(Ph. Eur. monograph 1074)
C21H30ClNO 347.9 1235-82-1
Action and use
Anticholinergic.
DEFINITION
(1RS)-1-[(1RS,2SR,4RS)-Bicyclo[2.2.1]hept-5-en-2-yl]-1-phenyl-3-(piperidin-1-yl)propan-1-ol hydrochloride.
Content
99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Slightly soluble in water and in ethanol (96 per cent), very slightly soluble in methylene chloride.
mp
About 280 °C, with decomposition.
IDENTIFICATION
First identification: A, D.
Second identification: B, C, D.
A. Infrared absorption spectrophotometry (2.2.24).
Comparison biperiden hydrochloride CRS.
B. Thin-layer chromatography (2.2.27).
Test solution Dissolve 25 mg of the substance to be examined in methanol R and dilute to 5 mL with the same solvent. Reference solution (a) Dissolve 25 mg of biperiden hydrochloride CRS in methanol R and dilute to 5 mL with the same solvent.
Reference solution (b) Dissolve 5 mg of biperiden impurity A CRS in reference solution (a) and dilute to 2 mL with the same solution.
Plate TLC silica gel F254 plate R.
Mobile phase diethylamine R, methanol R, toluene R (1:1:20 V/V/V).
Application 5 μL.
Development Over a path of 15 cm.
Drying In air.
Detection A Examine in ultraviolet light at 254 nm.
Results A 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).
Detection B Spray with dilute potassium iodobismuthate solution R and then with sodium nitrite solution R and examine in daylight.
Results B The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with reference solution (a).
System suitability Reference solution (b):
— the chromatogram shows 2 clearly separated spots.
C. To about 20 mg add 5 mL of phosphoric acid R. A green colour develops.
D. It gives reaction (a) of chlorides (2.3.1).
TESTS
Solution S
Dissolve 0.10 g in carbon dioxide-free water R, heating gently if necessary, and dilute to 50 mL with the same solvent.
Appearance of solution
Solution S is not more opalescent than reference suspension II (2.2.1) and is colourless (2.2.2, Method II).
pH (2.2.3)
5.0 to 6.5 for solution S.
Related substances
Gas chromatography (2.2.28).
Test solution Dissolve 0.10 g of the substance to be examined in methanol R and dilute to 10 mL with the same solvent.
Reference solution (a) Dilute 0.5 mL of the test solution to 100 mL with methanol R. Dilute 10 mL of this solution to 50 mL with methanol R.
Reference solution (b) Dissolve 5 mg of the substance to be examined and 5 mg of biperiden impurity A CRS in methanol R and dilute to 5 mL with the same solvent. Dilute 1 mL of the solution to 10 mL with methanol R.
Column:
— material: fused silica;
— size: l = 50 m, Ø = 0.25 mm;
— stationary phase: phenyl(5)methyl(95)polysiloxane R (film thickness 0.25 μm).
Carrier gas nitrogen for chromatography R.
Flow rate 0.4 mL/min.
Split ratio 1:250.
Temperature:
| Time (min) |
Temperature (°C) |
|
| Column | 0 – 5 | 200 |
| 5 – 40 | 200 → 270 | |
| Injection port | 250 | |
| Detector | 300 |
Detection Flame ionisation.
Injection 2 μL.
Run time Twice the retention time of biperiden.
Relative retention With reference to biperiden: impurities A, B and C = between 0.95 and 1.05.
System suitability:
— resolution: minimum 2.5 between the peak due to biperiden (1 peak) and the peak due to impurity A (2 peak) in the chromatogram obtained with reference solution (b);
— signal-to-noise ratio: minimum 6 for the principal peak in the chromatogram obtained with reference solution (a).
Limits:
— impurities A, B, C: for each impurity, maximum 0.50 per cent of the area of the principal peak;
— any other impurity: for each impurity, maximum 0.10 per cent of the area of the principal peak;
— total of impurities A, B and C: maximum 1.0 per cent of the area of the principal peak;
— total of impurities other than A, B and C: maximum 0.50 per cent of the area of the principal peak;
— disregard limit: 0.05 per cent of the area of the principal peak.
Impurity F (2.4.24)
Maximum 2 ppm.
st nd
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C for 2 h.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.200 g in 60 mL of ethanol (96 per cent) R. In a closed vessel, titrate with 0.1 M alcoholic potassium hydroxide, determining the end-point potentiometrically (2.2.20).
1 mL of 0.1 M alcoholic potassium hydroxide is equivalent to 34.79 mg of C21H30ClNO.
STORAGE
In an airtight container, protected from light.
IMPURITIES
Specified impurities A, B, C, 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) D, E.
A. (1RS)-1-[(1SR,2SR,4SR)-bicyclo[2.2.1]hept-5-en-2-yl]-1-phenyl-3-(piperidin-1-yl)propan-1-ol (endo form),
B. (1RS)-1-[(1SR,2RS,4SR)-bicyclo[2.2.1]hept-5-en-2-yl]-1-phenyl-3-(piperidin-1-yl)propan-1-ol,
C. (1RS)-1-[(1RS,2RS,4RS)-bicyclo[2.2.1]hept-5-en-2-yl]-1-phenyl-3-(piperidin-1-yl)propan-1-ol,
D. 1-[(1RS,2SR,4RS)-bicyclo[2.2.1]hept-5-en-2-yl]-3-(piperidin-1-yl)propan-1-one,
E. 1-[(1RS,2RS,4RS)-bicyclo[2.2.1]hept-5-en-2-yl]-3-(piperidin-1-yl)propan-1-one,
F. benzene.
