Cetirizine Hydrochloride

(Cetirizine Dihydrochloride, Ph Eur monograph 1084)

C₂₁H₂₅ClN₂O₃,2HCl    461.8    83881-52-1

Histamine H₁ receptor antagonist; antihistamine.

Cetirizine Oral Solution

Cetirizine Tablets

Ph Eur

(RS)-2-[2-[4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl]ethoxy]acetic acid dihydrochloride.

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

White or almost white powder.

Freely soluble in water, practically insoluble in acetone and in methylene chloride.

First identification   B, D.

Second identification   A, C, D.

A. Ultraviolet and visible absorption spectrophotometry (2.2.25).

Test solution  Dissolve 20.0 mg in 50 mL of a 10.3 g/L solution of hydrochloric acid R and dilute to 100.0 mL with the same acid. Dilute 10.0 mL of this solution to 100.0 mL with a 10.3 g/L solution of hydrochloric acid R.

Spectral range  210-350 nm.

Absorption maximum  At 231 nm.

Specific absorbance at the absorption maximum  359 to 381.

B. Infrared absorption spectrophotometry (2.2.24).

Comparison   cetirizine dihydrochloride CRS.

C. Thin-layer chromatography (2.2.27).

Test solution  Dissolve 10 mg of the substance to be examined in water R and dilute to 5 mL with the same solvent.

Reference solution (a)  Dissolve 10 mg of cetirizine dihydrochloride CRS in water R and dilute to 5 mL with the same solvent.

Reference solution (b)  Dissolve 10 mg of chlorphenamine maleate CRS in water R and dilute to 5 mL with the same solvent. Mix 1 mL of the solution and 1 mL of reference solution (a).

Plate  TLC silica gel GF₂₅₄ plate R.

Mobile phase  ammonia R, methanol R, methylene chloride R (1:10:90 V/V/V).

Application  5 µL.

Development  Over 2/3 of the plate.

Drying  In a current of cold air.

Detection  Examine in ultraviolet light at 254 nm.

System suitability  Reference solution (b):

• — the chromatogram shows 2 clearly separated spots.

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

D. It gives reaction (a) of chlorides (2.3.1).

Dissolve 1.0 g in carbon dioxide-free water R and dilute to 20 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).

1.2 to 1.8 for solution S.

Liquid chromatography (2.2.29).

Test solution  Dissolve 20 mg of the substance to be examined in the mobile phase and dilute to 100.0 mL with the mobile phase.

Reference solution (a)  Dissolve 2 mg of cetirizine dihydrochloride CRS and 2 mg of cetirizine impurity A CRS in the mobile phase and dilute to 50.0 mL with the mobile phase. Dilute 1.0 mL of the solution to 100.0 mL with the mobile phase.

Reference solution (b)  Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase.

Reference solution (c)  Dissolve the contents of a vial of cetirizine for peak identification CRS (containing impurities B, C, D, E and F) in 5.0 mL of the mobile phase.

• — size: l = 0.25 m, Ø = 4.6 mm;

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

Mobile phase  dilute sulfuric acid R, water R, acetonitrile R (0.4:6.6:93 V/V/V).

Flow rate  1 mL/min.

Detection  Spectrophotometer at 230 nm.

Injection  20 µL.

Run time  3 times the retention time of cetirizine.

Identification of impurities  Use the chromatogram supplied with cetirizine for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peaks due to impurities B, C, D, E and F; use the chromatogram obtained with reference solution (a) to identify the peak due to impurity A.

Relative retention  With reference to cetirizine (retention time = about 9 min): impurity D = about 0.6; impurity B = about 0.8; impurity C = about 0.9; impurity E = about 1.2; impurity F = about 1.37; impurity A = about 1.42.

System suitability  Reference solution (c):

• — peak-to-valley ratio: minimum 5, where H_p = height above the baseline of the peak due to impurity C and H_v = height above the baseline of the lowest point of the curve separating this peak from the peak due to cetirizine.

• — correction factors: for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor: impurity A = 0.7; impurity C = 1.9; impurity D = 0.6; impurity E = 1.3; impurity F = 1.9;

• — impurities A, B, C, D, E, F: for each impurity, not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.15 per cent);

• — unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);

• — total: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.3 per cent);

• — disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).

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

Maximum 0.2 per cent, determined on 1.0 g.

Dissolve 0.100 g in 70 mL of a mixture of 30 volumes of water R and 70 volumes of acetone R. Titrate with 0.1 M sodium hydroxide to the 2^nd point of inflexion. Determine the end-point potentiometrically (2.2.20). Carry out a blank titration.

1 mL of 0.1 M sodium hydroxide is equivalent to 15.39 mg of C₂₁H₂₇Cl₃N₂O₃.

Protected from light.

Specified impurities   A, B, C, D, E, F.

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): G.

A. (RS)-1-[(4-chlorophenyl)phenylmethyl]piperazine,

B. (RS)-2-[4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl]acetic acid,

C. (RS)-2-[2-[4-[(2-chlorophenyl)phenylmethyl]piperazin-1-yl]ethoxy]acetic acid,

D. 1,4-bis[(4-chlorophenyl)phenylmethyl]piperazine,

E. (RS)-2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl]ethoxy]ethoxy]acetic acid (ethoxycetirizine),

F. 2-[2-[4-(diphenylmethyl)piperazin-1-yl]ethoxy]acetic acid,

G. (RS)-2-[4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl]ethan-1-ol.

Ph Eur