Clemastine Fumarate

Clemastine Hydrogen Fumarate

(Ph. Eur. monograph 1190)

C₂₁H₂₆ClNO,C₄H₄O₄    460.0    14976-57-9

Histamine H₁ receptor antagonist; antihistamine.

Clemastine Oral Solution

Clemastine Tablets

Ph Eur

(2R)-2-[2-[(R)-1-(4-Chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine (E)-butenedioate.

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

White or almost white, crystalline powder.

Very slightly soluble in water, sparingly soluble in ethanol (70 per cent V/V), slightly soluble in ethanol (50 per cent V/V) and in methanol.

First identification   A, B.

Second identification   A, C, D.

A. Specific optical rotation (see Tests).

B. Infrared absorption spectrophotometry (2.2.24).

Comparison   clemastine fumarate CRS.

C. Examine the chromatograms obtained in the test for related substances.

Results  The principal spot in the chromatogram obtained with test solution (b) is similar in position, colour and size to the principal spot in the chromatogram obtained with reference solution (a).

D. Thin-layer chromatography (2.2.27).

Test solution  Dissolve 40 mg of the substance to be examined in methanol R and dilute to 2 mL with the same solvent.

Reference solution  Dissolve 50 mg of fumaric acid CRS in ethanol (96 per cent) R and dilute to 10 mL with the same solvent.

Plate  TLC silica gel G plate R.

Mobile phase  water R, anhydrous formic acid R, di-isopropyl ether R (5:25:70 V/V/V).

Application  5 µL.

Development  Over a path of 15 cm.

Drying  At 100-105 °C for 30 min and allow to cool.

Detection  Spray with a 16 g/L solution of potassium permanganate R and examine in daylight.

Results  The spot with the highest R_F value 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.

Dissolve 0.500 g in methanol R and dilute to 50.0 mL with the same solvent.

Solution S is clear (2.2.1) and not more intensely coloured than reference solution BY₇ (2.2.2, Method II).

3.2 to 4.2.

Suspend 1.0 g in 10 mL of carbon dioxide-free water R.

+ 15.0 to + 18.0 (dried substance), determined on solution S.

Thin-layer chromatography (2.2.27).

Test solution (a)  Dissolve 0.100 g of the substance to be examined in methanol R and dilute to 5.0 mL with the same solvent.

Test solution (b)  Dilute 1.0 mL of test solution (a) to 10.0 mL with methanol R.

Reference solution (a)  Dissolve 20.0 mg of clemastine fumarate CRS in methanol R and dilute to 10.0 mL with the same solvent.

Reference solution (b)  Dilute 1.5 mL of test solution (b) to 50.0 mL with methanol R.

Reference solution (c)  Dilute 0.5 mL of test solution (b) to 50.0 mL with methanol R.

Reference solution (d)  Dissolve 10.0 mg of diphenhydramine hydrochloride CRS in 5.0 mL of reference solution (a).

Plate   TLC silica gel G plate R.

Mobile phase  concentrated ammonia R, methanol R, tetrahydrofuran R (1:20:80 V/V/V).

Application  5 µL.

Development  Over a path of 15 cm.

Drying  In a current of cold air for 5 min.

Detection  Spray with a freshly prepared mixture of 1 volume of potassium iodobismuthate solution R and 10 volumes of dilute acetic acid R and then with dilute hydrogen peroxide solution R; cover the plate immediately with a glass plate of the same size and examine the chromatograms after 2 min.

System suitability  Reference solution (d):

• — the chromatogram shows 2 clearly separated spots.

Limits  Test solution (a):

• — any impurity: any spot, apart from the principal spot, is not more intense than the principal spot in the chromatogram obtained with reference solution (b) (0.3 per cent) and at most 4 such spots are more intense than the principal spot in the chromatogram obtained with reference solution (c) (0.1 per cent);

• — disregard limit: disregard any spot remaining at the point of application (fumaric acid).

Liquid chromatography (2.2.29).

Solvent mixture  acetonitrile R1, 10 g/L solution of ammonium dihydrogen phosphate R (25:75 V/V).

Test solution  Dissolve 20 mg of the substance to be examined in the solvent mixture and dilute to 100 mL with the solvent mixture.

Reference solution (a)  Dissolve 6 mg of 1-(4-chlorophenyl)-1-phenylethanol CRS (impurity C) in the solvent mixture and dilute to 100 mL with the solvent mixture.

Reference solution (b)  Dilute 1 mL of reference solution (a) to 100 mL with the solvent mixture.

Reference solution (c)  Dissolve 10 mg of the substance to be examined in the solvent mixture and dilute to 100 mL with the solvent mixture. To 1 mL of this solution add 1 mL of reference solution (a) and dilute to 100 mL with the solvent mixture.

• — size: l = 0.1 m, Ø = 4.6 mm;

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

Mobile phase  phosphoric acid R, acetonitrile R1, 10 g/L solution of ammonium dihydrogen phosphate R (0.1:45:55 V/V/V).

Flow rate  1 mL/min.

Detection  Spectrophotometer at 220 nm.

Injection  100 µL.

System suitability  Reference solution (c):

• — resolution: minimum 2.2 between the peaks due to clemastine and impurity C.

• — impurity C: not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.3 per cent).

Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C for 6 h.

Maximum 0.1 per cent, determined on 1.0 g.

Dissolve 0.350 g in 60 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).

1 mL of 0.1 M perchloric acid is equivalent to 46.00 mg of C₂₅H₃₀ClNO₅.

Specified impurities  A, B, C.

Other detectable impurities (the following substances would, 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 impurities in substances for pharmaceutical use): D.

A. (1RS,2R)-2-[2-[(R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine 1-oxide,

B. 4-[1-(4-chlorophenyl)-1-phenylethoxy]-1-methylazepane,

C. (RS)-1-(4-chlorophenyl)-1-phenylethanol,

D. 2-[(2RS)-1-methylpyrrolidin-2-yl]ethanol.

Ph Eur