EUROPEAN PHARMACOPOEIA 11.

0 Chloroquine sulfate

Second identification : A, C, D. 01/2017:0545

A. Dissolve 0.100 g in water R and dilute to 100.0 mL with the
same solvent. Dilute 1.0 mL of this solution to 100.0 mL
with water R. Examined between 210 nm and 370 nm
(2.2.25), the solution shows absorption maxima at 220 nm,
235 nm, 256 nm, 329 nm and 342 nm. The specific CHLOROQUINE SULFATE
absorbances at the maxima are respectively 600 to 660, 350
to 390, 300 to 330, 325 to 355 and 360 to 390. Chloroquini sulfas
B. Examine by infrared absorption spectrophotometry
(2.2.24), comparing with the spectrum obtained with
the base isolated from chloroquine sulfate CRS. Record
the spectra using solutions prepared as follows : dissolve
separately 0.1 g of the substance to be examined and 80 mg
of the reference substance in 10 mL of water R, add 2 mL
of dilute sodium hydroxide solution R and shake with 2
quantities, each of 20 mL, of methylene chloride R ; combine
the organic layers, wash with water R, dry over anhydrous C18H28ClN3O4S,H2O Mr 436.0
sodium sulfate R, evaporate to dryness and dissolve the
residues separately, each in 2 mL of methylene chloride R. DEFINITION
Chloroquine sulfate contains not less than 98.5 per cent
C. Dissolve 25 mg in 20 mL of water R and add 8 mL of picric and not more than the equivalent of 101.0 per cent of
acid solution R1. The precipitate, washed with water R, N4-(7-chloroquinolin-4-yl)-N1,N1-diethylpentane-1,4-diamine
with alcohol R and finally with methylene chloride R, melts sulfate, calculated with reference to the anhydrous substance.
(2.2.14) at 206-209 °C.
D. Dissolve 0.1 g in 10 mL of water R, add 2 mL of dilute CHARACTERS
sodium hydroxide solution R and shake with 2 quantities, A white or almost white, crystalline powder, freely soluble in
each of 20 mL, of methylene chloride R. The aqueous layer, water and in methanol, very slightly soluble in ethanol (96 per
acidified by the addition of nitric acid R, gives reaction (b) cent).
of phosphates (2.3.1). It melts at about 208 °C (instantaneous method).

TESTS
Solution S. Dissolve 2.5 g in carbon dioxide-free water R and
dilute to 25 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution BY5 or GY5
(2.2.2, Method II).
pH (2.2.3). The pH of solution S is 3.8 to 4.3.
Related substances. Examine by thin-layer chromatography
(2.2.27), using silica gel GF254 R as the coating substance.
Test solution. Dissolve 0.50 g of the substance to be examined
in water R and dilute to 10 mL with the same solvent.
Reference solution (a). Dilute 1 mL of the test solution to
100 mL with water R.
Reference solution (b). Dilute 5 mL of reference solution (a)
to 10 mL with water R.
Apply to the plate 2 μL of each solution. Develop over a path
of 12 cm using a mixture of 10 volumes of diethylamine R,
40 volumes of cyclohexane R and 50 volumes of chloroform R.
Allow the plate to dry in air. Examine in ultraviolet light at C. Dissolve 25 mg in 20 mL of water R and add 8 mL of picric
254 nm. Any spot in the chromatogram obtained with the test
solution, apart from the principal spot, is not more intense
than the spot in the chromatogram obtained with reference
solution (a) (1.0 per cent) and not more than one such spot is
more intense than the spot in the chromatogram obtained
with reference solution (b) (0.5 per cent).
Loss on drying (2.2.32) : maximum 2.0 per cent, determined Solution S. Dissolve 2.0 g in carbon dioxide-free water R and
on 1.000 g by drying in an oven at 105 °C.
ASSAY
Dissolve 0.200 g in 50 mL of anhydrous acetic acid R. Titrate (2.2.2, Method II).
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 25.79 mg of
C18H32ClN3O8P2.
STORAGE
In an airtight container, protected from light.
IDENTIFICATION
First identification : B, D.
Second identification : A, C, D.
A. Dissolve 0.100 g in water R and dilute to 100.0 mL with the
same solvent. Dilute 1.0 mL of this solution to 100.0 mL
with water R. Examined between 210 nm and 370 nm
(2.2.25), the solution shows absorption maxima at 220 nm,
235 nm, 256 nm, 329 nm and 342 nm. The specific
absorbances at the maxima are respectively 730 to 810, 430
to 470, 370 to 410, 400 to 440 and 430 to 470.
B. Examine by infrared absorption spectrophotometry
(2.2.24), comparing with the spectrum obtained with
the base isolated from chloroquine sulfate CRS. Record
the spectra using solutions prepared as follows : dissolve
separately 0.1 g of the substance to be examined and of the
reference substance in 10 mL of water R, add 2 mL of dilute
sodium hydroxide solution R and shake with 2 quantities,
each of 20 mL, of methylene chloride R ; combine the
organic layers, wash with water R, dry over anhydrous
sodium sulfate R, evaporate to dryness and dissolve the
residues separately each in 2 mL of methylene chloride R.
acid solution R1. The precipitate, washed with water R,
with ethanol (96 per cent) R and finally with ether R, melts
(2.2.14) at 206 °C to 209 °C.
D. It gives reaction (a) of sulfates (2.3.1).
TESTS
dilute to 25 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution BY5 or GY5
pH (2.2.3). The pH of solution S is 4.0 to 5.0.
Related substances. Examine by thin-layer chromatography
(2.2.27), using silica gel GF254 R as the coating substance.
Test solution. Dissolve 0.50 g of the substance to be examined
in water R and dilute to 10 mL with the same solvent.
Reference solution (a). Dilute 1 mL of the test solution to
100 mL with water R.

