EUROPEAN PHARMACOPOEIA 11.

0 Imatinib mesilate

Apply to the plate 5 μL of each solution. Develop over a

path of 15 cm using a mixture of 1 volume of methylene
chloride R and 10 volumes of acetone R. Dry the plate
at 115 °C for 45 min. Proceed as described in test A for
related substances. Any spot corresponding to impurity E
or impurity F in the chromatogram obtained with the B. bis[3-[(2-chloroethyl)amino]propyl] dihydrogen
test solution is not more intense than the corresponding diphosphate,
spot in the chromatogram obtained with reference
solution (a) (0.25 per cent). The test is not valid unless the
chromatogram obtained with reference solution (b) shows C. 2-chloroethanamine,
2 clearly separated spots.
Chlorides (2.4.4). Dilute 5 mL of solution S to 15 mL with
water R. The freshly prepared solution complies with the limit
D. 2-aminoethanol.
test for chlorides (100 ppm).
Water (2.5.12). Not more than 0.5 per cent, determined on
1.00 g by the semi-micro determination of water.
E. 3-chloro-N-(2-chloroethyl)propan-1-amine,
ASSAY
Examine by liquid chromatography (2.2.29). Use the solutions
within 24 h.
Solution A. Dissolve 50.0 mg of ethyl parahydroxybenzoate R F. (RS)-2-chloro-3-(2-chloroethyl)-1,3,2-oxazaphosphinane
in 25 mL of alcohol R, dilute to 100.0 mL with water R and mix. 2-oxide.
Test solution. To 0.150 g of the substance to be examined add
10.0 mL of solution A and dilute to 250.0 mL with water R. 07/2017:2736
corrected 9.6
Reference solution. To 15.0 mg of ifosfamide CRS add 1.0 mL
of solution A and dilute to 25.0 mL with water R.
The chromatography may be carried out using :
– a stainless steel column 0.25 m long and 4.6 mm in
internal diameter packed with octadecylsilyl silica gel for IMATINIB MESILATE
chromatography R (5 μm),
– as mobile phase at a flow rate of 1.5 mL/min a mixture of Imatinibi mesilas
30 volumes of acetonitrile R and 70 volumes of water R,
– as detector a spectrophotometer set at 195 nm.
Inject 1 μL of the reference solution six times. The assay is
not valid unless the resolution between the peaks due to
ifosfamide and to ethyl parahydroxybenzoate is not less than
6.0 and the relative standard deviation of the peak area for C30H35N7SO4 Mr 589.7
ifosfamide is at most 2.0 per cent. [220127-57-1]
Inject 1 μL of the test solution. Calculate the percentage DEFINITION
content of C7H15Cl2N2O2P from the area of the corresponding 4-[(4-Methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[[4-
peak in the chromatogram obtained and the declared content (pyridin-3-yl)pyrimidin-2-yl]amino]phenyl]benzamide
of ifosfamide CRS. methanesulfonate.
Content : 98.0 per cent to 102.0 per cent (anhydrous substance).
STORAGE
PRODUCTION
Store in an airtight container.
It is considered that alkyl methanesulfonate esters are
IMPURITIES genotoxic and are potential impurities in imatinib
mesilate. The manufacturing process should be developed
Test A for related substances : A, B, C, D. taking into consideration the principles of quality risk
Test B for related substances : E, F. management, together with considerations of the quality
of starting materials, process capability and validation.
Specified impurities : A, B, C, E, F. The general methods 2.5.37. Methyl, ethyl and isopropyl
Other detectable impurities (the following substances would, methanesulfonate in methanesulfonic acid, 2.5.38. Methyl,
if present at a sufficient level, be detected by one or other of ethyl and isopropyl methanesulfonate in active substances and
the tests in the monograph. They are limited by the general 2.5.39. Methanesulfonyl chloride in methanesulfonic acid are
acceptance criterion for other/unspecified impurities and/or available to assist manufacturers.
by the general monograph Substances for pharmaceutical
CHARACTERS
use (2034). It is therefore not necessary to identify these
impurities for demonstration of compliance. See also 5.10. Appearance : white or almost white, slightly brownish or
Control of impurities in substances for pharmaceutical use): D. yellowish powder ; yellow or pale yellow, very hygroscopic, for
the amorphous form.
Solubility : freely soluble in water, slightly soluble in ethanol
(96 per cent), practically insoluble in methylene chloride.
It shows polymorphism (5.9).
IDENTIFICATION
A. 3-[(2-chloroethyl)amino]propyl dihydrogen phosphate, Infrared absorption spectrophotometry (2.2.24).

