Terfenadine

(Ph Eur monograph 0955)

C₃₂H₄₁NO₂    471.7    50679-08-8

Histamine H₁ receptor antagonist; antihistamine.

Terfenadine Oral Suspension

Terfenadine Tablets

Ph Eur

(1RS)-1-[4-(1,1-Dimethylethyl)phenyl]-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butan-1-ol.

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

White or almost white, crystalline powder.

Very slightly soluble in water, freely soluble in methylene chloride, soluble in methanol. It is very slightly soluble in dilute hydrochloric acid.

It shows polymorphism (5.9).

First identification  C.

Second identification  A, B, D.

A.  Melting point (2.2.14): 146 °C to 152 °C.

B.  Ultraviolet and visible absorption spectrophotometry (2.2.25).

Test solution  Dissolve 50.0 mg in methanol R and dilute to 100.0 ml with the same solvent.

Spectral range  230-350 nm.

Absorption maximum  At 259 nm.

Shoulders  At 253 nm and 270 nm.

Specific absorbance at the absorption maximum  13.5 to 14.9.

C.  Infrared absorption spectrophotometry (2.2.24).

Comparison  terfenadine CRS.

D.  Thin-layer chromatography (2.2.27).

Test solution  Dissolve 50 mg of the substance to be examined in methylene chloride R and dilute to 10 ml with the same solvent.

Reference solution  Dissolve 50 mg of terfenadine CRS in methylene chloride R and dilute to 10 ml with the same solvent.

Plate  TLC silica gel F₂₅₄ plate R.

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

Application  10 µl.

Development  Over a path of 15 cm.

Drying  In air.

Detection  Examine in ultraviolet light at 254 nm.

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 the reference solution.

Liquid chromatography (2.2.29).

Test solution  Dissolve 15 mg of the substance to be examined in the mobile phase and dilute to 10.0 ml with the mobile phase.

Reference solution (a)  Dilute 1.0 ml of the test solution to 10.0 ml with the mobile phase. Dilute 1.0 ml of this solution to 20.0 ml with the mobile phase.

Reference solution (b)  Dissolve 15 mg of terfenadine impurity A CRS in the mobile phase and dilute to 10.0 ml with the mobile phase. To 5.0 ml of this solution, add 5.0 ml of the test solution and dilute to 50.0 ml with the mobile phase.

Reference solution (c)  Dilute 10.0 ml of reference solution (a) to 25.0 ml with the mobile phase.

Reference solution (d)  Dissolve 0.1 g of potassium iodide R in the mobile phase and dilute to 100 ml with the mobile phase. Dilute 1 ml of this solution to 100 ml with the mobile phase.

• — size: l = 0.25 m, Ø = 4.6 mm;

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

Mobile phase  Dilute 600 ml of acetonitrile R1 to 1 litre with diethylammonium phosphate buffer solution pH 6.0 R.

Flow rate  1 ml/min.

Detection  Spectrophotometer at 217 nm.

Injection  20 µl.

Run time  5 times the retention time of terfenadine.

System suitability  Reference solution (b):

• — resolution: minimum 5.0 between the peaks due to terfenadine and impurity A;

• — mass distribution ratio: minimum 2.0 for the peak due to terfenadine; use potassium iodide R as the unretained compound (reference solution (d)).

• — impurities A, B, C, D, E, F, G, H, I, J: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.2 per cent);

• — total: not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5 per cent);

• — disregard limit: 0.025 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.005 per cent).

Maximum 0.5 per cent, determined on 1.000 g by drying at 60 °C at a pressure not exceeding 0.5 kPa.

Maximum 0.1 per cent, determined on 1.0 g.

Dissolve 0.400 g in 50 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 47.17 mg of C₃₂H₄₁NO₂.

Protected from light.

Specified impurities  A, B, C, D, E, F, G, H, I, J.

A.  R1 + R2 = O, R3 = OH: 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butan-1-one,

B.  R1 = OH, R2 = R3 = H: (1RS)-1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethyl)piperidin-1-yl]butan-1-ol,

H.  R1 = R2 = H, R3 = OH: [1-[4-[4-(1,1-dimethylethyl)phenyl]butyl]piperidin-4-yl]diphenylmethanol,

C.  1-[(4RS)-4-[4-(1,1-dimethylethyl)phenyl]-4-hydroxybutyl]-4-(hydroxydiphenylmethyl)piperidine 1-oxide,

D.  (1RS)-1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethylene)piperidin-1-yl]butan-1-ol,

E.  R = H: 1-[(4RS)-4-[4-(1,1-dimethylethyl)phenyl]-4-hydroxybutyl]piperidine-4-carboxylic acid,

J.  R = C₂H₅: ethyl 1-[(4RS)-4-[4-(1,1-dimethylethyl)phenyl]-4-hydroxybutyl]piperidine-4-carboxylate,

F.  1-[4-[4-(1,1-dimethylethyl)phenyl]but-3-enyl]-4-(diphenylmethylene)piperidine,

G.  [1-[4-[4-(1,1-dimethylethyl)phenyl]but-3-enyl]piperidin-4-yl]diphenylmethanol,

I.  diphenyl(piperidin-4-yl)methanol.

Ph Eur