Esomeprazole magnesium dihydrate EUROPEAN PHARMACOPOEIA 11.

Column :
– size : l = 0.125 m, Ø = 4.0 mm ;
– stationary phase : spherical octadecylsilyl silica gel for
chromatography R (5 μm).
Mobile phase : dissolve 0.95 g of sodium hexanesulfonate R
in 1000 mL of a mixture of 25 volumes of acetonitrile R and C. (2-chlorophenyl)(1-hydroxycyclopentyl)methanone,
75 volumes of water R and add 4 mL of acetic acid R.
Flow rate : 1.0 mL/min.
Detection : spectrophotometer at 215 nm.
Injection : 20 μL.
Run time : 10 times the retention time of esketamine.
Relative retention with reference to esketamine : D. (2R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone
impurity A = about 1.6 ; impurity B = about 3.3 ; ((R)-ketamine).
impurity C = about 4.6.
System suitability : reference solution (a) : 07/2014:2787
– retention time : esketamine = 3.0 min to 4.5 min ;
– resolution : minimum 1.5 between the peaks due to
impurity A and esketamine.
Limits : ESOMEPRAZOLE MAGNESIUM
– impurities A, B, C : for each impurity, not more than DIHYDRATE
0.4 times the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.2 per cent) ;
Esomeprazolum magnesicum dihydricum
– any other impurity : for each impurity, not more than
0.2 times the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.1 per cent) ;
– total : not more than the area of the principal peak in
the chromatogram obtained with reference solution (b)
(0.5 per cent) ;
– disregard limit : 0.2 times the area of the principal peak in
the chromatogram obtained with reference solution (b)
(0.1 per cent). C34H36MgN6O6S2,2H2O Mr 749.2
[217087-10-0]
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on
1.0 g. DEFINITION
Magnesium bis[5-methoxy-2-[(S)-[(4-methoxy-3,5-
ASSAY dimethylpyridin-2-yl)methyl]sulfinyl]-1H-benzimidazol-1-
Dissolve 0.200 g in 50 mL of methanol R and add 1.0 mL of ide] dihydrate.
0.1 M hydrochloric acid. Carry out a potentiometric titration Content : 98.0 per cent to 102.0 per cent (anhydrous substance).
(2.2.20), using 0.1 M sodium hydroxide. Read the volume
added between the 2 points of inflexion. CHARACTERS
Appearance : white or slightly coloured powder, slightly
1 mL of 0.1 M sodium hydroxide is equivalent to 27.42 mg
hygroscopic.
of C13H17Cl2NO.
Solubility : slightly soluble in water, soluble in methanol,
STORAGE practically insoluble in heptane.
It shows polymorphism (5.9).
Protected from light.
IDENTIFICATION
IMPURITIES A. Infrared absorption spectrophotometry (2.2.24).
Specified impurities : A, B, C, D. Comparison : esomeprazole magnesium dihydrate CRS.
If the spectra obtained in the solid state show differences,
dissolve the substance to be examined and the reference
substance separately in methanol R, evaporate to dryness and
record new spectra using the residues.
B. Enantiomeric purity (see Tests).
C. Ignite about 0.5 g of the substance to be examined
according to the procedure for the sulfated ash test (2.4.14).
Dissolve the residue in 10 mL of water R. 2 mL of this
A. 1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol, solution gives the reaction of magnesium (2.3.1).
D. Water (see Tests).
TESTS
Absorbance (2.2.25) : maximum 0.20 at 440 nm.
Dissolve 0.500 g in methanol R and dilute to 25.0 mL with the
same solvent. Filter through a membrane filter (nominal pore
B. (2RS)-2-(2-chlorophenyl)-2-hydroxycyclohexanone, size 0.45 μm).

2682 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 11.0 Esomeprazole magnesium dihydrate