General Notices (1) apply to all monographs and other texts 3067
Imatinib mesilate EUROPEAN PHARMACOPOEIA 11.0

Comparison : imatinib mesilate CRS. Reference solution (a). Dissolve the contents of a vial of
If the spectra obtained in the solid state show differences, imatinib impurity A CRS in 1.0 mL of the solvent mixture.
dissolve the substance to be examined and the reference Reference solution (b). Dissolve 60.0 mg of imatinib
substance separately in anhydrous ethanol R, evaporate to impurity H CRS in the solvent mixture and dilute to 20.0 mL
dryness and record new spectra using the residues. with the solvent mixture. Dilute 1.0 mL of the solution to
100.0 mL with the solvent mixture.
TESTS
Reference solution (c). Dilute 5.0 mL of reference solution (b)
Impurity F. Liquid chromatography (2.2.29) coupled with to 50.0 mL with the solvent mixture.
mass spectrometry (2.2.43).
Reference solution (d). Dissolve 0.150 g of the substance to be
Solvent mixture : acetonitrile R1, water for chromatography R examined in the solvent mixture, add 1.0 mL each of reference
(30:70 V/V). solutions (a) and (b) and dilute to 10.0 mL with the solvent
Test solution. Dissolve 50.0 mg of the substance to be mixture.
examined in the solvent mixture and dilute to 100.0 mL with Column :
the solvent mixture.
– size : l = 0.25 m, Ø = 4.6 mm ;
Reference solution. Dissolve 2.0 mg of imatinib impurity F CRS
in the solvent mixture and dilute to 100.0 mL with the solvent – stationary phase : end-capped octadecylsilyl silica gel for
mixture. Dilute 1.0 mL of the solution to 200.0 mL with the chromatography R (5 μm) ;
solvent mixture. Dilute 1.0 mL of this solution to 10.0 mL – temperature : 35 °C.
with the solvent mixture. Mobile phase :
Column : – mobile phase A : dissolve 2.3 g of sodium octanesulfonate
– size : l = 0.15 m, Ø = 3.0 mm ; monohydrate R in 700 mL of water for chromatography R
– stationary phase : end-capped octadecylsilyl amorphous and add 300 mL of acetonitrile R1 and 1.2 mL of dilute
organosilica polymer for chromatography R (3.5 μm) ; phosphoric acid R ;
– temperature : 40 °C. – mobile phase B : dissolve 2.3 g of sodium octanesulfonate
monohydrate R in 100 mL of water for chromatography R
Mobile phase :
and add 900 mL of acetonitrile R1 and 1.2 mL of dilute
– mobile phase A : 1.26 g/L solution of ammonium formate R phosphoric acid R ;
in water for chromatography R adjusted to pH 3.4-3.5 with
anhydrous formic acid R ; Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
– mobile phase B : 0.05 per cent V/V solution of anhydrous
formic acid R in acetonitrile R1 ; 0 - 6 98 2

