Bromperidol

(Ph Eur monograph 1178)

C ₂₁ H ₂₃ BrFNO ₂     420.3     10457-90-6

Dopamine receptor antagonist; neuroleptic.

Ph Eur

4-[4-(4-Bromophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one.

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

White or almost white powder.

Practically insoluble in water, sparingly soluble in methanol and in methylene chloride, slightly soluble in ethanol (96 per cent).

First identification   B, E.

Second identification   A, C, D, E.

A. Melting point (2.2.14): 156 °C to 159 °C.

B. Infrared absorption spectrophotometry (2.2.24).

Comparison   bromperidol CRS.

C. Thin-layer chromatography (2.2.27).

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

Reference solution (a)  Dissolve 10 mg of bromperidol CRS in methanol R and dilute to 10 mL with the same solvent.

Reference solution (b)  Dissolve 10 mg of bromperidol CRS and 10 mg of haloperidol CRS in methanol R and dilute to 10 mL with the same solvent.

Plate  TLC octadecylsilyl silica gel plate R.

Mobile phase  tetrahydrofuran R, methanol R, 58 g/L solution of sodium chloride R (10:45:45 V/V/V).

Application  1 µL.

Development  In an unsaturated tank, over 3/4 of the plate.

Drying  In air.

Detection  Examine in ultraviolet light at 254 nm.

System suitability  Reference solution (b):

• — the chromatogram shows 2 spots which may, however, not be completely separated.

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. Dissolve about 10 mg in 5 mL of anhydrous ethanol R. Add 0.5 mL of dinitrobenzene solution R and 0.5 mL of 2 M alcoholic potassium hydroxide R. A violet colour is produced that becomes brownish-red after 20 min.

E. To 0.1 g in a porcelain crucible add 0.5 g of anhydrous sodium carbonate R. Heat over an open flame for 10 min. Allow to cool. Take up the residue with 5 mL of dilute nitric acid R and filter. To 1 mL of the filtrate add 1 mL of water R. The solution gives reaction (a) of bromides (2.3.1).

The solution is clear (2.2.1) and not more intensely coloured than reference solution Y₇ (2.2.2, Method II).

Dissolve 0.2 g in 20 mL of a 1 per cent V/V solution of lactic acid R.

Liquid chromatography (2.2.29).

Test solution  Dissolve 0.100 g of the substance to be examined in methanol R and dilute to 10.0 mL with the same solvent.

Reference solution (a)  Dissolve 2.5 mg of bromperidol CRS and 5.0 mg of haloperidol CRS in methanol R and dilute to 50.0 mL with the same solvent.

Reference solution (b)  Dilute 5.0 mL of the test solution to 100.0 mL with methanol R. Dilute 1.0 mL of this solution to 10.0 mL with methanol R.

• — size: l  = 0.1 m, Ø = 4.0 mm;

• — stationary phase: base-deactivated octadecylsilyl silica gel for chromatography R (3 µm).

• — mobile phase A: 17 g/L solution of tetrabutylammonium hydrogen sulfate R;

• — mobile phase B: acetonitrile R;

Flow rate  1.5 mL/min.

Detection  Spectrophotometer at 230 nm.

Injection  10 µL.

Relative retention  With reference to bromperidol (retention time = about 6 min): impurity A = about 0.5; impurity B = about 0.8; haloperidol = about 0.9; impurity C = about 1.4; impurity D = about 1.5; impurity E = about 1.8; impurity F = about 1.85.

System suitability  Reference solution (a):

• — resolution: minimum 3.0 between the peaks due to haloperidol and bromperidol.

• — impurities A, B, C, D, E, F: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.5 per cent);

• — unspecified impurities: for each impurity, not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);

• — total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (1 per cent);

• — disregard limit: 0.1 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 0.1 per cent, determined on 1.0 g in a platinum crucible.

Dissolve 0.300 g in 50 mL of a mixture of 1 volume of anhydrous acetic acid R and 7 volumes of methyl ethyl ketone R. Titrate with 0.1 M perchloric acid, using 0.2 mL of naphtholbenzein solution R as indicator.

1 mL of 0.1 M perchloric acid is equivalent to 42.03 mg of C₂₁H₂₃BrFNO₂.

Protected from light.

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

A. 1-(4-fluorophenyl)-4-(4-hydroxy-4-phenylpiperidin-1-yl)butan-1-one,

B. 4-[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]-1-(2-fluorophenyl)butan-1-one,

C. 4-[4-(biphenyl-4-yl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one,

D. 4-[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]-1-(3-ethyl-4-fluorophenyl)butan-1-one,

E. 4-[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]-1-[4-[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]phenyl]butan-1-one,

F. 4-[4-(4′-bromobiphenyl-4-yl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one.

Ph Eur