Clofibrate

(Ph. Eur. monograph 0318)

C₁₂H₁₅ClO₃    242.7    637-07-0

Fibrate; lipid-regulating drug.

Clofibrate Capsules

Ph Eur

Ethyl 2-(4-chlorophenoxy)-2-methylpropionate.

Clear, almost colourless liquid.

Very slightly soluble in water, miscible with ethanol (96 per cent).

A. Infrared absorption spectrophotometry (2.2.24).

Comparison   clofibrate CRS.

B. Ultraviolet and visible absorption spectrophotometry (2.2.25).

Test solution (a)  Dissolve 0.10 g in methanol R and dilute to 100.0 mL with the same solvent. Dilute 10.0 mL of this solution to 100.0 mL with methanol R.

Test solution (b)  Dilute 10.0 mL of test solution (a) to 100.0 mL with methanol R.

Spectral range  250-350 nm for test solution (a); 220-250 nm for test solution (b).

Absorption maxima  At 280 nm and 288 nm for test solution (a); at 226 nm for test solution (b).

• — at 226 nm: about 460 for test solution (b);

• — at 280 nm: about 44 for test solution (a);

• — at 288 nm: about 31 for test solution (a).

1.138 to 1.147.

1.500 to 1.505.

To 1.0 g add 10 mL of anhydrous ethanol R and 0.1 mL of phenol red solution R. Not more than 1.0 mL of 0.01 M sodium hydroxide is required to change the colour of the indicator.

Gas chromatography (2.2.28).

Test solution  To 10.0 g of the substance to be examined add a mixture of 10 mL of dilute sodium hydroxide solution R and 10 mL of water R. Shake, separate the lower (organic) layer, wash with 5 mL of water R and add the washings to the aqueous layer. Dry the organic layer with anhydrous sodium sulfate R and use as the test solution. Reserve the aqueous layer for the test for 4-chlorophenol.

Reference solution (a)  Dissolve 0.12 g of the substance to be examined in chloroform R and dilute to 100.0 mL with the same solvent. Dilute 1.0 mL of this solution to 10.0 mL with chloroform R.

Reference solution (b)  Dissolve 0.12 g of methyl 2-(4-chlorophenoxy)-2-methylpropionate CRS in the substance to be examined and dilute to 10.0 mL with the same solvent. Dilute 1.0 mL of the solution to 10.0 mL with the substance to be examined. Dilute 1.0 mL of this solution to 10.0 mL with the substance to be examined.

• — size: l = 1.5 m, Ø = 4 mm;

• — stationary phase: silanised diatomaceous earth for gas chromatography R (250-420 µm) impregnated with 30 per cent m/m of poly(dimethyl)siloxane R; or silanised diatomaceous earth for gas chromatography R (150-180 µm) impregnated with 10 per cent m/m of poly(dimethyl)siloxane R;

• — temperature: 185 °C.

Carrier gas   nitrogen for chromatography R.

Detection  Flame ionisation.

Injection  2 µL.

System suitability  Reference solution (b):

• — peak-to-valley ratio: minimum 4, where H_p = height above the baseline of the peak due to methyl 2-(4-chlorophenoxy)-2-methylpropionate and H_v = height above the baseline of the lowest point of the curve separating this peak from the peak due to clofibrate.

• — total: not more than 10 times the area of the peak due to clofibrate in the chromatogram obtained with reference solution (a) (0.1 per cent).

Gas chromatography (2.2.28) as described in the test for volatile related substances with the following modifications.

Test solution  Shake the aqueous layer reserved in the test for volatile related substances with 2 quantities, each of 5 mL, of chloroform R and discard the organic layers. Acidify the aqueous layer by the dropwise addition of hydrochloric acid R. Shake with 3 quantities, each of 3 mL, of chloroform R. Combine the organic layers and dilute to 10.0 mL with chloroform R.

Reference solution  Dissolve 0.25 g of chlorophenol R in chloroform R and dilute to 100.0 mL with the same solvent. Dilute 1.0 mL of this solution to 100.0 mL with chloroform R.

• — 4-chlorophenol: not more than the area of the peak due to 4-chlorophenol in the chromatogram obtained with the reference solution (25 ppm).

Ph Eur