Indomethacin Sodium
(in'' doe meth' a sin soe' dee um).
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C19H15ClNNaO4·3H2O 433.82

1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-, sodium salt, trihydrate.
Sodium 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate, trihydrate [74252-25-8].

Anhydrous 379.78.
» Indomethacin Sodium contains not less than 98.0 percent and not more than 101.0 percent of C19H15ClNNaO4, calculated on the dried basis.
Packaging and storage— Preserve in well-closed, light-resistant containers.
Labeling— Where it is intended for use in preparing injectable dosage forms, the label states that it is sterile or must be subjected to further processing during the preparation of injectable dosage forms.
USP Reference standards 11
USP Indomethacin RS Click to View Structure
Identification—
A: It responds to Identification test B under Indomethacin for Injection.
B: Ignite a small amount of it on a platinum wire in a non-luminous flame: an intense yellow flame is produced.
C: The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that of the Standard preparation as obtained in the Assay.
Loss on drying 731 Dry it at 100 for 2 hours at a pressure not exceeding 5 mm of mercury: it loses between 11.5% and 13.5% of its weight.
Limit of acetone—
Standard solution— Transfer 1.0 mL of acetone to a 100-mL volumetric flask, dilute with water to volume, and mix. Transfer 1.0 mL of this solution to a 200-mL volumetric flask, dilute with water to volume, and mix. Insert the stopper, and cool in an ice bath.
Test solution— Transfer about 100 mg of Indomethacin Sodium, accurately weighed, to a 15-mL centrifuge tube, and dissolve in 1.0 mL of cool water. While vortexing this solution, add 1.0 mL of 0.24 N hydrochloric acid, centrifuge promptly, and filter the supernatant. Collect the filtrate in a suitable tube, cap, and cool in an ice bath.
Chromatographic system (see Chromatography 621)—The gas chromatograph is equipped with a flame-ionization detector and a 3-mm × 1.8-m column that contains support S3. The column temperature is maintained at 165. The carrier gas is nitrogen. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the capacity factor, k¢, for acetone is between 4 and 7; and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Using the solvent flush technique, with water as the flushing agent, separately inject equal volumes (about 3 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms for 6 minutes, and measure the areas for the acetone peaks. Calculate the percentage of acetone in the portion of Indomethacin Sodium taken by the formula:
0.79(10 / WU)(rU / rS)
in which 0.79 is the specific gravity of acetone; WU is the quantity, in mg, of Indomethacin Sodium taken to prepare the Test solution; and rU and rS are the acetone peak areas obtained from the Test solution and the Standard solution, respectively: not more than 0.1% is found.
Chromatographic purity—
Mobile phase , Diluent, and Chromatographic system—Proceed as directed in the Assay.
Standard preparation— Transfer 2.0 mL of the Stock impurity solution, prepared as directed in the Assay, to a 200-mL volumetric flask, dilute with Diluent to volume, and mix. Each mL of this Standard preparation contains 0.002 mg of 4-chlorobenzoic acid and 0.002 mg of 5-methoxy-2-methyl-3-indoleacetic acid.
Test preparation— Use the stock solution used to prepare the Assay preparation as directed in the Assay.
Procedure— [note—Use peak areas where peaks responses are indicated. ] Separately inject equal volumes (about 20 µL) of the Standard preparation and the Test preparation, record the chromatograms for 25 minutes, and measure the response for the peaks having retention times corresponding to the major peaks obtained in the chromatogram of the Standard preparation. The relative standard deviation for replicate injections of the Standard preparation is not more than 5.0%. Calculate the percentages of 4-chlorobenzoic acid and of 5-methoxy-2-methyl-3-indoleacetic acid in the portion of Indomethacin Sodium taken by the formula:
20(rU / rS) / [WU (1.00 0.01L)]
in which rU and rS are the peak responses of the corresponding analytes obtained from the Test preparation and the Standard preparation, respectively; WU is the quantity, in mg, of Indomethacin Sodium taken to prepare the Assay preparation, as described in the Assay; and L is the percentage of weight loss obtained in the test for Loss on drying: the sum of the percentages of 4-chlorobenzoic acid and 5-methoxy-2-methyl-3-indoleacetic acid does not exceed 0.2%. Calculate the percentage of each peak other than the solvent peak, the main indomethacin peak, the 4-chlorobenzoic acid peak, and the 5-methoxy-2-methyl-3-indoleacetic acid peak in the chromatogram of the Test preparation taken by the formula:
100ri / rt
in which ri is the response of each other peak; and rt is the sum of the responses of all the peaks, excluding that of the solvent peak: not more than 0.5% of any individual peak is found, and the sum of these individual peaks is not more than 1.0%.
Other requirements— Where the label states that Indomethacin Sodium is sterile, it meets the requirements for Sterility Tests 71 and for Pyrogen under Indomethacin for Injection. Where the label states that Indomethacin Sodium must be subjected to further processing during the preparation of injectable dosage forms, it meets the requirements for Pyrogen under Indomethacin for Injection.
Assay—
Mobile phase— Prepare a suitable filtered and degassed mixture of methanol, water, acetonitrile, and phosphoric acid (550: 300:150:1). Make adjustments if necessary (see System Suitability under Chromatography 621).
Diluent— Prepare a sufficient quantity of a mixture of acetonitrile and water (3:1).
Standard preparation— Dissolve an accurately weighed quantity of USP Indomethacin RS quantitatively in Diluent to obtain a stock solution containing 0.80 mg per mL. Dilute an accurately measured volume of this stock solution quantitatively with Diluent to obtain a solution containing 0.16 mg per mL (Standard preparation).
Assay preparation— Transfer about 100 mg of Indomethacin Sodium, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with Diluent to volume, and mix. Transfer 10.0 mL of this stock solution to a 50-mL volumetric flask, dilute with Diluent to volume, and mix.
Stock impurity solution— Dissolve accurately weighed quantities of 4-chlorobenzoic acid and 5-methoxy-2-methyl-3-indoleacetic acid quantitatively in Diluent to obtain a solution containing 0.20 mg of each per mL.
Resolution solution— Prepare a mixture of the stock solution used to prepare the Diluent, the Standard preparation, and the Stock impurity solution (7:2:1).
Chromatographic system (see Chromatography 621)—The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm × 15-cm column that contains packing L1, and is maintained at a temperature of 35 ± 1. The flow rate is about 1.5 mL per minute. Chromatograph the Resolution solution, and record the peak responses as directed under Procedure: the capacity factor, k¢, for the indomethacin peak is not less than 2.5, the column efficiency determined from the indomethacin peak is not less than 3500 theoretical plates, the tailing factor for the indomethacin peak is not more than 1.3, and the resolution, R, between the 4-chlorobenzoic acid peak and the 5-methoxy-2-methyl-3-indoleacetic acid peak is not less than 3.5. Chromatograph the Standard preparation, and record the peak responses as directed under Procedure: the relative standard deviation for replicate injections is not more than 1.0%.
Procedure— [note—Use peak areas where peak responses are indicated. ] Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of indomethacin sodium (C19H15ClNNaO4) in the portion of Indomethacin Sodium taken by the formula:
(379.78 / 357.79)(500C)(rU / rS)
in which 379.78 and 357.79 are the molecular weights of anhydrous indomethacin sodium and indomethacin, respectively; C is the concentration, in mg per mL, of USP Indomethacin RS in the Standard preparation; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Clydewyn M. Anthony, Ph.D.
Senior Scientific Liaison
1-301-816-8139
(SM22010) Monographs - Small Molecules 2
Reference Standards RS Technical Services
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USP35–NF30 Page 3501