(Ph. Eur. monograph 1357)
C20H24N2O4 356.4 132-20-7
Action and use
Histamine H1 receptor antagonist; antihistamine.
DEFINITION
(3RS)-N,N-Dimethyl-3-phenyl-3-(pyridin-2-yl)propan-1-amine (Z)-butenedioate.
Content
99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Very soluble in water, freely soluble in ethanol (96 per cent), in methanol and in methylene chloride.
IDENTIFICATION
First identification: C.
Second identification: A, B, D.
A. Melting point (2.2.14): 106 °C to 109 °C.
B. Ultraviolet and visible absorption spectrophotometry (2.2.25).
Test solution: Dissolve 40.0 mg in 0.1 M hydrochloric acid and dilute to 100.0 mL with the same acid. Dilute 5.0 mL of the solution to 50.0 mL with 0.1 M hydrochloric acid.
Spectral range: 220-320 nm.
Absorption maximum: At 265 nm.
Shoulder: At 261 nm.
Specific absorbance at the absorption maximum 200 to 220.
C. Infrared absorption spectrophotometry (2.2.24).
Comparison: pheniramine maleate CRS.
D. Thin-layer chromatography (2.2.27).
Test solution: Dissolve 0.10 g of the substance to be examined in methanol R and dilute to 5.0 mL with the same solvent.
Reference solution (a): Dissolve 65 mg of maleic acid R in methanol R and dilute to 10 mL with the same solvent.
Reference solution (b): Dissolve 0.10 g of pheniramine maleate CRS in methanol R and dilute to 5.0 mL with the same solvent.
Plate: TLC silica gel F254 plate R.
Mobile phase: water R, anhydrous formic acid R, methanol R, di-isopropyl ether R (3:7:20:70 V/V/V/V).
Application: 5 μL.
Development: Over 2/3 of the plate.
Detection: Examine in ultraviolet light at 254 nm.
Results: The chromatogram obtained with the test solution shows 2 clearly separated spots; the upper spot is similar in position and size to the spot in the chromatogram obtained with reference solution (a); the lower spot is similar in position and size to the lower spot in the chromatogram obtained with reference solution (b).
TESTS
Solution S
Dissolve 2.0 g in water R and dilute to 20.0 mL with the same solvent.
Appearance of solution
Solution S is clear (2.2.1) and not more intensely coloured than reference solution BY6 (2.2.2, Method II).
pH (2.2.3)
4.5 to 5.5.
Dissolve 0.20 g in 20 mL of carbon dioxide-free water R.
Related substances
Liquid chromatography (2.2.29).
Solvent mixture acetonitrile R, mobile phase A (10:90 V/V).
Test solution: Dissolve 20.0 mg of the substance to be examined in the solvent mixture and dilute to 20.0 mL with the solvent mixture.
Reference solution (a): Dissolve 10.0 mg of pheniramine impurity A CRS and 10 mg of 4-benzylpyridine R (impurity B) in 10.0 mL of the solvent mixture and dilute to 100.0 mL with the solvent mixture.
Reference solution (b): Dilute 1.0 mL of the test solution to 100.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture.
Reference solution (c): Dilute 1.0 mL of reference solution (a) to 50.0 mL with the solvent mixture.
Reference solution (d): Dilute 1.0 mL of the test solution to 10.0 mL with reference solution (a). Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture.
Column:
— size: l = 0.30 m, Ø = 3.9 mm;
— stationary phase: octadecylsilyl silica gel for chromatography R (10 μm).
Mobile phase:
— mobile phase A: dissolve 5.056 g of sodium heptanesulfonate R in 900 mL of water R, adjust to pH 2.5 with dilute phosphoric acid R and dilute to 1000 mL with water R;
— mobile phase B: acetonitrile R;
| Time (min) |
Mobile phase A (per cent V/V) |
Mobile phase B (per cent V/V) |
| 0 – 2 | 90 | 10 |
| 2 – 37 | 90 → 62 | 10 → 38 |
Flow rate: 1 mL/min.
Detection:Spectrophotometer at 264 nm.
Injection: 20 μL.
Identification of impurities: Use the chromatogram obtained with reference solution (a) to identify the peaks due to impurities A and B.
Relative retention: With reference to pheniramine (retention time = about 31 min): maleic acid = about 0.1; impurity A = about 0.9; impurity B = about 0.97.
System suitability: Reference solution (d):
— resolution: minimum 1.5 between the peaks due to impurity B and pheniramine.
Limits:
— impurity A: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (c) (0.2 per cent);
— impurity B: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent);
— unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);
— total: maximum 1.0 per cent;
— disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent); disregard the peak due to maleic acid.
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on 1.000 g by drying in vacuo at 60 °C for 3 h.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.130 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 17.82 mg of C20H24N2O4.
STORAGE
Protected from light.
IMPURITIES
Specified impurities A, B.
A. 2-benzylpyridine,
B. 4-benzylpyridine.
