Clobetasone Butyrate

(Ph. Eur. monograph 1090)

C₂₆H₃₂ClFO₅    479.0    25122-57-0

Glucocorticoid.

Clobetasone Cream

Clobetasone Ointment

Ph Eur

21-Chloro-9-fluoro-16β-methyl-3,11,20-trioxopregna-1,4-dien-17-yl butanoate.

97.0 per cent to 102.0 per cent (dried substance).

White or almost white powder.

Practically insoluble in water, freely soluble in acetone and in methylene chloride, slightly soluble in ethanol (96 per cent).

About 178 °C.

Infrared absorption spectrophotometry (2.2.24).

Comparison   clobetasone butyrate CRS.

+ 131 to + 138 (dried substance).

Dissolve 0.250 g in ethanol R1 and dilute to 25.0 mL with the same solvent.

Liquid chromatography (2.2.29). Prepare the solutions immediately before use.

Solvent mixture  anhydrous formic acid R, acetonitrile R, water R (0.1:43:57 V/V/V).

Test solution  Dissolve 65 mg of the substance to be examined in 5.0 mL of acetonitrile R and dilute to 25.0 mL with the solvent mixture.

Reference solution (a)  Dissolve 13 mg of clobetasone butyrate for system suitability CRS (containing impurity F) in 1 mL of acetonitrile R and dilute to 5.0 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.

• — size: l = 0.15 m, Ø = 4.6 mm;

• — stationary phase: end-capped octadecylsilyl silica gel for chromatography R (3.5 µm);

• — temperature: 40 °C.

• — mobile phase A: anhydrous formic acid R, water R (0.1:99.9 V/V);

• — mobile phase B: anhydrous formic acid R, acetonitrile R (0.1:99.9 V/V);

Flow rate  1.5 mL/min.

Detection  Spectrophotometer at 241 nm.

Injection  10 µL.

Identification of impurities  Use the chromatogram supplied with clobetasone butyrate for system suitability CRS and the chromatogram obtained with reference solution (a) to identify the peak due to impurity F.

Relative retention  With reference to clobetasone butyrate (retention time = about 14 min): impurity F = about 0.9.

• — resolution: minimum 3.5 between the peaks due to impurity F and clobetasone butyrate in the chromatogram obtained with reference solution (a);

• — signal-to-noise ratio: minimum 10 for the principal peak in the chromatogram obtained with reference solution (b).

• — 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: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.5 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).

Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C.

Dissolve 20.0 mg in ethanol (96 per cent) R and dilute to 100.0 mL with the same solvent. Dilute 5.0 mL of the solution to 50.0 mL with ethanol (96 per cent) R. Measure the absorbance (2.2.25) at the absorption maximum at 235 nm.

Calculate the content of C₂₆H₃₂ClFO₅, taking the specific absorbance to be 327.

Protected from light.

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, C, D, E, F, G, H, I.

A. R1 = H, R2 = Cl: 21-chloro-9-fluoro-17-hydroxy-16β-methylpregna-1,4-diene-3,11,20-trione (clobetasone),

G. R1 = CO-CH₂-CH₂-CH₃, R2 = O-CO-CH₂-CH₃: 9-fluoro-16β-methyl-3,11,20-trioxo-21-(propanoyloxy)pregna-1,4-dien-17-yl butanoate,

H. R1 = CO-CH₂-CH₃, R2 = Cl: 21-chloro-9-fluoro-16β-methyl-3,11,20-trioxopregna-1,4-dien-17-yl propanoate (17-O-propionyl clobetasone),

I. R1 = CO-CH(CH₃)₂, R2 = Cl: 21-chloro-9-fluoro-16β-methyl-3,11,20-trioxopregna-1,4-dien-17-yl 2-methylpropanoate (17-O-isobutyryl clobetasone),

C. 21-chloro-9-fluoro-16β-methyl-3,11,20-trioxopregn-1-en-17-yl butanoate (4,5-dihydroclobetasone butyrate),

D. R = Br: 2α-bromo-21-chloro-9-fluoro-16β-methyl-3,11,20-trioxopregn-1-en-17-yl butanoate (2-bromoclobetasone butyrate),

E. R = H: 21-chloro-9-fluoro-16β-methyl-3,11,20-trioxopregn-4-en-17-yl butanoate (1,2-dihydroclobetasone butyrate),

F. 21-chloro-9-fluoro-16α-methyl-3,11,20-trioxopregna-1,4-dien-17-yl butanoate (16α-methyl clobetasone butyrate).

Ph Eur