(Ph. Eur. monograph 0636)
C14H18N2O 230.3 479-92-5
Action and use
Pyrazolone analgesic.
DEFINITION
1,5-Dimethyl-2-phenyl-4-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one.
Content
99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or slightly yellowish, crystalline powder.
Solubility
Slightly soluble in water, freely soluble in ethanol (96 per cent) and in methylene chloride.
IDENTIFICATION
First identification: A, B.
Second identification: A, C, D.
A. Melting point (2.2.14): 102 °C to 106 °C.
B. Infrared absorption spectrophotometry (2.2.24).
Comparison: propyphenazone CRS.
C. Thin-layer chromatography (2.2.27).
Test solution: Dissolve 80 mg of the substance to be examined in methanol R and dilute to 5 mL with the same solvent.
Reference solution: Dissolve 80 mg of propyphenazone CRS in methanol R and dilute to 5 mL with the same solvent.
Plate: TLC silica gel F254 plate R.
Mobile phase: butanol R, cyclohexane R, ethyl acetate R (10:45:45 V/V/V).
Application: 5 μL.
Development: Over 2/3 of the plate.ư
Drying: In a current of hot air for 15 min.
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.
D. To 1 mL of solution S (see Tests) add 0.1 mL of ferric chloride solution R1. A brownish-red colour appears which becomes yellow on addition of 1 mL of dilute hydrochloric acid R.
TESTS
Solution S
Dissolve 2 g in a mixture of equal volumes of carbon dioxide-free water R and ethanol (96 per cent) R and dilute to 50 mL with the same mixture of solvents.
Appearance of solution
Solution S is clear (2.2.1) and colourless (2.2.2, Method II).
Acidity or alkalinity
To 10 mL of solution S add 0.1 mL of phenolphthalein solution R. The solution is colourless. Add 0.2 mL of a 0.40 g/L solution of sodium hydroxide R; the solution becomes pink. Add 0.4 mL of a 1.03 g/L solution of hydrochloric acid R; the solution becomes colourless. Add 0.2 mL of methyl red solution R; the solution becomes orange or red.
Related substances
Liquid chromatography (2.2.29).
Test solution: Dissolve 20.0 mg of the substance to be examined in the mobile phase and dilute to 20.0 mL with the mobile phase.
Reference solution (a): 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 (b): Dissolve 1 mg of phenazone R (impurity A) in the mobile phase, add 1 mL of the test solution and dilute to 10 mL with the mobile phase.
Column:
— size: l = 0.25 m, Ø = 4.0 mm;
— stationary phase: end-capped octylsilyl silica gel for chromatography R (5 μm).
Mobile phase: Dissolve 13.7 g of potassium dihydrogen phosphate R in 900 mL of water for chromatography R, adjust to pH 5.2 with dilute sodium hydroxide solution R and dilute to 1000 mL with water for chromatography R. Mix 60 volumes of the solution and 40 volumes of acetonitrile R1.
Flow rate: 1.2 mL/min.
Detection: Spectrophotometer at 210 nm.
Injection: 20 μL.
Run time: 4 times the retention time of propyphenazone.
Identification of impurities: Use the chromatogram obtained with reference solution (b) to identify the peak due to impurity A.
Relative retention: With reference to propyphenazone (retention time = about 7 min): impurity A = about 0.4.
System suitability: Reference solution (b):
— resolution: minimum 4.0 between the peaks due to impurity A and propyphenazone.
Limits:
— unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent);
— total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);
— disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent).
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on 1.000 g by drying in vacuo at 60 °C for 4 h.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 0.5 g.
ASSAY
Dissolve 0.175 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 23.03 mg of C14H18N2O .
STORAGE
Protected from light.
IMPURITIES
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) A, B, C.
A. 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (phenazone),
B. 5-methoxy-3-methyl-1-phenyl-4-(propan-2-yl)-1H-pyrazole,
C. 1,5-dimethyl-4-[(2RS)-4-methylpentan-2-yl]-2-phenyl-1,2-dihydro-3H-pyrazol-3-one.
