Ranitidine hydrochloride

EUROPEAN PHARMACOPOEIA 5.0

01/2005:0946

RANITIDINE HYDROCHLORIDE
Ranitidini hydrochloridum
J. (2R,3aR,6aR)-1-[(R)-2-[[(R)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid ((R,R-R,R,R) isomer of
ramipril),
C13H23ClN4O3S

Mr 350.9

DEFINITION
Ranitidine hydrochloride contains not less than 98.5 per cent
and not more than the equivalent of 101.0 per cent of N-[2-[[[5[(dimethylamino)methyl]furan-2-yl]methyl]sulphanyl]ethyl]N-methyl-2-nitroethene-1,1-diamine hydrochloride,
calculated with reference to the dried substance.
K. (2S)-2-[(3S,5aS,8aS,9aS)-3-methyl-1,4-dioxodecahydro2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl]-4phenylbutanoic acid (ramipril diketopiperazine acid),

CHARACTERS
A white or pale yellow, crystalline powder, freely soluble in
water and in methanol, sparingly soluble in ethanol, very
slightly soluble in methylene chloride.
It shows polymorphism.

M. (2R,3R)-2,3-di(benzoyloxy)butanedioic acid
(dibenzoyltartric acid),

IDENTIFICATION
First identification : B, D.
Second identification : A, C, D.
A. Dissolve 10 mg in water R and dilute to 100.0 ml with the
same solvent. Dilute 5.0 ml of the solution to 50.0 ml with
water R. Examined between 220 nm and 360 nm (2.2.25),
the solution shows two absorption maxima, at 229 nm
and 315 nm. The ratio of the absorbance measured at the
maximum at 229 nm to that measured at the maximum
at 315 nm is 1.01 to 1.07.
B. Examine by infrared absorption spectrophotometry
(2.2.24), comparing with the spectrum obtained
with ranitidine hydrochloride CRS. Examine the
substances as mulls in liquid paraffin R. If the spectra
show differences, dissolve 20 mg of the substance to
be examined and 20 mg of the reference substance
separately in 5 ml of methanol R. Evaporate to dryness in
a water-bath at 40 C under reduced pressure and with
constant stirring. Dry the residues under high vacuum at
60 C for 1 h and record new spectra using the residues.
C. Examine the chromatograms obtained in the test for
related substances (see Tests). 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 (a).
D. It gives reaction (a) of chlorides (2.3.1).

N. (2R,3aR,6aR)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid ((S,S-R,R,R) isomer of

ramipril).

TESTS
Solution S. Dissolve 1.0 g in carbon dioxide-free water R
and dilute to 100.0 ml with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
more intensely coloured than reference solution BY5 (2.2.2,
Method II).
pH (2.2.3). The pH of solution S is 4.5 to 6.0.
Related substances. Examine by thin-layer chromatography
(2.2.27), using silica gel G R as the coating substance.
Test solution (a). Dissolve 0.50 g of the substance to be
examined in methanol R and dilute to 25 ml with the same
solvent.

L. ethyl (2S)-2-[(3S,5aS,8aS,9aS)-9a-hydroxy-3-methyl1,4-dioxodecahydro-2H-cyclopenta[4,5]pyrrolo[1,
2-a]pyrazin-2-yl]-4-phenylbutanoate (ramipril
hydroxydiketopiperazine),

General Notices (1) apply to all monographs and other texts

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Ranitidine hydrochloride

EUROPEAN PHARMACOPOEIA 5.0

Test solution (b). Dilute 1 ml of test solution (a) to 10 ml

with methanol R.

STORAGE
Store in an airtight container, protected from light.

Reference solution (a). Dissolve 20 mg of ranitidine

hydrochloride CRS in methanol R and dilute to 10 ml with
the same solvent.

