(kloe fye' brate).
Propanoic acid, 2-(4-chlorophenoxy)-2-methyl-, ethyl ester.
Ethyl 2-(p-chlorophenoxy)-2-methylpropionate [637-07-0].
» Clofibrate contains not less than 97.0 percent and not more than 103.0 percent of C12H15ClO3, calculated on the anhydrous basis.
Packaging and storage Preserve in tight, light-resistant containers.
USP Reference standards 11
Solution: 20 µg per mL.
Refractive index 831: between 1.500 and 1.505, at 20.
Acidity Mix 10.0 g with 100 mL of neutralized alcohol, add 3 drops of phenolphthalein TS, and titrate with 0.10 N sodium hydroxide: not more than 0.90 mL is required for neutralization.
Water, Method I 921: not more than 0.2%.
Standard preparation Prepare a solution in chloroform having known concentrations of about 0.1 mg of USP Clofibrate RS and 0.03 mg of p-chlorophenol per mL. To 10.0 mL of this solution add 5.0 µL of tributyrin, and mix.
Test preparation To 10.0 mL of Clofibrate add 5.0 µL of tributyrin, and mix.
Chromatographic system (see Chromatography 621)The gas chromatograph is equipped with a split injector with a 20:1 split ratio, a flame-ionization detector, and a 0.53-mm × 15-m column to the internal walls of which is bonded a 1.5-µm film of phase G1. The chromatograph is programmed to maintain the column temperature at 120 for 1 minute, then to increase the temperature at a rate of 5 per minute for 12 minutes, and finally to maintain a temperature of 180 for 9 minutes. Maintain the injection port at 210 and the detector block at 220. Helium is used as the carrier gas flowing at a rate of about 2 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed under Procedure: the relative retention times are about 0.2 for p-chlorophenol, 0.55 for clofibrate, and 1.0 for tributyrin.
Procedure [noteUse peak areas where peak responses are indicated. ] Separately inject equal volumes (about 1 µL) of the Standard preparation and the Test preparation into the chromatograph, record the chromatograms, and measure the peak responses. Calculate the percentage of each impurity, other than p-chlorophenol, in the Clofibrate taken by the formula:
0.1C(RU / RS)in which C is the concentration, in mg per mL, of USP Clofibrate RS in the Standard preparation, RU is the ratio of the response of each individual impurity peak (other than the p-chlorophenol peak) to that of the tributyrin peak obtained from the Test preparation, and RS is the ratio of the response of the clofibrate peak to that of the tributyrin peak obtained from the Standard preparation: the percentage of any impurity, other than p-chlorophenol, does not exceed 0.01%, and the total percentage of all such impurities does not exceed 0.12%.
Limit of p-chlorophenol Use the chromatograms obtained in the test for Chromatographic purity. Calculate the percentage of p-chlorophenol in the portion of Clofibrate taken by the formula:
0.1C(RU / RS)in which C is the concentration, in mg per mL, of p-chlorophenol in the Standard preparation, and RU and RS are the ratios of the responses of the p-chlorophenol and tributyrin peaks obtained from the Test preparation and the Standard preparation, respectively: not more than 0.003% of p-chlorophenol is found.
Ion-exchange resin To a beaker containing 75 mL of 1 N sodium hydroxide add about 3 g of a 50- to 100-mesh strongly basic styrene-divinylbenzene anion-exchange resin, and allow the mixture to stand for about 15 minutes, with occasional stirring. Wash the resin with water until the last washing is neutral to litmus paper, then wash with three 50-mL portions of methanol.
Ion-exchange column Place a plug of glass wool in the base of a 1- × 15-cm ion-exchange tube, and transfer to the tube a sufficient amount of Ion-exchange resin, slurried in methanol, to produce a column bed height of from 6 cm to 8 cm.
Standard preparation Dissolve an accurately weighed quantity of USP Clofibrate RS in methanol, and dilute quantitatively and stepwise with methanol to obtain a solution having a known concentration of about 20 µg per mL.
Assay preparation Transfer about 200 mg of Clofibrate, accurately weighed, to a 100-mL volumetric flask, add methanol to volume, and mix. Transfer 10.0 mL of this solution to the Ion-exchange column, and collect the eluate in a 100-mL volumetric flask. Rinse the column with 25 mL of methanol, collect the rinsing in the volumetric flask, dilute with methanol to volume, and mix. Transfer 5.0 mL of this solution to a 50-mL volumetric flask, dilute with methanol to volume, and mix.
Procedure Concomitantly determine the absorbances of the Standard preparation and the Assay preparation in 1-cm cells at the wavelength of maximum absorbance at about 226 nm, with a suitable spectrophotometer, using methanol as the blank. Calculate the quantity, in mg, of C12H15ClO3 in the portion of Clofibrate taken by the formula:
10C(AU / AS)in which C is the concentration, in µg per mL, of USP Clofibrate RS in the Standard preparation; and AU and AS are the absorbances of the Assay preparation and the Standard preparation, respectively.
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USP35NF30 Page 2719