• British Pharmacopoeia Volume I & II
  • Monographs: Medicinal and Pharmaceutical Substances

Hyoscine Butylbromide

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General Notices

(Ph. Eur. monograph 0737)

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C21H30BrNO4    440.4    149-64-4

Action and use

Anticholinergic.

Preparations

Hyoscine Butylbromide Injection

Hyoscine Butylbromide Tablets

Ph Eur

DEFINITION

(1R,2R,4S,5S,7s,9r)-9-Butyl-7-[[(2S)-3-hydroxy-2-phenylpropanoyl]oxy]-9-methyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide.

Content

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

CHARACTERS
Appearance

White or almost white, crystalline powder.

Solubility

Freely soluble in water and in methylene chloride, sparingly soluble in anhydrous ethanol.

IDENTIFICATION

First identification   A, C, F.

Second identification   A, B, D, E, F.

A. Specific optical rotation (see Tests).

B. Melting point (2.2.14): 139 °C to 141 °C.

C. Infrared absorption spectrophotometry (2.2.24).

Comparison   hyoscine butylbromide CRS.

D. To about 1 mg add 0.2 mL of nitric acid R and evaporate to dryness on a water-bath. Dissolve the residue in 2 mL of acetone R and add 0.1 mL of a 30 g/L solution of potassium hydroxide R in methanol R. A violet colour develops.

E. To 5 mL of solution S (see Tests) add 2 mL of dilute sodium hydroxide solution R. No precipitate is formed.

F. It gives reaction (a) of bromides (2.3.1).

TESTS
Solution S

Dissolve 1.25 g in carbon dioxide-free water R and dilute to 25.0 mL with the same solvent.

Appearance of solution

Solution S is clear (2.2.1) and colourless (2.2.2, Method II).

pH (2.2.3)

5.5 to 6.5 for solution S.

Specific optical rotation (2.2.7)

- 18 to - 20 (dried substance), determined on solution S.

Related substances

Liquid chromatography (2.2.29).

Test solution  Dissolve 50.0 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 50.0 mL with the mobile phase. Dilute 5.0 mL of this solution to 50.0 mL with the mobile phase.

Reference solution (b)  Dilute 10.0 mL of reference solution (a) to 20.0 mL with the mobile phase.

Reference solution (c)  Dissolve 5.0 mg of hyoscine butylbromide impurity E CRS in the mobile phase, add 1.0 mL of the test solution and dilute to 10.0 mL with the mobile phase. Dilute 5.0 mL of this solution to 50.0 mL with the mobile phase.

Column:
  • size: l =  0.125 m, Ø = 4.0 mm;
  • temperature: 25 ± 1 °C.

Mobile phase  Dissolve 5.8 g of sodium dodecyl sulfate R in a mixture of 410 mL of acetonitrile R and 605 mL of a 7.0 g/L solution of potassium dihydrogen phosphate R previously adjusted to pH 3.3 with 0.05 M phosphoric acid.

Flow rate  2.0 mL/min.

Detection  Spectrophotometer at 210 nm.

Injection  10 µL.

Run time  3.5 times the retention time of butylhyoscine.

Relative retention  With reference to butylhyoscine (retention time = about 7.0 min): impurity B = about 0.1; impurity A = about 0.36; impurity C = about 0.40; impurity D = about 0.7; impurity E = about 0.8; impurity F = about 0.9; impurity G = about 3.0.

System suitability  Reference solution (c):

  • resolution: minimum 1.5 between the peaks due to impurity E and butylhyoscine;
Limits:
  • correction factors: for the calculation of contents, multiply the peak areas of the following impurities by the corresponding correction factor: impurity B = 0.3; impurity G = 0.6;
  • impurities B, C, D, E, F, G: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);
  • impurity A: not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent);
  • any other impurity: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent);
  • total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.4 per cent); disregard any peak due to the bromide ion which appears close to the solvent peak;
  • disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).
Loss on drying (2.2.32)

Maximum 2.5 per cent, determined on 0.500 g by drying in an oven at 105 °C.

Sulfated ash (2.4.14)

Maximum 0.1 per cent, determined on 0.5 g.

ASSAY

Dissolve 0.400 g in 50 mL of water R. Titrate with 0.1 M silver nitrate, determining the end-point potentiometrically (2.2.20) using a silver indicator electrode and a silver-silver chloride reference electrode.

1 mL of 0.1 M silver nitrate is equivalent to 44.04 mg of C21H30BrNO4.

IMPURITIES

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

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A. (1R,2R,4S,5S,7s)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl (2S)-3-hydroxy-2-phenylpropanoate (hyoscine),

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B. (2RS)-3-hydroxy-2-phenylpropanoic acid (dl-tropic acid),

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C. R1 = CH2OH, R2 = H, R3 = R4 = CH3: (1R,2R,4S,5S,7s)-7-[[(2S)-3-hydroxy-2-phenylpropanoyl]oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane (methylhyoscine),

D. R1 = CH2OH, R2 = H, R3 = CH3, R4 = CH2-CH2-CH3: (1R,2R,4S,5S,7s,9r)-7-[[(2S)-3-hydroxy-2-phenylpropanoyl]oxy]-9-methyl-9-propyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane (propylhyoscine),

F. R1 = CH2OH, R2 = H, R3 = CH2-CH2-CH2-CH3, R4 = CH3: (1R,2R,4S,5S,7s,9s)-9-butyl-7-[[(2S)-3-hydroxy-2-phenylpropanoyl]oxy]-9-methyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane (pseudo-isomer),

G. R1 + R2 = CH2 , R3 = CH3, R4 = CH2-CH2-CH2-CH3: (1R,2R,4S,5S,7s,9r)-9-butyl-9-methyl-7-[(2-phenylprop-2-enoyl)oxy]-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane (apo-N-butylhyoscine);

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E. (1R,2R,4S,5S,7s)-9-butyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl (2S)-3-hydroxy-2-phenylpropanoate (N-butylhyoscine).

Ph Eur