IMPURITIES

Reference solution (b). Dilute 3.0 ml of test solution (b) to

100 ml with methanol R.
Reference solution (c). Dilute 2.0 ml of test solution (b) to
100 ml with methanol R.
Reference solution (d). Dilute 1.0 ml of test solution (b) to
100 ml with methanol R.
Reference solution (e). Dilute 0.5 ml of test solution (b) to
100 ml with methanol R.

A. N,N-bis[2-[[[5-[(dimethylamino)methyl]furan-2yl]methyl]sulphanyl]ethyl]-2-nitroethene-1,1-diamine,

Reference solution (f). Dissolve 10 mg of ranitidine

impurity A CRS in methanol R and dilute to 100 ml with
the same solvent.
Reference solution (g). Dissolve 10 mg of ranitidine
impurity B CRS in methanol R and dilute to 10 ml with the
same solvent.
Reference solution (h). Dissolve 10 mg of ranitidine
impurity B CRS in test solution (a) and dilute to 10 ml with
the same solution.

B. R = S-CH2-CH2-NH2 : 2-[[[5-[(dimethylamino)methyl]furan2-yl]methyl]sulphanyl]ethanamine,

D. R = S-CH2-CH2-NH-CO-CH2-NO2 : N-[2-[[[5-[(dimethylamino)methyl]furan-2-yl]methyl]sulphanyl]ethyl]-2-niApply to the plate 10 l of each solution. Develop over a path

troacetamide,
of 15 cm using a mixture of 2 volumes of water R, 4 volumes
of concentrated ammonia R1, 15 volumes of 2-propanol R
F. R = OH : [5-[(dimethylamino)methyl]furan-2-yl]methanol,
and 25 volumes of ethyl acetate R. Allow the plate to dry
in air and expose to iodine vapour until the spots are
clearly visible. Examine in daylight. In the chromatogram
obtained with test solution (a) : any spot corresponding to
ranitidine impurity A is not more intense than the spot in the
chromatogram obtained with reference solution (f) (0.5 per
cent) ; any spot apart from the principal spot and any spot
corresponding to ranitidine impurity A is not more intense
than the spot in the chromatogram obtained with reference
solution (b) (0.3 per cent) ; at most three such spots are
C. N-[2-[[[5-[(dimethylamino)methyl]furan-2more intense than the spot in the chromatogram obtained
yl]methyl]sulphinyl]ethyl]-N-methyl-2-nitroethene-1,1with reference solution (d) (0.1 per cent) and at most one of
diamine,
these is more intense than the spot in the chromatogram
obtained with reference solution (c) (0.2 per cent). The
test is not valid unless the chromatogram obtained with
reference solution (h) shows two clearly separated spots,
corresponding to ranitidine impurity B (whose Rf value is
obtained from the chromatogram obtained with reference
solution (g)) and ranitidine, and the chromatogram obtained
with reference solution (e) shows a clearly visible spot.
Heavy metals (2.4.8). 1.0 g complies with limit test C for
heavy metals (20 ppm). Prepare the standard using 2 ml of
lead standard solution (10 ppm Pb) R.

E. N,N-dimethyl[5-[[[2-[[1-(methylamino)-2nitroethenyl]amino]ethyl]sulphanyl]methyl]furan2-yl]methanamine N-oxide,

Loss on drying (2.2.32). Not more than 0.75 per cent,

determined on 1.000 g by drying under high vacuum at
60 C.
Sulphated ash (2.4.14). Not more than 0.1 per cent,
determined on 1.0 g.
G. 3-(methylamino)-5,6-dihydro-2H-1,4-thiazin-2-one oxime,
ASSAY
Dissolve 0.280 g in 35 ml of water R. Titrate with
0.1 M sodium hydroxide, determining the end-point
potentiometrically (2.2.20).
1 ml of 0.1 M sodium hydroxide is equivalent to 35.09 mg
of C13H23ClN4O3S.
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H. N-methyl-2-nitroacetamide.

See the information section on general monographs (cover pages)