Clemastine Oral Solution

Histamine H₁ receptor antagonist; antihistamine.

Clemastine Oral Solution contains Clemastine Fumarate in a suitable vehicle.

The oral solution complies with the requirements stated under Oral Liquids and with the following requirements.

90.0 to 105.0% of the stated amount.

A. In the test for Related substances, the principal spot in the chromatogram obtained with solution (2) corresponds to that in the chromatogram obtained with solution (3).

B. In the Assay, the retention time of the principal peak in the chromatogram obtained with solution (1) is the same as that of the principal peak in the chromatogram obtained with solution (2).

Carry out the method for liquid chromatography, Appendix III D, using the following solutions in a mixture of 25 volumes of acetonitrile and 75 volumes of a 1% w/v solution of ammonium dihydrogen orthophosphate.

(1) Dilute a quantity of the oral solution containing the equivalent of 0.5 mg of clemastine to 25 mL.

(2) 0.00008% w/v of 1-(4-chlorophenyl)-1-phenylethanol BPCRS.

(3) 0.000335% w/v of clemastine fumarate BPCRS and 0.00008% w/v of 1-(4-chlorophenyl)-1-phenylethanol BPCRS.

(a) A stainless steel column (10 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 µm) (Nucleosil C18 is suitable).

(b) Use isocratic elution and the mobile phase described below.

(c) Use a flow rate of 1 mL per minute.

(d) Use an ambient column temperature.

(e) Use a detection wavelength of 220 nm.

(f) Inject 10 µL of each solution.

0.1 volume of orthophosphoric acid, 45 volumes of acetonitrile and 55 volumes of a 1% w/v solution of ammonium dihydrogen orthophosphate.

The test is not valid unless the resolution factor between the peaks due to clemastine fumarate and 1-(4-chlorophenyl)-1-phenylethanol in the chromatogram obtained with solution (3) is at least 2.2.

In the chromatogram obtained with solution (1):

the area of any peak corresponding to 1-(4-chlorophenyl)-1-phenylethanol is not greater than the area of the peak in the chromatogram obtained with solution (2) (3%).

Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions in methanol.

(1) Add 20 mL of water, 20 mL of a saturated solution of sodium chloride and 2 mL of 13.5m ammonia to a quantity of the oral solution containing the equivalent of 8 mg of clemastine, extract with four 40 mL quantities of dichloromethane, washing each extract with the same 40 mL of water, filter the dichloromethane extracts and evaporate to dryness at a temperature of 30° to 40° under reduced pressure. Dissolve the residue in 50 mL of methanol, evaporate to dryness under the same conditions and dissolve the residue in 4 mL of methanol.

(2) Dilute 1 volume of solution (1) to 10 volumes.

(3) 0.027% w/v of clemastine fumarate BPCRS.

(4) 0.00135% w/v of clemastine fumarate BPCRS.

(5) 0.0135% w/v of each of clemastine fumarate BPCRS and diphenhydramine hydrochloride BPCRS.

(6) 0.0054% w/v of 2-(2-hydroxyethyl)-1-methylpyrrolidine BPCRS.

(a) Use as the coating silica gel 60 F₂₅₄.

(b) Use the mobile phase as described below.

(c) Apply 10 µL of each solution.

(d) Develop the plate to 15 cm.

(e) After removal of the plate, dry it in a current of cold air for 5 minutes, spray with a freshly prepared mixture of 1 volume of potassium iodobismuthate solution and 10 volumes of 2m acetic acid and then with hydrogen peroxide solution (10 vol). Cover the plate immediately with a glass plate of the same size and examine the chromatograms after 2 minutes.

1 volume of 13.5m ammonia, 20 volumes of methanol and 80 volumes of stabiliser-free tetrahydrofuran.

The test is not valid unless the chromatogram obtained with solution (5) shows two clearly separated spots.

In the chromatogram obtained with solution (1):

any spot corresponding to 2-(2-hydroxyethyl)-1-methylpyrrolidine is not more intense than the spot in the chromatogram obtained with solution (6) (2%, with reference to clemastine fumarate);

any orange-brown secondary spot is not more intense than the spot in the chromatogram obtained with solution (4) (0.5%, with reference to clemastine fumarate).

Disregard any spot remaining on the line of application and any spot with an Rf value greater than that of the principal spot.

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Dilute a quantity of the oral solution containing the equivalent of 0.5 mg of clemastine to 20 mL with a mixture of 25 volumes of acetonitrile and 75 volumes of a 1% w/v solution of ammonium dihydrogen orthophosphate.

(2) 0.00335% w/v of clemastine fumarate BPCRS in a mixture of 25 volumes of acetonitrile and 75 volumes of a 1% w/v solution of ammonium dihydrogen orthophosphate.

(a) A stainless steel column (10 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 µm) (Nucleosil C18 is suitable).

(b) Use isocratic elution and the mobile phase described below.

(c) Use a flow rate of 1 mL per minute.

(d) Use an ambient column temperature.

(e) Use a detection wavelength of 220 nm.

(f) Inject 10 µL of each solution.

0.1 volume of orthophosphoric acid, 45 volumes of acetonitrile and 55 volumes of a 1% w/v solution of ammonium dihydrogen orthophosphate.

Determine the weight per mL of the oral solution, Appendix V G, and calculate the content of C₂₁H₂₆ClNO, weight in volume, using the declared content of C₂₁H₂₆ClNO in clemastine fumarate BPCRS.

The quantity of the active ingredient is stated in terms of the equivalent amount of clemastine.