Niclosamide Monohydrate

(Ph. Eur. monograph 0680)

C₁₃H₈Cl₂N₂O₄,H₂O              345.1

Action and use

Anthelminthic.

Preparation

Niclosamide Tablets

DEFINITION

5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide monohydrate.

Content

98.0 per cent to 101.0 per cent (dried substance).

CHARACTERS

Appearance

Yellowish, fine crystals.

Solubility

Practically insoluble in water, sparingly soluble in acetone, slightly soluble in anhydrous ethanol.

IDENTIFICATION

First identification: B, E.

Second identification: A, C, D, E.

A. Melting point (2.2.14): 227 °C to 232 °C, determined after drying at 100-105 °C for 4 h.

B. Infrared absorption spectrophotometry (2.2.24).

Preparation: Dry the substance to be examined at 100-105 °C for 4 h and examine as discs prepared using about 0.5 mg of substance and 0.3 g of potassium bromide R.

Comparison: anhydrous niclosamide CRS.

C. To 50 mg add 5 mL of 1 M hydrochloric acid and 0.1 g of zinc powder R, heat in a water-bath for 10 min, cool and filter. To the filtrate add 1 mL of a 5 g/L solution of sodium nitrite R and allow to stand for 3 min; add 2 mL of a 20 g/L solution of ammonium sulfamate R, shake, allow to stand for 3 min and add 2 mL of a 5 g/L solution of naphthylethylenediamine dihydrochloride R. A violet colour is produced.

D. Heat the substance on a copper wire in a non-luminous flame. The flame becomes green.

E. Loss on drying (see Tests).

TESTS

Related substances

Liquid chromatography (2.2.29).

Test solution: Dissolve 50 mg of the substance to be examined in methanol R, heating gently, cool and dilute to 50.0 mL with the same solvent.

Reference solution: Dilute 1.0 mL of the test solution to 100.0 mL with acetonitrile R. Dilute 1.0 mL of this solution to 20.0 mL with acetonitrile R.

Column:

— size: l = 0.125 m, Ø = 4 mm;

— stationary phase: octadecylsilyl silica gel for chromatography R (5 μm).

Mobile phase: Mixture of equal volumes of acetonitrile R and a solution containing 2 g/L of potassium dihydrogen phosphate R, 1 g/L of disodium hydrogen phosphate dodecahydrate R and 2 g/L of tetrabutylammonium hydrogen sulfate R.

Flow rate: 1.0 mL/min.

Detection: Spectrophotometer at 230 nm.

Injection: 20 μL.

Run time: Twice the retention time of niclosamide.

Limits:

— total: not more than 4 times the area of the principal peak in the chromatogram obtained with the reference solution (0.2 per cent);

— disregard limit: 0.1 times the area of the principal peak in the chromatogram obtained with the reference solution (0.005 per cent).

5-Chlorosalicylic acid

Maximum 60 ppm.

Test solution: To 1.0 g add 15 mL of water R, boil for 2 min, cool, filter through a membrane filter (nominal pore size 0.45 μm), wash the filter and dilute the combined filtrate and washings to 20.0 mL with water R.

Reference solution: Dissolve 30 mg of 5-chlorosalicylic acid R in 20 mL of methanol R and dilute to 100.0 mL with water R. Dilute 1.0 mL of this solution to 100.0 mL with water R.

To 10.0 mL of the test solution and to 10.0 mL of the reference solution add separately 0.1 mL of ferric chloride solution R2. Any violet colour produced in the test solution is not more intense than that in the reference solution.

2-Chloro-4-nitroaniline

Maximum 100 ppm.

Test solution To 0.250 g add 5 mL of methanol R, heat to boiling, cool, add 45 mL of 1 M hydrochloric acid, heat again to boiling, cool, filter and dilute the filtrate to 50.0 mL with 1 M hydrochloric acid.

Reference solution Dissolve 50 mg of 2-chloro-4-nitroaniline R in methanol R and dilute to 100.0 mL with the same solvent. Dilute 1.0 mL of the solution to 100.0 mL with methanol R. Dilute 2.0 mL of this solution to 20.0 mL with 1 M hydrochloric acid.

To 10.0 mL of the test solution and to 10.0 mL of the reference solution add separately 0.5 mL of a 5 g/L solution of sodium nitrite R and allow to stand for 3 min. Add 1 mL of a 20 g/L solution of ammonium sulfamate R, shake, allow to stand for 3 min and add 1 mL of a 5 g/L solution of naphthylethylenediamine dihydrochloride R. Any pinkish-violet colour produced in the test solution is not more intense than that in the reference solution.

Chlorides (2.4.4)

Maximum 500 ppm.

To 2 g add a mixture of 1.2 mL of acetic acid R and 40 mL of water R, boil for 2 min, cool and filter. Dilute 2 mL of the filtrate to 15 mL with water R.

Loss on drying (2.2.32)

4.5 per cent to 6.0 per cent, determined on 1.000 g by drying in an oven at 105 °C for 4 h.

Sulfated ash (2.4.14)

Maximum 0.1 per cent, determined on 1.0 g.

ASSAY

Dissolve 0.3000 g in 80 mL of a mixture of equal volumes of acetone R and methanol R. Titrate with 0.1 M tetrabutylammonium hydroxide, determining the end-point potentiometrically (2.2.20).

1 mL of 0.1 M tetrabutylammonium hydroxide is equivalent to 32.71 mg of C₁₃H₈Cl₂N₂O₄.

STORAGE

Protected from light.