(Ph. Eur. monograph 2768)
C27H29F3O6S 538.6 397864-44-7
Action and use
Glucocorticoid.
DEFINITION
6α,9-Difluoro-17β-[[(fluoromethyl)sulfanyl]carbonyl]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl furan-2- carboxylate.
Content
98.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance
White or almost white powder.
Solubility
Practically insoluble in water, slightly soluble to practically insoluble in anhydrous ethanol, practically insoluble in heptane.
IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
Comparison: fluticasone furoate CRS.
TESTS
Related substances
A. Liquid chromatography (2.2.29). Protect the solutions from light.
Solvent mixture acetonitrile R, water R (50:50 V/V).
Test solution: Dissolve 25.0 mg of the substance to be examined in 50 mL of acetonitrile R using sonication until complete dissolution, add about 48 mL of water R, mix, allow to equilibrate at room temperature and dilute to 100.0 mL with water R.
Reference solution (a): Dissolve 25.0 mg of fluticasone furoate CRS in 50 mL of acetonitrile R using sonication until complete dissolution, add about 48 mL of water R, mix, allow to equilibrate at room temperature and dilute to 100.0 mL with water R.
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): Dissolve 2.5 mg of fluticasone furoate for peak identification CRS (containing impurities A, B and K) in 5 mL of acetonitrile R using sonication until complete dissolution and dilute to 10 mL with water R.
Reference solution (d): Dissolve 2.5 mg of fluticasone furoate for system suitability CRS (containing impurity F) in 5 mL of acetonitrile R using sonication until complete dissolution and dilute to 10 mL with water R.
Column:
— size: l = 0.15 m, Ø = 4.6 mm;
— stationary phase: octylsilyl silica gel for chromatography R (3.5 μm);
— temperature: 50 °C.
Mobile phase:
— mobile phase A: methanol R1, acetonitrile for chromatography R, 0.1 per cent V/V solution of trifluoroacetic acid R (10:30:60 V/V/V);
— mobile phase B: methanol R1, acetonitrile for chromatography R (25:75 V/V);
| Time
(min) |
Mobile phase A
(per cent V/V) |
Mobile phase B
(per cent V/V) |
| 0 – 2 | 100 | 0 |
| 2 – 32 | 100 → 33 | 0 → 67 |
Flow rate: 1.5 mL/min.
Detection: Spectrophotometer at 245 nm.
Injection: 10 μL of the test solution and reference solutions (b), (c) and (d).
Identification of impurities: Use chromatogram A supplied with fluticasone furoate for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peaks due to impurities A, B and K; use chromatogram A supplied with fluticasone furoate for system suitability CRS and the chromatogram obtained with reference solution (d) to identify the peak due to impurity F.
Relative retention: With reference to fluticasone furoate (retention time = about 15 min): impurity A = about 0.6; impurity B = about 0.8; impurities E, F and G = about 1.1; impurity K = about 1.3.
System suitability: Reference solution (d):
— resolution: minimum 4.0 between the peaks due to fluticasone furoate and impurity F.
Calculation of percentage contents:
— correction factors: multiply the peak areas of the following impurities by the corresponding correction factor: impurity B = 1.6; impurity K = 1.7;
— for each impurity, use the concentration of fluticasone furoate in reference solution (b).
Limits:
— impurity K: maximum 0.3 per cent;
— impurities A, B: for each impurity, maximum 0.15 per cent;
— sum of impurities E, F and G: maximum 0.15 per cent;
— unspecified impurities: for each impurity, maximum 0.10 per cent;
— total: maximum 1.0 per cent;
— reporting threshold: 0.05 per cent.
B. Perform test B only in cases where, in test A, any peak with a relative retention of about 1.1 and/or 1.16 exceeds the prescribed limits.
Liquid chromatography (2.2.29) as described in test A for related substances with the following modifications.
Column:
— temperature: 55 °C.
Mobile phase: Mix 18 volumes of tetrahydrofuran R, 28 volumes of methanol R1 and 54 volumes of water for chromatography R and add 0.05 volumes of trifluoroacetic acid R.
Flow rate: 1.3 mL/min.
Run time: 3.5 times the retention time of fluticasone furoate.
Identification of impurities: Use chromatogram B supplied with fluticasone furoate for peak identification CRS and thechromatogram obtained with reference solution (c) to identify the peaks due to impurities A, B and K; use chromatogram B supplied with fluticasone furoate for system suitability CRS and the chromatogram obtained with reference solution (d) to
identify the peak due to impurity F. Relative retention With reference to fluticasone furoate (retention time = about 14 min): impurity F = about 1.1.
System suitability: Reference solution (d):
— resolution: minimum 2.0 between the peaks due to fluticasone furoate and impurity F.
Calculation of percentage contents:
— for each impurity, use the concentration of fluticasone furoate in reference solution (b).
Limits:
— any impurity: for each impurity, maximum 0.10 per cent;
— reporting threshold: 0.05 per cent; disregard the peaks due to impurities A, B and K.
Water (2.5.32)
Maximum 0.2 per cent, determined on 0.100 g using the evaporation technique at 110 °C.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g in a platinum crucible.
ASSAY
Liquid chromatography (2.2.29) as described in test A for related substances with the following modification
Injection: Test solution and reference solution (a).
Calculate the percentage content of C27H29F3O6S taking into account the assigned content of fluticasone furoate CRS.
STORAGE
Protected from light.
IMPURITIES
Specified impurities A, B, E, F, G, K.
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) H, I, J, L.
A. 6α,9-difluoro-17α-[(furan-2-carbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid,
B. 6α,9-difluoro-17β-[[(fluoromethyl)sulfanyl]carbonyl]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl acetate (fluticasone propionate impurity C),
E. 9-fluoro-17β-[[(fluoromethyl)sulfanyl]carbonyl]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl furan-2-carboxylate,
F. propan-2-yl 6α,9-difluoro-17α-[(furan-2-carbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate,
G. 9-chloro-6α-fluoro-17β-[[(fluoromethyl)sulfanyl]carbonyl]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-ylfuran-2-carboxylate,
H. 6α-chloro-9-fluoro-17β-[[(fluoromethyl)sulfanyl]carbonyl]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl furan-2-carboxylate,
I. 6α,9-difluoro-17β-[(fluoromethoxy)carbonothioyl]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl furan-2-carboxylate,
J. 6α,9-difluoro-17β-[[(fluoromethyl)sulfanyl]carbonyl]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl 5-chlorofuran-2-carboxylate,
K. 6α,9-difluoro-17β-[[(fluoromethyl)sulfanyl]carbonyl]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl 6α,9-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate (fluticasone propionate impurity G),
L. 6α,9-difluoro-17α-[(furan-2-carbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic 6α,9-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17β-carboxylic dithioperoxyanhydride.
