Omeprazole

(Ph Eur monograph 0942)

 

C17H19N3O3S 345.4 73590-58-6

 

Ph Eur


 

 

Definition

 

Omeprazole contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of 5-methoxy-2-[(RS)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-sulphinyl]-1H-benzimidazole, calculated with reference to the dried substance.

 

Characters

 

A white or almost white powder, very slightly soluble in water, soluble in methylene chloride, sparingly soluble in alcohol and in methanol. It dissolves in dilute solutions of alkali hydroxides.

 

Identification

 

First identification

 

B.

 

Second identification

 

A, C.

 

A.    Dissolve 2.0 mg in 0.1M sodium hydroxide and dilute to 100.0 ml with the same solvent. Examined between 230 nm and 350 nm (2.2.25), the solution shows two absorption maxima, at 276 nm and 305 nm. The ratio of the absorbance measured at the maximum at 305 nm to that measured at the maximum at 276 nm is 1.6 to 1.8.

 

B.    Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with omeprazole CRS.

 

C.    Examine the chromatograms obtained in the test for omeprazole impurity C. The principal spot in the chromatogram obtained with test solution (b) is similar in position and size to the principal spot in the chromatogram obtained with reference solution (a). Place the plate in a tank saturated with vapour from acetic acid R. The spots rapidly turn brown.

 

Tests

 

Solution S

 

Dissolve 0.50 g in methylene chloride R and dilute to 25 ml with the same solvent.

 

Appearance of solution

 

Solution S is clear  (2.2.1).

 

Absorbance (2.2.25)

 

The absorbance of solution S measured at 440 nm is not more than 0.10. (This limit corresponds to 0.035 per cent of omeprazole impurity F or omeprazole impurity G).

 

Omeprazole impurity C

 

Examine by thin-layer chromatography (2.2.27), using a TLC silica gel F254 plate R.

 

Test solution (a)

 

Dissolve 0.10 g of the substance to be examined in 2.0 ml of a mixture of equal volumes of methanol  R and methylene chloride R.

 

Test solution (b)

 

Dilute 1.0 ml of test solution (a) to 10 ml with methanol  R.

 

Reference solution (a)

 

Dissolve 10 mg of omeprazole CRS in 2.0 ml of methanol  R.

 

Reference solution (b)

 

Dilute 1 ml of test solution (a) to 10 ml with a mixture of equal volumes of methanol  R and methylene chloride R. Dilute 1 ml of this solution to 100 ml with a mixture of equal volumes of methanol  R and methylene chloride R.

 

Apply to the plate 10 ml of each solution. Develop over a path of 15 cm using a mixture of 20 volumes of 2-propanol  R, 40 volumes of methylene chloride R previously shaken with concentrated ammonia R (shake 100 ml of methylene chloride R with 30 ml of concentrated ammonia R in a separating funnel; allow the layers to separate and use the lower layer) and 40 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 test solution (a) with a higher Rf value than that of the spot corresponding to omeprazole is not more intense than the spot in the chromatogram obtained with reference solution (b) (0.1 per cent).

 

Related substances

 

Examine by liquid chromatography (2.2.29).

 

Test solution

 

Dissolve 3.0 mg of the substance to be examined in the mobile phase and dilute to 25.0 ml with the mobile phase.

 

Reference solution (a)

 

Dissolve 1.0 mg of omeprazole CRS and 1.0 mg of omeprazole impurity D CRS in the mobile phase and dilute to 10.0 ml with the mobile phase.

 

Reference solution (b)

 

Dilute 1.0 ml of the test solution to 100.0 ml with the mobile phase. Dilute 1.0 ml of this solution to 10.0 ml with the mobile phase.

 

The chromatographic procedure may be carried out using:

 

a stainless steel column 0.15 m long and 4 mm in internal diameter packed with octylsilyl silica gel for chromato-graphy R (5 mm),

 

as mobile phase at a flow rate of 1 ml/min a mixture of 27 volumes of acetonitrile R and 73 volumes of a 1.4 g/l solution of disodium hydrogen phosphate R previously adjusted to pH 7.6 with phosphoric acid R,

 

as detector a spectrophotometer set at 280 nm.

 

When the chromatograms are recorded under the prescribed conditions, the retention time of omeprazole is about 9 min and the relative retention time of omeprazole impurity D is about 0.8. Inject separately 40 ml of each solution and continue the chromatography for three times the retention time of omeprazole. Adjust the sensitivity of the system so that the height of the principal peak in the chromatogram obtained with reference solution (b) is at least 15 per cent of the full scale of the recorder. The test is not valid unless in the chromatogram obtained with reference solution (a), the resolution between the peaks corresponding to omeprazole impurity D and omeprazole is greater than 3. If necessary, adjust the pH of the mobile phase or the concentration of acetonitrile R; an increase in the pH will improve the resolution. The area of any peak apart from the principal peak, in the chromatogram obtained with the test solution is not greater than the area of the peak in the chromatogram obtained with reference solution (b) (0.1 per cent).

 

Residual solvents

 

Examine by head-space gas chromatography (2.2.28), using the standard additions method. The content of chloroform is not more than 50 ppm, the content of methylene chloride is not more than 100 ppm and the content of trichloroethylene is not more than 100 ppm.

 

The chromatographic procedure may be carried out using:

 

a fused-silica column 30 m long and 0.32 mm in internal diameter coated with a 1.8 mm film of cross-linked poly[(cyanopropyl)(methyl)][(phenyl)(methyl)]siloxane R,

 

nitrogen for chromatography R as the carrier gas,

 

a flame-ionisation detector,

 

a suitable headspace sampler.

 

Place 0.50 g of the substance to be examined in a 10 ml vial. Add 4.0 ml of dimethylacetamide R and stopper the vial. Equilibrate the vial at 80C for 1 h.

 

Loss on drying (2.2.32)

 

Not more than 0.2 per cent, determined on 1.000 g by drying under high vacuum at 60C for 4 h.

 

Sulphated ash (2.4.14)

 

Not more than 0.1 per cent, determined on 1.0 g.

 

Assay

 

Dissolve 1.100 g in a mixture of 10 ml of water  R and 40 ml of alcohol  R. Titrate with 0.5M sodium hydroxide, determining the end-point potentiometrically (2.2.20).

 

1 ml of 0.5M sodium hydroxide corresponds to 0.1727 g of C17H19N3O3S.

 

Storage

 

Store in an airtight container , protected from light, at a temperature between 2C and 8C.

 

Impurities

 

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

 

B.    R = H, X = SO: 2-[(RS)-[(3,5-dimethylpyridin-2-yl)methyl]sulphinyl]-5-methoxy-1H-benzimidazole,

 

C.    R = OCH3, X = S: 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphanyl]-1H-benzimidazole (ufiprazole),

 

D.    R = OCH3, X = SO2: 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphonyl]-1H-benzimidazole (omeprazole sulphone),

 

E.    4-methoxy-2-[[(RS)-(5-methoxy-1H-benzimidazol-2-yl)sulphinyl]methyl]-3,5-dimethylpyridine 1-oxide,

 

F.    R = OCH3, R¢ = H: 1,3-dimethyl-8-methoxy-12-thioxopyrido[1¢,2¢:3,4]imidazo[1,2-a]benzimidazol-2(12H)-one,

 

G.    R = H, R¢= OCH3: 1,3-dimethyl-9-methoxy-12-thioxopyrido[1¢,2¢:3,4]imidazo[1,2-a]benzimidazol-2(12H)-one.

 

 


 Ph Eur

 

Action and use

 

Treatment of peptic ulcer.