Edition: BP 2025 (Ph. Eur. 11.6 update)
Action and use
Selective oestrogen receptor modulator.
DEFINITION
[6-Hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-[2-(piperidin-1-yl)ethoxy]phenyl]methanone hydrochloride.Content
97.5 per cent to 102.0 per cent (dried substance).
CHARACTERS
Appearance
Almost white or pale-yellow powder.
Solubility
Very slightly soluble or practically insoluble in water and in acetone, slightly soluble in ethanol (96 per cent V/V).
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
Comparison raloxifene hydrochloride CRS.
B. Dissolve 20 mg of the substance to be examined in 2 mL of methanol R. The solution gives reaction (a) of chlorides (2.3.1).
TESTS
Related substances
Liquid chromatography (2.2.29).
Solvent mixture acetonitrile R, mobile phase A (30:70 V/V).
Test solution Dissolve 30 mg of the substance to be examined in the solvent mixture and dilute to 10.0 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) In order to produce impurity C in situ, to 6 mg of the substance to be examined add 15 mL of acetonitrile R, 3 mL of water R and 5 mL of stabilised strong hydrogen peroxide solution R. Store at 30 °C for at least 6 h then dilute to 50.0 mL with mobile phase A. To 1.0 mL of this solution add 3 mg of the substance to be examined dissolved in the solvent mixture and dilute to 10.0 mL with the solvent mixture.
Reference solution (c) Dissolve 3 mg of raloxifene for peak identification CRS (containing impurity A) in the solvent mixture and dilute to 10.0 mL with the solvent mixture.
Column:
— size: l = 0.25 m, Ø = 4.6 mm;
— stationary phase: base-deactivated octylsilyl silica gel for chromatography R (5 µm);
— temperature: 35 °C.
Mobile phase:
— mobile phase A: 9.0 g/L solution of potassium dihydrogen phosphate R adjusted to pH 3.0 with phosphoric acid R;
— mobile phase B: acetonitrile R;
| Time (min) | Mobile phase A (per cent V/V) | Mobile phase B (per cent V/V) |
| 0 – 9 | 75 | 25 |
| 9 – 40 | 75 → 50 | 25 → 50 |
Flow rate 1.0 mL/min.
Detection Spectrophotometer at 280 nm.
Injection 10 µL.
Identification of impurity A Use the chromatogram supplied with raloxifene for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peak due to impurity A.
Relative retention With reference to raloxifene (retention time = about 18 min): impurity A = about 0.7; impurity C = about 1.2.
System suitability Reference solution (b):
— resolution: minimum 3.0 between the peaks due to raloxifene and impurity C.
Limits:
— impurity A: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (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 (a) (0.10 per cent);
— total: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5 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 an oven at 105 °C for 3 h.
Sulfated ash (2.4.14)
Maximum 0.1 per cent determined on 1.0 g.
ASSAY
Liquid chromatography (2.2.29).
Buffer solution pH 2.5 7.2 g/L solution of potassium dihydrogen phosphate R adjusted to pH 2.5 with phosphoric acid R.
Test solution Dissolve 50.0 mg of the substance to be examined in the mobile phase and dilute to 100.0 mL with the mobile phase. Dilute 5.0 mL of this solution to 50.0 mL with the mobile phase.
Reference solution (a) Dissolve 50.0 mg of raloxifene hydrochloride CRS in the mobile phase and dilute to 100.0 mL with the mobile phase. Dilute 5.0 mL of this solution to 50.0 mL with the mobile phase.
Reference solution (b) In order to produce impurity C in situ, to 6 mg of the substance to be examined add 15 mL of acetonitrile R, 3 mL of water R and 5 mL of stabilised strong hydrogen peroxide solution R. Store at 30 °C for at least 6 h, then dilute to 50.0 mL with buffer solution pH 2.5.
Column:
— size: l = 0.15 m, Ø = 4.6 mm;
— stationary phase: octylsilyl silica gel for chromatography R2 (3.5 µm);
— temperature: 35 °C.
Mobile phase acetonitrile R, buffer solution pH 2.5 (33:67 V/V). Flow rate 1.5 mL/min.
Detection Spectrophotometer at 280 nm.
Injection 10 µL.
Run time Twice the retention time of raloxifene.
Relative retention With reference to raloxifene (retention time = about 3 min): impurity C = about 1.2.
System suitability Reference solution (b):
— resolution: minimum 2.0 between the peaks due to raloxifene and impurity C; if necessary, adjust the concentration of acetonitrile in the mobile phase.
Calculate the percentage content of C28H28ClNO4S taking into account the assigned content of raloxifene hydrochloride CRS.
IMPURITIES
Specified impurities A.
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.
A. [6-hydroxy-2-(4-hydroxyphenyl)-7-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-1-benzothiophen-3-yl][4-[2-(piperidin-1- yl)ethoxy]phenyl]methanone,
B. [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-7-yl][4-[2-(piperidin-1-yl)ethoxy]phenyl]methanone,
C. [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-[2-(piperidin-1-yl)ethoxy]phenyl]methanone N-oxide.
