Diluted Isosorbide Mononitrate

(Ph Eur monograph 1118)

 

C6H9NO6 191.1 16051-77-7

 

Ph Eur


 

 

Definition

 

Diluted isosorbide mononitrate is a dry mixture of isosorbide mononitrate and Lactose monohydrate (0187) or Mannitol (0559). It contains not less than 95.0 per cent m/m and not more than 105.0 per cent m/m of the content of 1,4:3,6-dianhydro-D-glucitol 5-nitrate stated on the label.

 

Characters

 

Undiluted isosorbide mononitrate is a white, crystalline powder, freely soluble in water, in acetone, in alcohol and in methylene chloride.

 

The solubility of the diluted product depends on the diluent and its concentration.

 

Identification

 

First identification

 

A, C, D.

 

Second identification

 

B, C, D.

 

A.    Examine by infrared absorption spectrophotometry (2.2.24) the residue obtained in identification test D, comparing with the spectrum obtained with isosorbide mononitrate CRS. Examine the substances prepared as discs.

 

B.    Examine by thin-layer chromatography (2.2.27), using silica gel G R as the coating substance.

 

Test solution

 

Shake a quantity of the substance to be examined corresponding to 10 mg of isosorbide mononitrate with 10 ml of alcohol  R for 5 min and filter.

 

Reference solution

 

Dissolve 10 mg of isosorbide mononitrate CRS in alcohol  R and dilute to 10 ml with the same solvent.

 

Apply to the plate 10 ml of each solution. Develop over a path of 15 cm using a mixture of 5 volumes of methanol  R and 95 volumes of methylene chloride R. Dry the plate in a current of air. Spray with freshly prepared potassium iodide and starch solution R. Expose to ultraviolet light at 254 nm for 15 min. Examine in daylight. The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with the reference solution.

 

C.    Examine by thin-layer chromatography (2.2.27), using silica gel G R as the coating substance.

 

Test solution

 

Shake a quantity of the substance to be examined corresponding to 0.10 g of lactose or mannitol with 10 ml of water  R. Filter if necessary.

 

Reference solution (a)

 

Dissolve 0.10 g of lactose R in water  R and dilute to 10 ml with the same solvent.

 

Reference solution (b)

 

Dissolve 0.10 g of mannitol  R in water  R and dilute to 10 ml with the same solvent.

 

Reference solution (c)

 

Mix equal volumes of reference solutions (a) and (b).

 

Apply to the plate 1 ml of each solution and thoroughly dry the starting points. Develop over a path of 15 cm using a mixture of 10 volumes of water  R, 15 volumes of methanol  R, 25 volumes of anhydrous acetic acid R and 50 volumes of ethylene chloride R, measured accurately since a slight excess of water produces cloudiness. Dry the plate in a current of warm air. Repeat immediately the development after renewing the mobile phase. Dry the plate in a current of warm air. Spray with 4-aminobenzoic acid solution R. Dry the plate in a current of cold air until the acetone is removed. Heat the plate at 100C for 15 min. Allow to cool and spray with a 2 g/l solution of sodium periodate R. Dry the plate in a current of cold air. Heat the plate at 100C for 15 min. The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with reference solution (a) for lactose or to the principal spot in the chromatogram obtained with reference solution (b) for mannitol. The identification is not valid unless the chromatogram obtained with reference solution (c) shows two clearly separated spots.

 

D.    Shake a quantity of the substance to be examined corresponding to 25 mg of isosorbide mononitrate with 10 ml of acetone R for 5 min. Filter, evaporate to dryness at a temperature below 40C and dry the residue over diphosphorus pentoxide R at a pressure of 0.7 kPa for 16 h. The melting point (2.2.14) of the residue is 89C to 91C.

 

Tests

 

Inorganic nitrates

 

Examine by thin-layer chromatography (2.2.27), using silica gel H R as the coating substance.

 

Test solution

 

Shake a quantity of the substance to be examined corresponding to 0.10 g of isosorbide mononitrate with 5 ml of alcohol  R and filter.

 

Reference solution

 

Dissolve 10 mg of potassium nitrate R in 1 ml of water  R and dilute to 100 ml with alcohol  R.

