Ibuprofen

(Ph. Eur. monograph 0721)

C₁₃H₁₈O₂    206.3    15687-27-1

Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.

Ibuprofen Cream

Ibuprofen Gel

Ibuprofen Oral Suspension

Ibuprofen Tablets

Prolonged-release Ibuprofen Capsules

Prolonged-release Ibuprofen Tablets

Ph Eur

(2RS)-2-[4-(2-Methylpropyl)phenyl]propanoic acid.

98.5 per cent to 101.0 per cent (dried substance).

White or almost white, crystalline powder or colourless crystals.

Practically insoluble in water, freely soluble in acetone, in methanol and in methylene chloride. It dissolves in dilute solutions of alkali hydroxides and carbonates.

First identification  A, C.

Second identification  A, B, D.

A. Melting point (2.2.14): 75 °C to 78 °C.

B. Ultraviolet and visible absorption spectrophotometry (2.2.25).

Test solution  Dissolve 50.0 mg in a 4 g/L solution of sodium hydroxide R and dilute to 100.0 mL with the same alkaline solution.

Spectral range  240-300 nm, using a spectrophotometer with a band width of 1.0 nm and a scan speed of not more than 50 nm/min.

Absorption maxima  At 264 nm and 272 nm.

Shoulder  At 258 nm.

• — A₂₆₄ / A₂₅₈ = 1.20 to 1.30;

• — A₂₇₂ / A₂₅₈ = 1.00 to 1.10.

C. Infrared absorption spectrophotometry (2.2.24).

Comparison  ibuprofen CRS.

D. Thin-layer chromatography (2.2.27).

Test solution  Dissolve 50 mg of the substance to be examined in methylene chloride R and dilute to 10 mL with the same solvent.

Reference solution  Dissolve 50 mg of ibuprofen CRS in methylene chloride R and dilute to 10 mL with the same solvent.

Plate  TLC silica gel plate R.

Mobile phase  anhydrous acetic acid R, ethyl acetate R, hexane R (5:24:71 V/V/V).

Application  5 µL.

Development  Over a path of 10 cm.

Drying  At 120 °C for 30 min.

Detection  Lightly spray with a 10 g/L solution of potassium permanganate R in dilute sulfuric acid R and heat at 120 °C for 20 min; examine in ultraviolet light at 365 nm.

Results  The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with the reference solution.

Dissolve 2.0 g in methanol R and dilute to 20 mL with the same solvent.

Solution S is clear (2.2.1) and colourless (2.2.2, Method II).

- 0.05° to + 0.05°.

Dissolve 0.50 g in methanol R and dilute to 20.0 mL with the same solvent.

Liquid chromatography (2.2.29).

Test solution  Dissolve 20 mg of the substance to be examined in 2 mL of acetonitrile R1 and dilute to 10.0 mL with mobile phase A.

Reference solution (a)  Dilute 1.0 mL of the test solution to 100.0 mL with mobile phase A. Dilute 1.0 mL of this solution to 10.0 mL with mobile phase A.

Reference solution (b)  Dilute 1.0 mL of ibuprofen impurity B CRS to 10.0 mL with acetonitrile R1 (solution A). Dissolve 20 mg of ibuprofen CRS in 2 mL of acetonitrile R1, add 1.0 mL of solution A and dilute to 10.0 mL with mobile phase A.

Reference solution (c)  Dissolve the contents of a vial of ibuprofen for peak identification CRS (mixture of impurities A, J and N) in 1 mL of acetonitrile R1 and dilute to 5 mL with mobile phase A.

• — size: l = 0.15 m, Ø = 4.6 mm;

• — stationary phase: octadecylsilyl silica gel for chromatography R (5 µm).

• — mobile phase A: mix 0.5 volumes of phosphoric acid R, 340 volumes of acetonitrile R1 and 600 volumes of water R; allow to equilibrate and dilute to 1000 volumes with water R;

• — mobile phase B: acetonitrile R1;

Flow rate  2 mL/min.

Detection  Spectrophotometer at 214 nm.

Injection  20 µL.

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

Relative retention  With reference to ibuprofen (retention time = about 21 min): impurity J = about 0.2; impurity N = about 0.3; impurity A = about 0.9; impurity B = about 1.1.

System suitability  Reference solution (b):

• — peak-to-valley ratio: minimum 1.5, where H_p = height above the baseline of the peak due to impurity B, and H_v = height above the baseline of the lowest point of the curve separating this peak from the peak due to ibuprofen. If necessary, adjust the concentration of acetonitrile in mobile phase A.

• — impurities A, J, N: for each impurity, 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 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent);

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

• — disregard limit: 0.3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.03 per cent).

Gas chromatography (2.2.28): use the normalisation procedure.