Time Mobile phase A Mobile phase B 6-8 98 → 20 2 → 80

(min) (per cent V/V) (per cent V/V) 8 - 10 20 80
0-6 80 20
Flow rate : 2.3 mL/min.
6 - 10 80 → 20 20 → 80
Detection : spectrophotometer at 227 nm.
10 - 15 20 80
Injection : 10 μL of the test solution and reference solutions (c)
NOTE : MS acquisition can be started at 3.5 min and stopped and (d).
at 6 min ; during non-acquisition the eluent is directed to waste. Identification of impurities: use the chromatogram obtained
Flow rate : 0.5 mL/min. with reference solution (d) to identify the peaks due to
impurities A and H.
Detection : mass detector : the following settings have been
found to be suitable and are given as examples ; if the detector Relative retention with reference to imatinib (retention
has different setting parameters, adjust the detector settings so time = about 8 min) : impurity A = about 0.17 ;
as to comply with the system suitability criterion : impurity H = about 0.2.
– ionisation : ESI-positive ; System suitability : reference solution (d) :
– detection m/z (SIM) : 278.2 ; – resolution : minimum 1.5 between the peaks due to
– gas temperature : 350 °C ; impurities A and H.
– drying gas flow : 12 L/min ; Calculation of percentage content :
– nebuliser pressure : 414 kPa ; – for impurity H, use the concentration of impurity H in
reference solution (c).
– capillary voltage (Vcap) : 3 kV.
Limit :
Injection : 10 μL.
– impurity H : maximum 0.02 per cent.
System suitability : reference solution :
– signal-to-noise ratio : minimum 20 for the principal peak ; Related substances. Liquid chromatography (2.2.29).
– repeatability : maximum relative standard deviation of Solvent mixture : acetonitrile R1, water for chromatography R
10 per cent determined on 6 injections. (30:70 V/V).
Calculation of percentage content : Test solution. Dissolve 25.0 mg of the substance to be
examined in the solvent mixture and dilute to 50.0 mL with
– for impurity F, use the concentration of impurity F in the the solvent mixture.
reference solution.
Reference solution (a). Dilute 1.0 mL of the test solution to
Limit :
100.0 mL with the solvent mixture. Dilute 1.0 mL of this
– impurity F : maximum 20 ppm. solution to 10.0 mL with the solvent mixture.
Impurity H. Liquid chromatography (2.2.29). Reference solution (b). Dissolve 1 mg of imatinib for system
Solvent mixture : acetonitrile R1, water for chromatography R suitability CRS (containing impurities A, B, C, D and J) in the
(30:70 V/V). solvent mixture and dilute to 2 mL with the solvent mixture.
Test solution. Dissolve 75.0 mg of the substance to be Reference solution (c). Dissolve 25.0 mg of imatinib
examined in the solvent mixture and dilute to 5.0 mL with the mesilate CRS in the solvent mixture and dilute to 50.0 mL
solvent mixture. with the solvent mixture.

3068 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 11.0 Imatinib mesilate

Column : Injection : test solution and reference solution (c).

– size : l = 0.25 m, Ø = 4.6 mm ; Calculate the percentage content of C30H35N7SO4 taking into
– stationary phase : end-capped octadecylsilyl silica gel for account the assigned content of imatinib mesilate CRS.
chromatography R (5 μm) ; IMPURITIES
– temperature : 35 °C. Specified impurities : A, B, C, D, F, H.
Mobile phase : Other detectable impurities (the following substances would,
– mobile phase A : dissolve 2.3 g of sodium octanesulfonate if present at a sufficient level, be detected by one or other of
monohydrate R in 700 mL of water for chromatography R the tests in the monograph. They are limited by the general
and add 300 mL of acetonitrile R1 and 1.2 mL of dilute acceptance criterion for other/unspecified impurities and/or
phosphoric acid R ; by the general monograph Substances for pharmaceutical
– mobile phase B : dissolve 2.3 g of sodium octanesulfonate use (2034). It is therefore not necessary to identify these
monohydrate R in 100 mL of water for chromatography R impurities for demonstration of compliance. See also 5.10.
and add 900 mL of acetonitrile R1 and 1.2 mL of dilute Control of impurities in substances for pharmaceutical use) : J.
phosphoric acid R ;
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0 - 16 98 2