 

Apply separately to the plate 10 ml of each solution. Develop over a path of 15 cm using a mixture of 15 volumes of glacial acetic acid R, 30 volumes of acetone R and 60 volumes of toluene R. Thoroughly dry the plate in a current of air until the acetic acid is completely removed. Spray copiously with freshly prepared potassium iodide and starch solution R. Expose the plate to ultraviolet light at 254 nm for 15 min. Examine in daylight. Any spot corresponding to nitrate ion in the chromatogram obtained with the test solution is not more intense than the spot in the chromatogram obtained with the reference solution (0.5 per cent, calculated as potassium nitrate).

 

Isosorbide dinitrate and isosorbide 2-nitrate

 

Examine by liquid chromatography (2.2.29) as described under Assay, changing the detection to 210 nm to 215 nm.

 

When the chromatograms are recorded in the prescribed conditions, the retention times are: isosorbide dinitrate about 5 min, isosorbide-2-nitrate about 8 min and isosorbide 5-nitrate about 11 min.

 

Inject 10 ml of reference solution (b). When a recorder is used, 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 20 per cent of the full scale of the recorder.

 

Inject 10 ml of reference solution (d). The test is not valid unless, in the chromatogram obtained with reference solution (d), the resolution between the peaks corresponding to isosorbide 2-nitrate and isosorbide 5-nitrate is at least 4.0.

 

Inject 10 ml of test solution (a), 10 ml of reference solution (b) and 10 ml of reference solution (c). In the chromatogram obtained with test solution (a): the area of any peak corresponding to isosorbide 2-nitrate is not greater than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.5 per cent); the area of any peak corresponding to isosorbide dinitrate is not greater than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.5 per cent).

 

Assay

 

Examine by liquid chromatography (2.2.29).

 

Test solution (a)

 

Sonicate a quantity of the substance to be examined corresponding to 25.0 mg of isosorbide mononitrate with 20 ml of the mobile phase for 15 min and dilute to 25.0 ml with the mobile phase. Filter the solution through a suitable membrane filter.

 

Test solution (b)

 

Dilute 1.0 ml of test solution (a) to 10.0 ml with the mobile phase.

 

Reference solution (a)

 

Dissolve 25.0 mg of isosorbide mononitrate CRS in the mobile phase and dilute to 25.0 ml with the mobile phase. Dilute 1.0 ml of the solution to 10.0 ml with the mobile phase.

 

Reference solution (b)

 

Dissolve 10.0 mg of isosorbide-2-nitrate CRS in the mobile phase and dilute to 10.0 ml with the mobile phase. Dilute 0.1 ml of the solution to 20.0 ml with the mobile phase.

 

Reference solution (c)

 

Sonicate a quantity of isosorbide dinitrate CRS corresponding to 10.0 mg of isosorbide dinitrate in 15 ml of the mobile phase for 15 min and dilute to 20.0 ml with the mobile phase. Filter the solution through a suitable membrane filter. Dilute 0.1 ml of the solution to 10.0 ml with the mobile phase.

 

Reference solution (d)

 

Dissolve 5 mg of isosorbide mononitrate CRS and 5 mg of isosorbide-2-nitrate CRS in the mobile phase and dilute to 10 ml with the mobile phase. Dilute 1 ml of the solution to 10 ml with the mobile phase.

 

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 aminopropylmethylsilyl silica gel for chromatography R (10 mm),

 

as mobile phase at a flow rate of 1 ml/min a mixture of 15 volumes of ethanol  R and 85 volumes of trimethylpentane R,

 

as detector a spectrophotometer set at 230 nm.

 

Inject 20 ml of reference solution (a). When a recorder is used, adjust the sensitivity of the system so that the height of the principal peak in the chromatogram obtained with reference solution (a) is at least 50 per cent of the full scale of the recorder. If the areas of the peaks from two successive injections do not agree to within 1.0 per cent, then inject a further four times and calculate, for the six injections, the relative standard deviation. The assay is not valid unless the relative standard deviation for the six injections is at most 2.0 per cent. Inject test solution (b) and reference solution (a), alternately.

 

Calculate the content of isosorbide mononitrate as a percentage of the declared content.

 

Storage

 

Store protected from light.

 

Labelling

 

The label states the percentage content of isosorbide mononitrate.

 

IMPURITIES

 

A.    inorganic nitrates,

 

B.    isosorbide dinitrate,

 

C.    isosorbide 2-nitrate.

 

 

 


Ph Eur

 

Action and use

 

Vasodilator.

 

Preparations

 

Isosorbide Mononitrate Tablets

 

Prolonged-release Isosorbide Mononitrate Tablets