Enantiomeric purity. Liquid chromatography (2.2.29): use identify the peak due to impurity E ; use the chromatogram
the normalisation procedure. obtained with reference solution (a) to identify the peak due
Buffer solution pH 6.0. Mix 20 mL of a 179.1 g/L solution of to impurity D.
disodium hydrogen phosphate dodecahydrate R and 70 mL of Relative retention with reference to esomeprazole
a 156.0 g/L solution of sodium dihydrogen phosphate R, then (retention time = about 9 min): impurity E = about 0.4 ;
dilute to 1000 mL with water R. Dilute 250 mL of this solution impurity D = about 0.7.
to 1000 mL with water R. System suitability : reference solution (a) :
Buffer solution pH 11.0. Mix 11 mL of a 95.0 g/L solution of – resolution : minimum 3.0 between the peaks due to
trisodium phosphate dodecahydrate R and 22 mL of a 179.1 g/L impurity D and omeprazole.
solution of disodium hydrogen phosphate dodecahydrate R,
then dilute to 1000 mL with water R. Limits :
Test solution. Dissolve 40 mg of the substance to be examined – impurities D, E : for each impurity, maximum 0.15 per cent ;
in 5 mL of methanol R and dilute to 50.0 mL with buffer – unspecified impurities : for each impurity, maximum
solution pH 11.0. Dilute 1.0 mL of this solution to 25.0 mL 0.10 per cent ;
with buffer solution pH 11.0. – total : maximum 0.3 per cent ;
Reference solution. Dissolve 2 mg of omeprazole CRS in buffer – disregard limit : 0.5 times the area of the principal peak in
solution pH 11.0 and dilute to 50.0 mL with the same buffer the chromatogram obtained with reference solution (c)
solution. Dilute 1.0 mL of the solution to 10.0 mL with buffer (0.05 per cent).
solution pH 11.0.
Magnesium : 3.30 per cent to 3.55 per cent (anhydrous
Column : substance).
– size : l = 0.1 m, Ø = 4.0 mm ; Dissolve 0.400 g in 25 mL of methanol R, sonicate until
– stationary phase : α1-acid-glycoprotein silica gel for chiral dissolution is complete. Add 25 mL of water R, 10 mL of
separation R (5 μm). concentrated ammonia R, 20.000 mL of 0.05 M sodium edetate
Mobile phase : acetonitrile R, buffer solution pH 6.0 and about 50 mg of mordant black 11 triturate R. Titrate the
(13:87 V/V). excess of sodium edetate with 0.05 M zinc sulfate until the
Flow rate : 0.6 mL/min. colour changes from full blue to violet. Carry out a blank
titration.
Detection : spectrophotometer at 302 nm.
1 mL of 0.05 M sodium edetate corresponds to 1.21525 mg
Injection : 20 μL. of Mg.
Relative retention with reference to esomeprazole (retention
Water (2.5.12) : 4.5 per cent to 6.1 per cent, determined on
time = about 5 min) : impurity F = about 0.7.
0.200 g.
System suitability : reference solution :
– resolution : minimum 3.0 between the peaks due to ASSAY
impurity F and esomeprazole. Liquid chromatography (2.2.29).
Limit : Buffer solution pH 11.0. Mix 11 mL of a 95.0 g/L solution of
– impurity F : maximum 0.6 per cent ; disregard any peak trisodium phosphate dodecahydrate R and 22 mL of a 179.1 g/L
other than impurity F and esomeprazole. solution of disodium hydrogen phosphate dodecahydrate R,
Related substances. Liquid chromatography (2.2.29) : use the then dilute to 100.0 mL with water R.
normalisation procedure. Prepare the solutions immediately Test solution. Dissolve 10.0 mg of the substance to be
before use. examined in about 10 mL of methanol R, add 10 mL of buffer
Test solution. Dissolve 14 mg of the substance to be examined solution pH 11.0 and dilute to 200.0 mL with water R.
in the mobile phase and dilute to 100.0 mL with the mobile Reference solution. Dissolve 10.0 mg of omeprazole CRS in
phase. about 10 mL of methanol R, add 10 mL of buffer solution
Reference solution (a). Dissolve 1 mg of omeprazole CRS and pH 11.0 and dilute to 200.0 mL with water R.
1 mg of omeprazole impurity D CRS in the mobile phase and Column :
dilute to 10.0 mL with the mobile phase. – size : l = 0.125 m, Ø = 4 mm ;
Reference solution (b). Dissolve 3 mg of omeprazole for peak – stationary phase : octylsilyl silica gel for chromatography R
identification CRS (containing impurity E) in the mobile phase (5 μm).
and dilute to 20.0 mL with the mobile phase. Mobile phase : mix 35 volumes of acetonitrile R and 65 volumes
Reference solution (c). Dilute 1.0 mL of the test solution to of a 1.4 g/L solution of disodium hydrogen phosphate
100.0 mL with the mobile phase. Dilute 1.0 mL of this solution dodecahydrate R previously adjusted to pH 7.6 with phosphoric
to 10.0 mL with the mobile phase. acid R.
Column : Flow rate : 1 mL/min.
– size : l = 0.125 m, Ø = 4.6 mm ; Detection : spectrophotometer at 280 nm.
– stationary phase : octylsilyl silica gel for chromatography R Injection : 20 μL.
(5 μm).
Run time : 1.5 times the retention time of esomeprazole.
Mobile phase : mix 27 volumes of acetonitrile R and 73 volumes
of a 1.4 g/L solution of disodium hydrogen phosphate Retention time : esomeprazole = about 4 min.
dodecahydrate R previously adjusted to pH 7.6 with phosphoric Calculate the percentage content of C34H36MgN6O6S2 taking
acid R. into account the assigned content of omeprazole CRS.
Flow rate : 1 mL/min. 1 g of omeprazole is equivalent to 1.032 g of esomeprazole
Detection : spectrophotometer at 280 nm. magnesium.
Injection : 40 μL. STORAGE
Run time : 4 times the retention time of esomeprazole. In an airtight container, protected from light.
Identification of impurities : use the chromatogram supplied
with omeprazole for peak identification CRS and the IMPURITIES
chromatogram obtained with reference solution (b) to Specified impurities : D, E, F.

