Ethacrynic Acid

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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1 DEFINITION

Ethacrynic Acid contains NLT 97.0% and NMT 102.0% of ethacrynic acid (C₁₃H₁₂Cl₂O₄), calculated on the dried basis.

[Caution—Use care in handling Ethacrynic Acid, because it irritates the skin, eyes, and mucous membranes.]

2 IDENTIFICATION

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A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197M or 197A (USP 1-Dec-2021)

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B. Spectroscopic Identification Tests 〈197〉, Ultraviolet-Visible Spectroscopy: 197U

Analytical wavelength: 271 nm

Sample solution: 50 μg/mL in methanol

Acceptance criteria: Absorptivities, calculated on the dried basis, do not differ by more than 3.0%. (USP 1-Dec-2021)

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B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. (USP1-Dec-2021)

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C. Procedure

Sample solution: 12.5 mg/mL in 1 N sodium hydroxide

Analysis: Heat 2 mL of Sample solution for several min in a boiling water bath. Cool the solution, acidify with 0.25 mL of 18 N sulfuric acid, add 0.5 mL of chromotropic acid sodium salt solution (1 in 10), then add, cautiously, 2 mL of sulfuric acid TS.

Acceptance criteria: A deep violet color is produced. (USP 1-Dec-2021)

3 ASSAY

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Procedure

Solution A: Triethylamine and water (1:100). Adjust with phosphoric acid to a pH of 6.8.

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and water (25:75)

Standard solution: 0.1 mg/mL of USP Ethacrynic Acid RS in Diluent. Sonicate to dissolve.

Sample solution: 0.1 mg/mL of Ethacrynic Acid in Diluent. Sonicate to dissolve.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 4.0-mm × 25-cm; 5-μm packing L1

Column temperature: 30°

Flow rate: 1.8 mL/min

Injection volume: 50 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.5

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ethacrynic acid (C₁₃H₁₂Cl₂O₄) in the portion of Ethacrynic Acid taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of ethacrynic acid from the Sample solution

r_S = peak response of ethacrynic acid from the Standard solution

C_S = concentration of USP Ethacrynic Acid RS in the Standard solution (mg/mL)

C_U = concentration of Ethacrynic Acid in the Sample solution (mg/mL) (USP 1-Dec-2021)

Acceptance criteria: 97.0%–102.0% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

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Organic Impurities

Solution A, Solution B, Diluent, and Chromatographic system: Proceed as directed in the Assay.

Mobile phase: See Table 2.

Table 2

System suitability solution: 1 mg/mL of USP Ethacrynic Acid RS and 1.5 μg/mL of USP Ethacrynic Acid Related Compound A RS in Diluent.

Sonicate to dissolve.

Sensitivity solution: 0.3 μg/mL of USP Ethacrynic Acid RS in Diluent

Standard solution: 3 μg/mL of USP Ethacrynic Acid RS in Diluent

Sample solution: 1 mg/mL of Ethacrynic Acid in Diluent. Sonicate to dissolve.

System suitability

Samples: System suitability solution, Sensitivity solution, and Standard solution

[Note—See Table 3 for the relative retention times.]

Suitability requirements

Resolution: NLT 2.0 between the ethacrynic acid related compound A and ethacrynic acid peaks, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Ethacrynic Acid taken:

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of ethacrynic acid from the Standard solution

C_S = concentration of USP Ethacrynic Acid RS in the Standard solution (mg/mL)

C_U = concentration of Ethacrynic Acid in the Sample solution (mg/mL)

F = relative response factor (see Table 3)

Acceptance criteria: See Table 3. The reporting threshold is 0.03%.

Table 3

^a {2,3-Dichloro-4-[2-{(dimethylamino)methyl}butanoyl]phenoxy}acetic acid hydrochloride.

^b {2,3-Dichloro-4-[2-(chloromethyl)butanoyl]phenoxy}acetic acid.

^c {4-[2-(4-(Carboxymethoxy)-2,3-dichlorobenzoyl]-2,5-diethyl-3,4-dihydro-2H-pyran-6-yl}-2,3-dichlorophenoxy)acetic acid.▲ (USP 1-Dec-2021)

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at a pressure not exceeding 5 mm of mercury at 60° for 2 h.

Acceptance criteria: NMT 0.25%

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Equivalent Weight

Sample solution: 400 mg in 100 mL of methanol. Add 5 mL of water.

Analysis: Titrate with 0.1 N sodium hydroxide VS, using a calomel–glass electrode system or other appropriate electrode (see Titrimetry〈541〉). Perform a blank determination, and make any necessary correction. Calculate the equivalent weight on the dried basis.

Acceptance criteria: Between 294 and 309 (USP 1-Dec-2021)

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Toluene Extractives

Sample solution: 1 g into a glass-stoppered, 100-mL cylinder. Add 50 mL of sodium sulfite solution (2 in 25), and agitate until the solid dissolves. Allow to stand for 20 min, and add 5 mL of hydrochloric acid.

Analysis: Divide the solution between two centrifuge tubes, each of which contains 15 mL of toluene. Close each tube tightly, using a polyethylene stopper, and shake vigorously for 2 min, occasionally relieving the pressure from the sulfur dioxide by loosening the stoppers.

Centrifuge the tubes, withdraw most of the upper layer by means of a syringe, avoiding withdrawal of any of the lower, aqueous phase, and transfer the toluene extracts to a tared evaporating dish. Repeat the extraction twice with additional 15-mL portions of toluene, and evaporate the combined extracts on a steam bath to dryness. Dry the residue at a pressure not exceeding 5 mm of mercury at 60° for 2 h.

Cool, and weigh.

Acceptance criteria: NMT 2.0% (USP 1-Dec-2021)

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at 25°, excursions permitted between 15° and 30°.

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USP Reference Standards 〈11〉

USP Ethacrynic Acid RS

USP Ethacrynic Acid Related Compound A RS

(4-Butyryl-2,3-dichlorophenoxy)acetic acid.