Adapalene

(Ph. Eur. monograph 2445)

C₂₈H₂₈O₃    412.5    106685-40-9

Vitamin A analogue (retinoid); treatment of acne.

Ph Eur

6-(4-Methoxy-3-tricyclo[3.3.1.1^3,7]dec-1-ylphenyl)naphthalene-2-carboxylic acid.

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

White or almost white powder.

Practically insoluble in water, sparingly soluble in tetrahydrofuran, practically insoluble in ethanol (96 per cent).

Infrared absorption spectrophotometry (2.2.24).

Comparison  adapalene CRS.

The solution is clear (2.2.1) and not more intensely coloured than reference solution BY₆ (2.2.2, Method II).

Dissolve 0.2 g in tetrahydrofuran R and dilute to 20 mL with the same solvent.

Liquid chromatography (2.2.29).

Solvent mixture  tetrahydrofuran R, acetonitrile R, water R (20:37:43 V/V/V).

Test solution (a)  Dissolve 40.0 mg of the substance to be examined in 10 mL of tetrahydrofuran R, add 7 mL of the solvent mixture and dilute to 20.0 mL with tetrahydrofuran R.

Test solution (b)  Dissolve 20.0 mg of the substance to be examined in 50 mL of tetrahydrofuran R, add 35 mL of the solvent mixture and dilute to 100.0 mL with tetrahydrofuran R. Dilute 5.0 mL of the solution to 50.0 mL with the solvent mixture.

Reference solution (a)  Dilute 1.0 mL of test solution (a) to 10.0 mL with tetrahydrofuran R. Dilute 1.0 mL of this solution to 100.0 mL with the solvent mixture.

Reference solution (b)  Dissolve 2.4 mg of adapalene impurity C CRS in 2 mL of tetrahydrofuran R and dilute to 20.0 mL with the same solvent. Dilute 2.0 mL of the solution to 20.0 mL with the solvent mixture. To 2.0 mL of this solution add 2.0 mL of reference solution (a) and dilute to 20.0 mL with the solvent mixture.

Reference solution (c)  Dissolve the contents of a vial of adapalene for peak identification CRS (containing impurities A, C and D) in 0.5 mL of tetrahydrofuran R and dilute to 1.0 mL with the solvent mixture.

Reference solution (d)  Dissolve 20.0 mg of adapalene CRS in 50 mL of tetrahydrofuran R, add 35 mL of the solvent mixture and dilute to 100.0 mL with tetrahydrofuran R. Dilute 5.0 mL of the solution to 50.0 mL with the solvent mixture.

• — size: l = 0.25 m, Ø = 4.6 mm;

• — stationary phase:end-capped phenylsilyl silica gel for chromatography R (5 µm) with a carbon loading of 7.5 per cent;

• — temperature: 30 °C.

• — mobile phase A:glacial acetic acid R, water R (0.1:100 V/V);

• — mobile phase B:tetrahydrofuran R, acetonitrile R (35:65 V/V);

Flow rate  1.2 mL/min.

Detection  Spectrophotometer at 270 nm.

Injection  25 µL of test solution (a) and reference solutions (a), (b) and (c).

Identification of impurities  Use the chromatogram supplied with adapalene for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peaks due to impurities A, C and D.

Relative retention  With reference to adapalene (retention time = about 20 min): impurity A = about 0.3; impurity C = about 0.9; impurity D = about 1.9.

System suitability  Reference solution (b):

• — resolution: minimum 4.5 between the peaks due to impurity C and adapalene;

• — signal-to-noise ratio: minimum 10 for the peak due to impurity C.

• — correction factors: for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor: impurity A = 0.7; impurity C = 7; impurity D = 1.4;

• — impurity A: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent);

• — impurity D: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);

• — impurity C: 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 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).

Maximum 20 ppm.

0.250 g complies with test G. Prepare the reference solution using 0.5 mL of lead standard solution (10 ppm Pb) R.

Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C for 4 h.

Maximum 0.1 per cent, determined on 1.0 g.

Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.

Injection  Test solution (b) and reference solution (d).

Calculate the percentage content of adapalene from the declared content of adapalene CRS.

Specified impurities  A, C, D.

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.

A. 2,2′-binaphthalene-6,6′-dicarboxylic acid,

B. 6-[3-(3-hydroxytricyclo[3.3.1.1^3,7]dec-1-yl)-4-methoxyphenyl]naphthalene-2-carboxylic acid,

C. 1-(2-methoxyphenyl)tricyclo[3.3.1.1^3,7]decane,

D. 1,1′-[4,4′-bis(methoxy)biphenyl-3,3′-diyl]bis(tricyclo[3.3.1.1^3,7]decane).

Ph Eur