General Notices (1) apply to all monographs and other texts 2683
Esomeprazole magnesium trihydrate EUROPEAN PHARMACOPOEIA 11.0

Other detectable impurities (the following substances would, 07/2014:2372

if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical use
(2034). It is therefore not necessary to identify these impurities
for demonstration of compliance. See also 5.10. Control of ESOMEPRAZOLE MAGNESIUM
impurities in substances for pharmaceutical use) : A, B, C. TRIHYDRATE
Esomeprazolum magnesicum trihydricum

A. 5-methoxy-1H-benzimidazole-2-thiol,

C34H36MgN6O6S2,3H2O Mr 767.2

[217087-09-7]
DEFINITION
Magnesium bis[5-methoxy-2-[(S)-[(4-methoxy-3,5-
B. 2-[(RS)-[(3,5-dimethylpyridin-2-yl)methyl]sulfinyl]-5- dimethylpyridin-2-yl)methyl]sulfinyl]-1H-benzimidazol-1-
methoxy-1H-benzimidazole, ide] trihydrate.
Content : 98.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance : white or slightly coloured powder, slightly
hygroscopic.
Solubility : slightly soluble in water, soluble in methanol,
practically insoluble in heptane.
IDENTIFICATION
C. 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2- A. Infrared absorption spectrophotometry (2.2.24).
yl)methyl]sulfanyl]-1H-benzimidazole (ufiprazole), Comparison : esomeprazole magnesium trihydrate CRS.
B. Enantiomeric purity (see Tests).
C. Ignite about 0.5 g of the substance to be examined
according to the procedure for the sulfated ash test (2.4.14).
Dissolve the residue in 10 mL of water R. 2 mL of this
solution gives the reaction of magnesium (2.3.1).
D. Water (see Tests).
TESTS
D. 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-
Absorbance (2.2.25) : maximum 0.20 at 440 nm.
yl)methyl]sulfonyl]-1H-benzimidazole (omeprazole
sulfone), Dissolve 0.500 g in methanol R and dilute to 25.0 mL with the
same solvent. Filter through a membrane filter (nominal pore
size 0.45 μm).
Enantiomeric purity. Liquid chromatography (2.2.29) : use
the normalisation procedure.
Buffer solution pH 6.0. Mix 20 mL of a 179.1 g/L solution of
disodium hydrogen phosphate dodecahydrate R and 70 mL of
a 156.0 g/L solution of sodium dihydrogen phosphate R, then
dilute to 1000 mL with water R. Dilute 250 mL of this solution
to 1000 mL with water R.
E. 4-methoxy-2-[[(RS)-(5-methoxy-1H-benzimidazol-2-
yl)sulfinyl]methyl]-3,5-dimethylpyridine 1-oxide, Buffer solution pH 11.0. Mix 11 mL of a 95.0 g/L solution of
trisodium phosphate dodecahydrate R and 22 mL of a 179.1 g/L
solution of disodium hydrogen phosphate dodecahydrate R,
then dilute to 1000 mL with water R.
Test solution. Dissolve 40 mg of the substance to be examined
in 5 mL of methanol R and dilute to 50.0 mL with buffer
solution pH 11.0. Dilute 1.0 mL of this solution to 25.0 mL
with buffer solution pH 11.0.
Reference solution. Dissolve 2 mg of omeprazole CRS in buffer
solution pH 11.0 and dilute to 50.0 mL with the same buffer
F. 5-methoxy-2-[(R)-[(4-methoxy-3,5-dimethylpyridin-2- solution. Dilute 1.0 mL of the solution to 10.0 mL with buffer
yl)methyl]sulfinyl]-1H-benzimidazole ((R)-omeprazole). solution pH 11.0.

2684 See the information section on general monographs (cover pages)