General Notices (1) apply to all monographs and other texts 2307
Chlorphenamine maleate
Reference solution (b). Dilute 5 mL of reference solution (a)
to 10 mL with water R.
Apply separately to the plate 2 μL of each solution. Develop
over a path of 12 cm using a mixture of 10 volumes of
diethylamine R, 40 volumes of cyclohexane R and 50 volumes
of methylene chloride R. Allow the plate to dry in air. Examine
in ultraviolet light at 254 nm. Any spot in the chromatogram
obtained with the test solution, apart from the principal
spot, is not more intense than the spot in the chromatogram
obtained with reference solution (a) (1.0 per cent) and not
more than one such spot is more intense than the spot in the
chromatogram obtained with reference solution (b) (0.5 per
cent).
Water (2.5.12) : 3.0 per cent to 5.0 per cent, determined on
0.500 g.
Sulfated ash (2.4.14). Not more than 0.1 per cent, determined
on 1.0 g.
ASSAY
Dissolve 0.400 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 41.8 mg of
C18H28ClN3O4S.
STORAGE
Store in an airtight container, protected from light.
01/2017:0386 Detection : spectrophotometer at 225 nm.
CHLORPHENAMINE MALEATE
Chlorphenamini maleas
C20H23ClN2O4 Mr 390.9
[113-92-8]
DEFINITION
(3RS)-3-(4-Chlorophenyl)-N,N-dimethyl-3-(pyridin-2-
yl)propan-1-amine hydrogen (Z)-butenedioate.
Content : 98.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance : white or almost white, crystalline powder.
Solubility : freely soluble in water, soluble in ethanol (96 per
cent).
IDENTIFICATION
A. Melting point (2.2.14) : 130 °C to 135 °C.
B. Infrared absorption spectrophotometry (2.2.24).
Comparison : chlorphenamine maleate CRS.
C. Optical rotation (see Tests).
TESTS
Solution S. Dissolve 2.0 g in water R and dilute to 20.0 mL
with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution BY6 (2.2.2,
Method II).
Optical rotation (2.2.7): − 0.10° to + 0.10°, determined on
solution S.
2308
EUROPEAN PHARMACOPOEIA 11.0
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 0.100 g of the substance to be examined
in the mobile phase and dilute to 100.0 mL with the mobile
phase.
Reference solution (a). Dilute 0.5 mL of the test solution to
100.0 mL with the mobile phase.
Reference solution (b). Dilute 1.0 mL of reference solution (a)
to 10.0 mL with the mobile phase.
Reference solution (c). Dissolve 5 mg of chlorphenamine
impurity C CRS in 5 mL of the test solution and dilute to
50.0 mL with the mobile phase. Dilute 2 mL of this solution to
20 mL with the mobile phase.
Reference solution (d). Dissolve 5 mg of 2,2′-dipyridylamine R
(impurity B) in the mobile phase and dilute to 100 mL with
the mobile phase.
Reference solution (e). Dissolve the contents of a vial of
chlorphenamine impurity A CRS in 2 mL of the test solution.
Sonicate for 5 min.
Column :
– size : l = 0.30 m, Ø = 3.9 mm ;
– stationary phase : octadecylsilyl silica gel for
chromatography R (10 μm).
Mobile phase : mix 20 volumes of acetonitrile R and 80 volumes
of a 8.57 g/L solution of ammonium dihydrogen phosphate R
previously adjusted to pH 3.0 with phosphoric acid R.
Flow rate : 1.2 mL/min.
Injection : 20 μL.
Run time : 3.5 times the retention time of chlorphenamine.
Relative retention with reference to chlorphenamine
(retention time = about 11 min) : maleic acid = about 0.2 ;
impurity A = about 0.3 ; impurity B = about 0.4 ;
impurity C = about 0.9 ; impurity D = about 3.0.
System suitability : reference solution (c) :
– resolution : minimum 1.5 between the peaks due to
impurity C and chlorphenamine.
Limits :
– correction factors : for the calculation of contents,
multiply the peak areas of the following impurities by
the corresponding correction factor : impurity A = 1.5 ;
impurity B = 1.4 ;
– impurity A : not more than 0.4 times the area of the
principal peak in the chromatogram obtained with
reference solution (a) (0.2 per cent) ;
– impurities B, C, D : for each impurity, not more than
0.2 times the area of the principal peak in the chromatogram
obtained with reference solution (a) (0.1 per cent) ;
– unspecified impurities : for each impurity, not more than
0.2 times the area of the principal peak in the chromatogram
obtained with reference solution (a) (0.10 per cent) ;
– total : not more than the area of the principal peak in the
chromatogram obtained with reference solution (a) (0.5 per
cent) ;
– disregard limit : the area of the principal peak in the
chromatogram obtained with reference solution (b)
(0.05 per cent); disregard the peak due to maleic acid.
Loss on drying (2.2.32) : maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 °C for 4 h.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Dissolve 0.150 g in 25 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 19.54 mg
of C20H23ClN2O4.
See the information section on general monographs (cover pages)