16 - 30 98 → 50 2 → 50
A. (2E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one,
Flow rate : 2.3 mL/min.
Detection : spectrophotometer at 267 nm.
Injection : 10 μL of the test solution and reference solutions (a)
and (b).
Identification of impurities : use the chromatogram supplied
with imatinib for system suitability CRS and the chromatogram B. N-(3-carbamimidamido-4-methylphenyl)-4-[(4-
obtained with reference solution (b) to identify the peaks due methylpiperazin-1-yl)methyl]benzamide,
to impurities A, B, C, D and J.
Relative retention with reference to imatinib (retention
time = about 11 min) : impurity A = about 0.2 ;
impurity B = about 0.6 ; impurity J = about 0.9 ;
impurity C = about 1.2 ; impurity D = about 2.3.
System suitability :
C. N-[4-methyl-3-[[4-(pyridin-3-yl)pyrimidin-2-
– resolution : minimum 3.0 between the peaks due to imatinib yl]amino]phenyl]-4-(piperazin-1-ylmethyl)benzamide
and impurity C in the chromatogram obtained with (desmethylimatinib),
reference solution (b) ;
– signal-to-noise ratio : minimum 45 for the principal peak in
the chromatogram obtained with reference solution (a) ;
– peak-to-valley ratio : minimum 1.3, where Hp = height
above the baseline of the peak due to impurity J and
Hv = height above the baseline of the lowest point of the
curve separating this peak from the peak due to imatinib
in the chromatogram obtained with reference solution (b).
Calculation of percentage contents :
– correction factors : multiply the peak areas of the following
impurities by the corresponding correction factor :
impurity A = 2.2 ; impurity B = 2.0 ;
– for each impurity, use the concentration of imatinib
mesilate in reference solution (a).
Limits : D. 1-methyl-1,4-bis[4-[[4-methyl-3-[[4-(pyridin-3-yl)-
pyrimidin-2-yl]amino]phenyl]carbamoyl]benzyl]-
– impurity C : maximum 0.3 per cent ; piperazin-1-ium (imatinib dimer),
– impurity D : maximum 0.2 per cent ;
– impurities A, B : for each impurity, maximum 0.15 per cent ;
– unspecified impurities : for each impurity, maximum
0.10 per cent ;
– total : maximum 0.8 per cent ;
– reporting threshold : 0.05 per cent. F. 4-methyl-N3-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-
Water (2.5.12) : maximum 3.0 per cent, determined on 1.00 g. diamine,
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. H. 1-(pyridin-3-yl)ethan-1-one,

General Notices (1) apply to all monographs and other texts 3069
Imidacloprid for veterinary use EUROPEAN PHARMACOPOEIA 11.0

– stationary phase : end-capped octylsilyl silica gel for

chromatography R (5 μm) ;
– temperature : 40 °C.
Mobile phase :
– mobile phase A : solution A ;
J. 4-[(4-methyl-4-oxidopiperazin-1-yl)methyl]- – mobile phase B : solution A, acetonitrile R (50:50 V/V) ;
N-[4-methyl-3-[[4-(pyridin-3-yl)pyrimidin-2-
yl]amino]phenyl]benzamide. Time Mobile phase A Mobile phase B Flow rate
(min) (per cent V/V) (per cent V/V) (mL/min)
0-3 90 10 1.0
01/2020:2924
3-9 90 → 80 10 → 20 1.0

9 - 9.5 80 20 1.5

9.5 - 15 80 → 55 20 → 45 1.5

IMIDACLOPRID FOR VETERINARY 15 - 21 55 → 40 45 → 60 1.5

USE 21 - 28 40 → 0 60 → 100 1.5

Detection : spectrophotometer at 268 nm.

