Ethacrynic Acid Tablets

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 Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of ethacrynic acid (C₁₃H₁₂Cl₂O₄).

2 IDENTIFICATION

Delete the following:

A. Ultraviolet Absorption (USP 1-Dec-2024)

Add the following:

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. (USP 1-Dec-2024)

Change to read:

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. (USP 1-Dec-2024)

3 ASSAY

Change to read:

Procedure

Buffer: 1% (v/v) triethylamine solution in water prepared as follows. Transfer a suitable aliquot of triethylamine to an appropriate volumetric flask containing 90% of the flask volume of water.▲ (USP 1-Dec-2024) Adjust with phosphoric acid to a pH of 6.8 (USP 1-Dec-2024) and dilute with water to volume. (USP 1-Dec-2024)

Mobile phase: Acetonitrile and Buffer (40:60).  (USP 1-Dec-2024)

Diluent: Acetonitrile and water (40:60)

Standard solution: 0.5 mg/mL of USP Ethacrynic Acid RS in Diluent

Sample solution: Nominally 0.5 mg/mL of ethacrynic acid in Diluent prepared as follows. Transfer a portion of the powder from NLT 20 finely powdered Tablets, equivalent to about 50 mg of ethacrynic acid, to a 100-mL volumetric flask, add about 80 mL of Diluent, and shake or sonicate as necessary. Dilute with Diluent to volume, and mix.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm. For Identification B, use a diode array detector in the range of 200–400 nm. (USP 1-Dec-2024)

Column: 3.9-mm × 30-cm; 10-μm (USP 1-Dec-2024) packing L1

Flow rate: 1 mL/min

Injection volume: 10 μL

Run time: NLT 2 times the retention time of ethacrynic acid (USP 1-Dec-2024)

System suitability

Sample: Standard solution

Suitability requirements

(USP 1-Dec-2024)

Tailing factor: NMT 2.0 (USP 1-Dec-2024)

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ethacrynic acid (C₁₃H₁₂Cl₂O₄) in the portion of Tablets 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 = nominal concentration of ethacrynic acid in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1

Medium: 0.1 M phosphate buffer, pH 8.0 (dissolve 13.6 g of monobasic potassium phosphate in water, adjust with 92.2 mL of 1 N sodium hydroxide VS to a pH of 8.0, and dilute with water to 1000 mL); (USP 1-Dec-2024) 900 mL

Apparatus 2: 50 rpm

Time: 45 min

Standard solution: A known concentration of USP Ethacrynic Acid RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute suitably with Medium.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.) (USP 1-Dec-2024)

Mode: UV

Analytical wavelength: 277 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ethacrynic acid (C₁₃H₁₂Cl₂O₄) dissolved:

Result = (A_U/A_S) × C_S × V × D × (1/L) × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

V = volume of Medium, 900 mL

D = dilution factor for the Sample solution

L = label claim (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of ethacrynic acid (C₁₃H₁₂Cl₂O₄) is dissolved.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: Citrate buffer, pH 3.0 (dissolve 17.2 g of citric acid and 5.3 g of sodium citrate dihydrate in 1 L of water, and adjust with 1 N sodium hydroxide VS (USP 1-Dec-2024) or 1 M acetic acid TS to a pH of 3.0 (USP 1-Dec-2024) ); 900 mL, deaerated

Apparatus 2: 50 rpm

Time: 30 min

Determine the percentage of the labeled amount of ethacrynic acid by using either the Chromatographic procedure or the Spectrophotometric procedure.

Chromatographic procedure

Buffer: (USP 1-Dec-2024) 1% (v/v) triethylamine solution in water prepared as follows. Transfer a suitable aliquot of triethylamine to an appropriate volumetric flask containing 90% of the ask volume of water. Adjust with phosphoric acid to a pH of 6.8. (USP 1-Dec-2024)

Dilute with water to volume.

Mobile phase: Acetonitrile and Buffer (40:60)

Standard stock solution: 0.3 (USP 1-Dec-2024) mg/mL of USP Ethacrynic Acid RS prepared as follows. Transfer a portion of USP

Ethacrynic Acid RS to a suitable volumetric flask and add methanol to 10% of the flask volume. Dilute with Medium to volume.

Standard solution: (L/900) (USP 1-Dec-2024) mg/mL of USP Ethacrynic Acid RS from the Standard stock solution in Medium, where L is the label claim in mg/Tablet (USP 1-Dec-2024)

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 277 nm

Column: 3.9-mm × 30-cm; 10-μm packing L1

Flow rate: 1 mL/min

Injection volume: 10 μL

Run time: NLT 2.4 times the retention time of ethacrynic acid

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ethacrynic acid (C₁₃H₁₂Cl₂O₄) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L) × 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)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Spectrophotometric procedure

Diluent: Acetonitrile and water (40:60)

Standard stock solution: 0.5 mg/mL of USP Ethacrynic Acid RS prepared as follows. Transfer a portion of USP Ethacrynic Acid RS to a suitable volumetric flask, add Diluent to 40% of the flask volume, and sonicate if necessary. Dilute with Medium to volume.