Methylating solution  Dilute 1 mL of N,N-dimethylformamide dimethylacetal R and 1 mL of pyridine R to 10 mL with ethyl acetate R.

Test solution  Weigh about 50.0 mg of the substance to be examined into a sealable vial, dissolve in 1.0 mL of ethyl acetate R, add 1 mL of the methylating solution, seal and heat at 100 °C in a block heater for 20 min. Allow to cool. Remove the reagents under a stream of nitrogen at room temperature. Dissolve the residue in 5 mL of ethyl acetate R.

Reference solution (a)  Dissolve 0.5 mg of ibuprofen impurity F CRS in ethyl acetate R and dilute to 10.0 mL with the same solvent.

Reference solution (b)  Weigh about 50.0 mg of ibuprofen CRS into a sealable vial, dissolve in 1.0 mL of reference solution (a), add 1 mL of the methylating solution, seal and heat at 100 °C in a block heater for 20 min. Allow to cool. Remove the reagents under a stream of nitrogen at room temperature. Dissolve the residue in 5 mL of ethyl acetate R.

• — material: fused silica;

• — size: l = 25 m, Ø = 0.53 mm;

• — stationary phase: macrogol 20 000 R (film thickness 2 µm).

Carrier gas  helium for chromatography R.

Flow rate  5.0 mL/min.

• — column: 150 °C;

• — injection port: 200 °C;

• — detector: 250 °C.

Detection  Flame ionisation.

Injection  1 µL of the test solution and reference solution (b).

Run time  Twice the retention time of ibuprofen.

• — relative retention with reference to ibuprofen (retention time = about 17 min): impurity F = about 1.5.

• — impurity F: maximum 0.1 per cent.

Maximum 10 ppm.

12 mL of solution S complies with test B. Prepare the reference solution using lead standard solution (1 ppm Pb) obtained by diluting lead standard solution (100 ppm Pb) R with methanol R.

Maximum 0.5 per cent, determined on 1.000 g by drying in vacuo.

Maximum 0.1 per cent, determined on 1.0 g.

Dissolve 0.450 g in 50 mL of methanol R. Add 0.4 mL of phenolphthalein solution R1. Titrate with 0.1 M sodium hydroxide until a red colour is obtained. Carry out a blank titration.

1 mL of 0.1 M sodium hydroxide is equivalent to 20.63 mg of C₁₃H₁₈O₂.

Specified impurities  A, F, J, N.

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, G, H, I, K, L, M, O, P, Q, R.

A. R1 = OH, R2 = CH₂-CH(CH₃)₂, R3 = H: (2RS)-2-[3-(2-methylpropyl)phenyl]propanoic acid,

B. R1 = OH, R2 = H, R3 = [CH₂]₃-CH₃: (2RS)-2-(4-butylphenyl)propanoic acid,

C. R1 = NH₂, R2 = H, R3 = CH₂-CH(CH₃)₂: (2RS)-2-[4-(2-methylpropyl)phenyl]propanamide,

D. R1 = OH, R2 = H, R3 = CH₃: (2RS)-2-(4-methylphenyl)propanoic acid,

E. 1-[4-(2-methylpropyl)phenyl]ethanone,

F. 3-[4-(2-methylpropyl)phenyl]propanoic acid,

G. (1RS,4RS)-7-(2-methylpropyl)-1-[4-(2-methylpropyl)phenyl]-1,2,3,4-tetrahydronaphthalene-1,4-dicarboxylic acid,

H. X = O: (3RS)-1,3-bis[4-(2-methylpropyl)phenyl]butan-1-one,

I. X = H2: 1-(2-methylpropyl)-4-[(3RS)-3-[4-(2-methylpropyl)phenyl]butyl]benzene,

J. R = CO-CH(CH₃)₂: (2RS)-2-[4-(2-methylpropanoyl)phenyl]propanoic acid,

N. R = C₂H₅: (2RS)-2-(4-ethylphenyl)propanoic acid,

K. R = CHO: (2RS)-2-(4-formylphenyl)propanoic acid,

L. R = CHOH-CH(CH₃)₂: 2-[4-(1-hydroxy-2-methylpropyl)phenyl]propanoic acid,

O. R = CH(CH₃)-C₂H₅: 2-[4-(1-methylpropyl)phenyl]propanoic acid,

M. R1 = OH, R2 = CH₃, R3 = CO₂H: (2RS)-2-hydroxy-2-[4-(2-methylpropyl)phenyl]propanoic acid,

P. R1 = H, R2 = CH₃, R3 = CH₂OH: (2RS)-2-[4-(2-methylpropyl)phenyl]propan-1-ol,

Q. R1 = R2 = H, R3 = CH₂OH: 2-[4-(2-methylpropyl)phenyl]ethanol,

R. 1,1′-(ethane-1,1-diyl)-4,4′-(2-methylpropyl)dibenzene.

Ph Eur