Imidaclopridum ad usum veterinarium Autosampler : set at 25 °C.
Injection : 10 μL of test solution (a) and reference solutions (b)
and (c).
Identification of impurities : use the chromatogram supplied
with imidacloprid for system suitability CRS and the
chromatogram obtained with reference solution (c) to identify
C9H10ClN5O2 Mr 255.7 the peaks due to impurities A, B and D.
[138261-41-3] Relative retention with reference to imidacloprid
(retention time = about 17 min) : impurity A = about 0.19 ;
DEFINITION impurity B = about 0.22 ; impurity D = 1.04.
N-[1-[(6-Chloropyridin-3-yl)methyl]-4,5-dihydro-1H- System suitability : reference solution (c) :
imidazol-2-yl]nitramide. – peak-to-valley ratio : minimum 3.0, where Hp = height above
Content : 96.5 per cent to 102.0 per cent (dried substance). the baseline of the peak due to impurity D and Hv = height
above the baseline of the lowest point of the curve
CHARACTERS separating this peak from the peak due to imidacloprid.
Appearance : white or almost white, crystalline powder. Calculation of percentage contents :
Solubility : practically insoluble in water, sparingly soluble in – correction factors : multiply the peak areas of the following
methanol, practically insoluble in heptane. impurities by the corresponding correction factor :
It shows polymorphism (5.9). impurity A = 0.5 ; impurity B = 0.4.
IDENTIFICATION – for each impurity, use the concentration of imidacloprid in
reference solution (b).
Infrared absorption spectrophotometry (2.2.24).
Limits :
Comparison : imidacloprid CRS.
– impurity A : maximum 0.7 per cent ;
If the spectra obtained in the solid state show differences,
dissolve the substance to be examined and the reference – impurity B : maximum 0.25 per cent ;
substance separately in acetonitrile R, evaporate to dryness – unspecified impurities : for each impurity, maximum
and record new spectra using the residues. 0.20 per cent ;
– total : maximum 1.5 per cent ;
TESTS
– reporting threshold : 0.10 per cent.
Related substances. Liquid chromatography (2.2.29). Prepare
Chlorides : maximum 0.5 per cent.
the solutions immediately before use.
Dissolve 0.500 g in 30 mL of acetone R. Add 20 mL of water R
Solution A. Dissolve 7.5 g of sodium hexanesulfonate R in
and 2 mL of dilute nitric acid R.
900 mL of water for chromatography R, adjust to pH 2.5
with phosphoric acid R and dilute to 1000 mL with water for Titrate with 0.1 M silver nitrate, determining the end-point
chromatography R. potentiometrically (2.2.20).
Test solution (a). Dissolve 40.0 mg of the substance to be 1 mL of 0.1 M silver nitrate is equivalent to 3.545 mg of Cl.
examined in 2 mL of acetonitrile R and dilute to 20.0 mL with Loss on drying (2.2.32) : maximum 1.0 per cent, determined
solution A. on 1.000 g by drying in an oven at 105 °C.
Test solution (b). Dilute 1.0 mL of test solution (a) to 10.0 mL ASSAY
with solution A.
Liquid chromatography (2.2.29) as described in the test for
Reference solution (a). Dissolve 40.0 mg of imidacloprid CRS related substances with the following modification.
in 2 mL of acetonitrile R and dilute to 20.0 mL with solution A.
Dilute 1.0 mL of this solution to 10.0 mL with solution A. Injection : 10 μL of test solution (b) and reference solution (a).
Reference solution (b). Dilute 1.0 mL of test solution (b) to Calculate the percentage content of C9H10ClN5O2 taking into
50.0 mL with solution A. account the assigned content of imidacloprid CRS.
Reference solution (c). Dissolve 10 mg of imidacloprid for IMPURITIES
system suitability CRS (containing impurities A, B and D) in Specified impurities : A, B.
0.5 mL of acetonitrile R and dilute to 5 mL with solution A. Other detectable impurities (the following substances would,
Column : if present at a sufficient level, be detected by one or other of
– size : l = 0.25 m, Ø = 4.6 mm ; the tests in the monograph. They are limited by the general

3070 See the information section on general monographs (cover pages)