EUROPEAN PHARMACOPOEIA 5.

0 Diclofenac potassium
Sulphated ash (2.4.14) : maximum 0.1 per cent, determined
on 1.0 g.
ASSAY
Dissolve 0.150 g in 75 ml of dimethylformamide R.
Carry out a potentiometric titration (2.2.20), using 0.1 M
tetrabutylammonium hydroxide. Read the volume added at
the second inflexion point. Carry out a blank titration.
1 ml of 0.1 M tetrabutylammonium hydroxide is equivalent
to 20.38 mg of C
17
H
9
Cl
3
N
4
O
2
.
STORAGE
Protected from light.
IMPURITIES
Specified impurities: A, B, C, D, E, F, G, H, I.
A. R = Cl, R = CO
2
H: 2-[3,5-dichloro-4-[(RS)-(4-
chlorophenyl)cyanomethyl]phenyl]-3,5-dioxo-2,3,4,5-
tetrahydro-1,2,4-triazine-6-carboxylic acid,
B. R = OH, R = H: (RS)-[2,6-dichloro-4-(3,5-dioxo-
4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl](4-
hydroxyphenyl)acetonitrile,
C. R = Cl, R = CONH
2
: 2-[3,5-dichloro-4-[(RS)-(4-
chlorophenyl)cyanomethyl]phenyl]-3,5-dioxo-2,3,4,5-
tetrahydro-1,2,4-triazine-6-carboxamide,
G. R = Cl, R = CO-O-[CH
2
]
3
-CH
3
: butyl 2-[3,5-dichloro-4-
[(RS)-(4-chlorophenyl)cyanomethyl]phenyl]-3,5-dioxo-2,3,
4,5-tetrahydro-1,2,4-triazine-6-carboxylate,
D. X = O: 2-[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]-1,2,4-
triazine-3,5(2H,4H)-dione,
F. X = H
2
: 2-[3,5-dichloro-4-(4-chlorobenzyl)phenyl]-1,2,4-
triazine-3,5(2H,4H)-dione,
E. R = NH
2
: (RS)-(4-amino-2,6-dichlorophenyl)(4-
chlorophenyl)acetonitrile,
H. R = H: (RS)-(4-chlorophenyl)(2,6-dichlorophenyl)aceto-
nitrile,
I. N,2-bis[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phe-
nyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxa-
mide.
01/2005:1508
DICLOFENAC POTASSIUM
Diclofenacum kalicum
C
14
H
10
Cl
2
KNO
2
M
r
334.2
DEFINITION
Potassium diclofenac contains not less than 99.0 per cent
and not more than the equivalent of 101.0 per cent of
potassium [2-[(2,6-dichlorophenyl)amino]phenyl]acetate,
calculated with reference to the dried substance.
CHARACTERS
A white or slightly yellowish, crystalline powder, slightly
hygroscopic, sparingly soluble in water, freely soluble in
methanol, soluble in alcohol, slightly soluble in acetone.
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
diclofenac potassium CRS. Examine the substances
prepared as discs.
B. Examine by thin-layer chromatography (2.2.27), using a
TLC silica gel GF
254
plate R.
Test solution. Dissolve 25 mg of the substance to be
examined in methanol R and dilute to 5 ml with the same
solvent.
Reference solution (a). Dissolve 25 mg of diclofenac
potassium CRS in methanol R and dilute to 5 ml with
the same solvent.
Reference solution (b). Dissolve 10 mg of indometacin R
in reference solution (a) and dilute to 2 ml with the same
solution.
Apply to the plate 5 l of each solution. Develop over
a path of 10 cm using a mixture of 10 volumes of
concentrated ammonia R, 10 volumes of methanol R and
80 volumes of ethyl acetate R. Allow the plate to dry in
air. Examine in ultraviolet light at 254 nm. The principal
spot in the chromatogram obtained with the test solution
is similar in position and size to the principal spot in the
General Notices (1) apply to all monographs and other texts 1419
Diclofenac sodium EUROPEAN PHARMACOPOEIA 5.0
chromatogram obtained with reference solution (a). The
test is not valid unless the chromatogram obtained with
reference solution (b) shows 2 clearly separated spots.
C. Dissolve about 10 mg in 10 ml of alcohol R. To 1 ml of the
solution add 0.2 ml of a mixture, prepared immediately
before use, of equal volumes of a 6 g/l solution of
potassium ferricyanide R and a 9 g/l solution of ferric
chloride R. Allow to stand protected from light for 5 min.