Standard solution: (L/900) mg/mL of USP Ethacrynic Acid RS from the Standard stock solution in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 10-μm pore size.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 277 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ethacrynic acid (C₁₃H₁₂Cl₂O₄) dissolved:

Result = (A_U/A_S) × C_S × V × (1/L) × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

(USP 1-Dec-2024)

Tolerances: NLT 80% (Q) of the labeled amount of ethacrynic acid (C₁₃H₁₂Cl₂O₄) is dissolved.

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: Citrate buffer, pH 3.0 (dissolve 17.4 g of citric acid, anhydrous and 2.7 g of sodium citrate dihydrate in 800 mL of water, adjust with 5 N sodium hydroxide TS to a pH of 3.0, and dilute with water to 1000 mL); 900 mL

Apparatus 2: 50 rpm

Time: 45 min

Diluent: Phosphate buffer, pH 8.0 prepared as follows. Dissolve 13.6 g of potassium phosphate, monobasic in 800 mL of water, add 92 mL of 1 N sodium hydroxide VS, and dilute with water to 1000 mL. Adjust with 1 N sodium hydroxide VS to a pH of 8.0.

Standard stock solution: 0.3 mg/mL of USP Ethacrynic Acid RS, prepared as follows. Transfer a portion of USP Ethacrynic Acid RS to a suitable volumetric flask, add Diluent to 60% of the flask volume, and sonicate to dissolve. Dilute with Diluent to volume.

Standard solution: (L/900) mg/mL of USP Ethacrynic Acid RS from the Standard stock solution in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size, discard a few milliliters, and collect the filtrate.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 277 nm

Blank: Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ethacrynic acid (C₁₃H₁₂Cl₂O₄) dissolved:

Result = (A_U/A_S) × C_S × V × (1/L) × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of ethacrynic acid (C₁₃H₁₂Cl₂O₄) is dissolved.

Change to read:

Uniformity of Dosage Units 〈905〉: Meet the requirements

(USP 1-Dec-2024)

Add the following:

5 IMPURITIES

Organic Impurities

Buffer: 1% (v/v) triethylamine solution in water. Adjust with phosphoric acid to a pH of 6.8.

Solution A: Acetonitrile and Buffer (30:70)

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile, methanol, and water (25:25:50)

Identification solution: 0.03 mg/mL of USP Ethacrynic Acid Related Compound C RS in Diluent. Sonicate if necessary.

Standard solution: 2 μg/mL of USP Ethacrynic Acid RS in Diluent

Sensitivity solution: 1 μg/mL of USP Ethacrynic Acid RS from the Standard solution in Diluent

Sample solution: Nominally 1 mg/mL of ethacrynic acid in Diluent prepared as follows. Transfer a portion equivalent to 25 mg of ethacrynic acid from finely powdered Tablets (NLT 20), to a suitable volumetric flask, add Diluent to 70% of the flask volume, and sonicate for about 20min with intermittent shaking. Dilute with Diluent to volume. Pass the solution through a suitable filter of 0.22-μm pore size. Discard the first few milliliters of the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 2.1-mm × 10-cm; 1.7-μm packing L7

Column temperature: 27°

Flow rate: 0.4 mL/min

Injection volume: 3 μL

System suitability

Samples: Standard solution and Sensitivity solution

Suitability requirements

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 5.0%, Standard solution

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

Analysis

Samples: Identification solution, Standard solution, and Sample solution

[Note—See Table 2 for the relative retention times.]

Calculate the percentage of each impurity in the portion of Tablets 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 = nominal concentration of ethacrynic acid in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.1%.

Table 2

^a [2,3-Dichloro-4-(2-ethyloxirane-2-carbonyl)phenoxy]acetic acid.

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

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

^d Ethacrynic acid pyrane dimer.

(USP 1-Dec-2024)

6 ADDITIONAL REQUIREMENTS

Change to read:

Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature. (USP 1-Dec-2024)

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

Change to read:

USP Reference Standards 〈11〉

USP Ethacrynic Acid RS

USP Ethacrynic Acid Related Compound C RS

{4-[2-(4-(Carboxymethoxy)-2,3-dichlorobenzoyl)-2,5-diethyl-3,4-dihydro-2H-pyran-6-yl]-2,3-dichlorophenoxy}acetic acid.

C₂₆H₂₄Cl₄O₈ 606.27 (USP 1-Dec-2024)