Mannitol

(Ph Eur monograph 0559)

 

C6H14O6   182.2      69-65-8

 

Ph Eur


 

 

DEFINITION

 

Mannitol contains not less than 98.0 per cent and not more than the equivalent of 102.0 per cent of D-mannitol, calculated with reference to the anhydrous substance.

 

CHARACTERS

 

White or almost white, crystalline powder or free-flowing granules, freely soluble in water, very slightly soluble in alcohol.

 

It shows polymorphism.

 

IDENTIFICATION

 

First identification

 

A.

 

Second identification

 

B, C, D.

 

A.    Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with mannitol  CRS. Examine the substances prepared as discs. If the spectra obtained show differences, dissolve the substance to be examined and the reference substance separately in water  R, evaporate to dryness and record new spectra using the residues.

 

B.    Melting point (2.2.14): 165 C to 170 C.

 

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

 

Test solution. Dissolve 25 mg of the substance to be examined in water  R and dilute to 10 ml with the same solvent.

 

Reference solution (a). Dissolve 25 mg of mannitol  CRS in water  R and dilute to 10 ml with the same solvent.

 

Reference solution (b). Dissolve 25 mg of mannitol  CRS and 25 mg of sorbitol  CRS in water  R and dilute to 10 ml with the same solvent.

 

Apply to the plate 2 µl of each solution. Develop over a path of 17 cm using a mixture of 10 volumes of water  R, 20 volumes of ethyl acetate R and 70 volumes of propanol  R. Allow the plate to dry in air and 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 100 C 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 100 C 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). The test is not valid unless the chromatogram obtained with reference solution (b) shows 2 clearly separated spots.

 

D.    Dissolve 2.00 g of the substance to be examined and 2.6 g of disodium tetraborate R in about 20 ml of water  R at a temperature of 30 C; shake continuously for 15C30 min without further heating. Dilute the resulting clear  solution to 25.0 ml with water  R. The specific optical rotation (2.2.7) is + 23 to + 25, calculated with reference to the anhydrous substance.

 

TESTS

 

Appearance of solution

 

Dissolve 5.0 g in water  R and dilute to 50 ml with the same solvent. The solution is clear  (2.2.1) and colourless (2.2.2, Method II).

 

Conductivity (2.2.38)

 

Not more than 20 µScm-1.

 

Dissolve 20.0 g in carbon dioxide-free water  R prepared from distilled water  R and dilute to 100.0 ml with the same solvent. Measure the conductivity of the solution while gently stirring with a magnetic stirrer.

 

Reducing sugars

 

Dissolve 5.0 g in 25 ml of water  R with the aid of gentle heat. Cool and add 20 ml of cupri-citric solution R and a few glass beads. Heat so that boiling begins after 4 min and maintain boiling for 3 min. Cool rapidly and add 100 ml of a 2.4 per cent V/V solution of glacial acetic acid R and 20.0 ml of 0.025 M iodine. With continuous shaking, add 25 ml of a mixture of 6 volumes of hydrochloric acid R and 94 volumes of water  R and, when the precipitate has dissolved, titrate the excess of iodine with 0.05 M sodium thiosulphate using 1 ml of starch solution R, added towards the end of the titration, as indicator. Not less than 12.8 ml of 0.05 M sodium thiosulphate is required (0.2 per cent, calculated as glucose equivalent).

 

Related substances

 

Examine by liquid chromatography (2.2.29) as described under Assay. Inject 20 µl of reference solution (b). Adjust the sensitivity of the system so that the height of the peak due to mannitol is at least 50 per cent of the full scale of the recorder. Inject 20 µl of the test solution and of reference solution (c) and continue the chromatography for twice the retention time of mannitol. 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 (b) (2 per cent); the sum of the areas of all the peaks, apart from the principal peak, is not greater than the area of the principal peak in the chromatogram obtained with reference solution (b) (2 per cent). Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.1 per cent).

 

Lead (2.4.10)

 

It complies with the limit test for lead in sugars (0.5 ppm). Dissolve the substance to be examined in 150.0 ml of the prescribed mixture of solvents.

 

Nickel (2.4.15)

 

It complies with the limit test for nickel in polyols (1 ppm). Dissolve the substance to be examined in 150.0 ml of the prescribed mixture of solvents.

 

Water (2.5.12)

 

Not more than 0.5 per cent, determined on 1.00 g by the semi-micro determination of water.

 

Microbial contamination

 

If intended for use in the manufacture of parenteral dosage forms, the total viable aerobic count (2.6.12) is not more than 102 bacteria and 102 fungi per gram, determined by plate count. It complies with the tests for Escherichia coli and Salmonella (2.6.13).

 

Bacterial endotoxins (2.6.14)

 

If intended for use in the manufacture of parenteral dosage forms without a further appropriate procedure for the removal of bacterial endotoxins, less than 4 IU/g for parenteral dosage forms having a concentration of 100 g/l or less of mannitol, and less than 2.5 IU/g for parenteral dosage forms having a concentration of more than 100 g/l of mannitol.

 

ASSAY

 

Examine by liquid chromatography (2.2.29).

 

Test solution

 

Dissolve 5.0 g of the substance to be examined in 25 ml of water  R and dilute to 100.0 ml with the same solvent.

 

Reference solution (a)

 

Dissolve 0.50 g of mannitol  CRS in 2.5 ml of water  R and dilute to 10.0 ml with the same solvent.

 

Reference solution (b)

 

Dilute 2.0 ml of the test solution to 100.0 ml with water  R.

 

Reference solution (c)

 

Dilute 5.0 ml of reference solution (b) to 100.0 ml with water  R.

 

Reference solution (d)

 

Dissolve 0.5 g of mannitol  R and 0.5 g of sorbitol  R in 5 ml of water  R and dilute to 10.0 ml with the same solvent.

 

The chromatography may be carried out using:

 

a stainless steel column 0.3 m long and 7.8 mm in internal diameter packed with strong cation exchange resin (calcium form) R (9 µm) and maintained at 85 1 C,

 

as mobile phase at a flow rate of 0.5 ml/min, degassed water  R,

 

as detector a refractometer maintained at a constant temperature.

 

Inject 20 µl of reference solution (d). Continue the chromatography for 3 times the retention time of mannitol.

 

When the chromatograms are recorded in the prescribed conditions, the retention time of mannitol is about 22 min and the relative retention of sorbitol with reference to mannitol is about 1.25. The test is not valid unless the resolution between the peaks due to mannitol and to sorbitol is at least 2 in the chromatogram obtained with reference solution (d).

 

Inject 20 µl of the test solution and 20 µl of reference solution (a). Continue the chromatography for twice the retention time of mannitol.

 

Calculate the percentage content of d-mannitol from the areas of the peaks and the declared content of mannitol  CRS.

 

LABELLING

 

The label states:

 

where applicable, the maximum concentration of bacterial endotoxins,

 

where applicable, that the substance is suitable for use in the manufacture of parenteral dosage forms.

 

IMPURITIES

 

A.    sorbitol,

 

B.    maltitol,

 

C.    6-O-a-d-glucopyranosyl-d-glucitol (isomaltitol).

 

 


 Ph Eur

 

Action and use

 

Diuretic.

 

Preparation

 

Mannitol Intravenous Infusion