Add 3 ml of a 10 g/l solution of hydrochloric acid R.
Allow to stand protected from light for 15 min. A blue
colour develops and a precipitate is formed.
D. Suspend 0.5 g of the substance to be examined in 10 ml
of water R. Stir, add water R until the substance is
dissolved. Add 2 ml of hydrochloric acid R1, stir for 1 h
and filter with the aid of vacuum. Neutralise the solution
with sodium hydroxide solution R. The solution gives
reaction (b) of potassium (2.3.1).
TESTS
Appearance of solution. Dissolve 1.25 g in methanol R and
dilute to 25.0 ml with the same solvent. The solution is clear
(2.2.1). The absorbance (2.2.25) measured at 440 nm is not
greater than 0.05.
Related substances. Examine by liquid chromatography
(2.2.29).
Test solution. Dissolve 50.0 mg of the substance to be
examined in methanol R and dilute to 50.0 ml with the same
solvent.
Reference solution (a). Dilute 2.0 ml of the test solution to
100.0 ml with methanol R. Dilute 1.0 ml of the solution to
10.0 ml with methanol R.
Reference solution (b). Dissolve 1.0 mg of diclofenac
impurity A CRS in methanol R, add 1.0 ml of the test
solution and dilute to 200.0 ml with methanol R.
The chromatographic procedure may be carried out using:
a stainless steel column 0.25 m long and 4.6 mm in
internal diameter packed with end-capped octylsilyl
silica gel for chromatography R (5 m),
as mobile phase at a flow rate of 1 ml/min a mixture
of 34 volumes of a solution containing 0.5 g/l of
phosphoric acid R and 0.8 g/l of sodium dihydrogen
phosphate R adjusted to pH 2.5 with phosphoric acid R,
and 66 volumes of methanol R,
as detector a spectrophotometer set at 254 nm.
Inject 20 l of reference solution (b). When the
chromatograms are recorded in the prescribed conditions,
the retention times are: diclofenac, about 25 min and
impurity A, about 12 min. Adjust the sensitivity of the
system so that the height of the peaks in the chromatogram
obtained is at least 50 per cent of the full scale of the
recorder. The test is not valid unless in the chromatogram
obtained the resolution between the peaks corresponding to
diclofenac and impurity A is not less than 6.5.
Inject 20 l of the test solution and 20 l of reference
solution (a). Continue the chromatography for 1.5 times the
retention time of the principal peak in the chromatogram
obtained with the test solution. In the chromatogram
obtained with the test solution: the area of any peak, apart
from the principal peak, is not greater than the area of the
principal peak in the chromatogram obtained with reference
solution (a) (0.2 per cent) ; the sum of the areas of all the
peaks, apart from the principal peak, is not greater than
2.5 times that of the principal peak in the chromatogram
obtained with reference solution (a) (0.5 per cent). Disregard
any peak with an area less than 0.25 times the area of the
principal peak in the chromatogram obtained with reference
solution (a).
Heavy metals (2.4.8). 2.0 g complies with limit test C
(10 ppm). Use a quartz crucible. Prepare the standard using
2 ml of lead standard solution (10 ppm Pb) R.
Loss on drying (2.2.32). Not more than 0.5 per cent,
determined on 1.000 g by drying in an oven at 100-105 C
for 3 h.
ASSAY
Dissolve 0.250 g in 30 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 33.42 mg of
C
14
H
10
Cl
2
KNO
2
.
STORAGE
In an airtight container, protected from light.
IMPURITIES
A. 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one,
B. R1 = CHO, R2 = Cl : 2-[(2,6-dichlorophenyl)amino]ben-
zaldehyde,
C. R1 = CH
2
OH, R2 = Cl : [2-[(2,6-dichlorophenyl)amino]phe-
nyl]methanol,
D. R1 = CH
2
-CO
2
H, R2 = Br: 2-[2-[(2-bromo-6-
chlorophenyl)amino]phenyl]acetic acid,
E. 1,3-dihydro-2H-indol-2-one.
01/2005:1002
DICLOFENAC SODIUM
Diclofenacum natricum
C
14
H
10
Cl
2
NNaO
2
M
r
318.1
1420 See the information section on general monographs (cover pages)