(Ketotifen Hydrogen Fumarate, Ph. Eur. monograph 1592)
C23H23NO5S 425.5 34580-14-8
Action and use
Histamine H1 receptor antagonist.
DEFINITION
4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one hydrogen (E)- butenedioate.
Content
98.5 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or brownish-yellow, fine, crystalline powder.
Solubility
Sparingly soluble in water, slightly soluble in methanol, practically insoluble in heptane.
IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
Comparison: ketotifen hydrogen fumarate CRS.
TESTS
Appearance of solution
The solution is clear (2.2.1) and not more intensely coloured than reference solution Y4, BY4 or B4 (2.2.2, Method II).
Dissolve 0.2 g in methanol R and dilute to 10 mL with the same solvent.
Related substances
Liquid chromatography (2.2.29). Carry out the test protected from light.
Solvent mixture: methanol R, water R (50:50 V/V).
Test solution: Dissolve 30.0 mg of the substance to be examined in the solvent mixture and dilute to 100.0 mL with the solvent mixture.
Reference solution (a): 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 (b): Dissolve the contents of a vial of ketotifen impurity G CRS in 1.0 mL of a solution prepared as follows: mix 1.0 mL of the test solution with 9.0 mL of the solvent mixture. Sonicate until dissolution of impurity G is complete.
Reference solution (c): Dissolve 5 mg of ketotifen for peak identification CRS (containing impurity A) in the solvent mixture and dilute to 5.0 mL with the solvent mixture.
Column:
— size: l = 0.15 m, Ø = 4.0 mm;
— stationary phase: base-deactivated end-capped octadecylsilyl silica gel for chromatography R (3 μm);
— temperature: 40 °C.
Mobile phase:
— mobile phase A: mix 175 μL of triethylamine R and 500 mL of water R;
— mobile phase B: mix 175 μL of triethylamine R and 500 mL of methanol R;
| Time (min) |
Mobile phase A (per cent V/V) |
Mobile phase B (per cent V/V) |
| 0 – 12 | 40 | 60 |
| 12 – 20 | 40 → 10 | 60 → 90 |
| 20 – 25 | 10 | 90 |
Flow rate: 1.0 mL/min.
Detection: Spectrophotometer at 297 nm.
Injection: 20 μL.
Identification of impurities: Use the chromatogram supplied with ketotifen for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peak due to impurity A; use the chromatogram obtained with reference solution (b) to identify the peak due to impurity G.
Relative retention: With reference to ketotifen (retention time = about 11 min): fumaric acid = about 0.1; impurity G = about 0.8; impurity A = about 1.9.
System suitability: Reference solution (b):
— resolution: minimum 1.5 between the peaks due to impurity G and ketotifen.
Limits:
— correction factor: for the calculation of content, multiply the peak area of impurity G by 1.4;
— impurity A: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);
— impurity G: not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.15 per cent);
— 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 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 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); disregard the peak due to fumaric acid.
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 4 h.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.350 g in a mixture of 30 mL of acetic anhydride R and 30 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 42.55 mg of C23H23NO5S.
IMPURITIES
Specified impurities A, G.
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) B, C, D, E, F.
A. 4-(4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidine,
B. (4RS)-10-methoxy-4-(1-methylpiperidin-4-yl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol,
C. (4RS)-4-hydroxy-4-(1-methylpiperidin-4-yl)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10- one,
D. 4-[(RaSa)-1-methylpiperidin-4-ylidene]-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one N-oxide (ketotifen N-oxide),
E. 10-(1-methylpiperidin-4-ylidene)-5,10-dihydro-4H-benzo[5,6]cyclohepta[1,2-b]thiophen-4-one,
F. 4-(1-methylpiperidin-4-ylidene)-4,10-dihydro-9H-benzo[4,5]cyclohepta[1,2-b]thiophen-9-one,
G. 4-(1-methylpiperidin-4-ylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9,10-dione.
