-acetate 2-benzoate
13-[(2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2 disregard limit : 0.5 times the area of the principal peak in
hydroxy-3-phenylpropanoate] (10-deoxy-10-oxodocetaxel),
the chromatogram obtained with reference solution (b)
(0.05 per cent).
Heavy metals (2.4.8) : maximum 20 ppm.
Solvent mixture : water R, dimethylformamide R (15:85 V/V).
Dissolve, using sonication, 1.0 g in the solvent mixture and
dilute to 20 mL with the solvent mixture. 12 mL of the solution
complies with test B. Prepare the reference solution using
lead standard solution (1 ppm Pb) obtained by diluting lead
standard solution (100 ppm Pb) R with the solvent mixture.
Water (2.5.32) : 5.0 per cent to 7.0 per cent.
Inject 200 L of a 100 mg/mL solution of the substance to be
C. 5,20-epoxy-1,7,10-trihydroxy-9-oxotaxexamined in dimethylformamide R.
11-ene-2,4,13-triyl 4-acetate 2-benzoate
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on
13-[(2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-21.0 g.
hydroxy-3-phenylpropanoate] (7-epi-docetaxel),
Bacterial endotoxins (2.6.14) : less than 0.3 IU/mg, if intended
for use in the manufacture of parenteral preparations without
a further appropriate procedure for the removal of bacterial
endotoxins.
Time
(min)
0-9

ASSAY
Liquid chromatography (2.2.29) as described in the test for
related substances with the following modication.
Injection : 10 L of the test solution and reference solution (a).
Calculate the percentage content of C43H53NO14 taking into
account the assigned content of docetaxel trihydrate CRS.
STORAGE
Protected from light.
General Notices (1) apply to all monographs and other texts

D. 5,20-epoxy-1,7-dihydroxy-9,10-dioxotax-11-ene2,4,13-triyl 4-acetate 2-benzoate 13-[(2R,3S)-3[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-3phenylpropanoate] (10-deoxy-10-oxo-7-epi-docetaxel).

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