Clofibrate Capsules

Fibrate; lipid-regulating drug.

Clofibrate Capsules contain Clofibrate.

The capsules comply with the requirements stated under Capsules and with the following requirements.

The contents of the capsules comply with the following tests.

A. The infrared absorption spectrum, Appendix II A, is concordant with the spectrum of clofibrate EPCRS.

B. The light absorption, Appendix II B, in the range 220 to 250 nm of a 0.001% w/v solution in methanol exhibits a maximum only at 226 nm. The A(1%, 1 cm) at the maximum is about 460.

C. The light absorption, Appendix II B, in the range 250 to 350 nm of a 0.01% w/v solution in methanol exhibits two maxima, at 280 nm and 288 nm. The A(1%, 1 cm) at the maxima are about 44 and about 31, respectively.

Add 10 mL of the contents of the capsules to 100 mL of ethanol (96%) previously neutralised to phenolphthalein solution R1 with 0.1m sodium hydroxide VS and titrate with 0.1m sodium hydroxide VS. Not more than 2.5 mL is required to change the colour of the solution.

1.500 to 1.505, determined on the contents of the capsules, Appendix V E.

1.138 to 1.147, determined on the contents of the capsules, Appendix V G.

Carry out the method for gas chromatography, Appendix III B.

(1) Extract a volume of the contents of the capsules containing 10.0 g of Clofibrate with 20 mL of 1m sodium hydroxide, wash the lower layer with 5 mL of water, add the washings to the aqueous layer and reserve the organic layer for the test for Volatile related substances. Extract the combined aqueous layer and washings with two 5-mL quantities of chloroform, discard the chloroform and acidify the aqueous layer by the drop wise addition of hydrochloric acid. Extract with three 3-mL quantities of chloroform, combine the organic extracts and dilute to 10 mL with chloroform.

(2) 0.0025% w/v of 4-chlorophenol in chloroform.

(a) Use a column (1.5 m × 4 mm) packed with either acid-washed, silanised diatomaceous support (Chromosorb W/AW/DMCS is suitable) (40 to 60 mesh) impregnated with 30% w/w of dimethyl silicone fluid (SE-30 ise suitable) or acid-washed, silanised diatomaceous support (80 to 100 mesh) coated with 10% w/w of dimethyl silicone fluid.

(b) Use helium as the carrier gas at 1.7 mL per minute.

(c) Use isothermal conditions maintained at 185°.

(d) Use an inlet temperature of 185°.

(e) Use a flame ionisation detector at a temperature of 185°.

(f) Inject 2 µL of each solution.

In the chromatogram obtained with solution (1):

the area of any peak corresponding to 4-chlorophenol is not greater than the area of the peak in the chromatogram obtained with solution (2) (25 ppm).

Carry out the method for gas chromatography, Appendix III B.

(1) Dry the organic layer reserved in the test for 4-Chlorophenol with anhydrous sodium sulfate.

(2) A solution of the contents of the capsules in chloroform containing 0.012% w/v of Clofibrate.

(3) 0.012% w/v solution of methyl 2-(4-chlorophenoxy)-2-methylpropionate EPCRS in the contents of the capsules.

The chromatographic conditions described under 4-Chlorophenol may be used.

In the chromatogram obtained with solution (3) measure from the baseline the height of the peak corresponding to methyl 2-(4-chlorophenoxy)-2-methylpropionate (a) and the height of the lowest part of the curve separating this peak from the peak corresponding to clofibrate (b). The test is not valid unless a is equal to at least 30% of full-scale deflection and a-b is greater than 75% of a.

In the chromatogram obtained with solution (1):

the sum of the areas of any secondary peaks is not greater than 10 times the area of the peak due to clofibrate in the chromatogram obtained with solution (2) (0.1%).

Carry out the test for Uniformity of weight for Soft Capsules described under Capsules. The average weight of the contents of the 20 capsules is 95.0 to 105.0% of the stated weight of Clofibrate.

Not less than 97.0% w/w when determined by the following method. To a weighed quantity of the mixed contents of 10 capsules containing 1 g of Clofibrate add 25 mL of 0.5m ethanolic potassium hydroxide and heat under a reflux condenser fitted with a soda lime guard tube for 2 hours, rotating the flask frequently. Allow to cool, add 10 mL of water down the condenser and titrate the contents of the flask with 0.2m hydrochloric acid VS using 1 mL of phenolphthalein solution R1 as indicator. Repeat the operation without the contents of the capsules. The difference between the titrations represents the amount of hydrochloric acid required. Each mL of 0.2m hydrochloric acid VS is equivalent to 48.54 mg of C₁₂H₁₅ClO₃.