Bumetanide 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

Bumetanide Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of bumetanide (C₁₇H₂₀N₂O₅S).

2 IDENTIFICATION

Change to read:

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

B. ▲The UV spectrum of the bumetanide peak of the Sample solution exhibits maxima and minima at the same wavelengths as those of the corresponding peak of the Standard solution, as obtained in the Assay.▲ (USP 1-May-2024)

3 ASSAY

Change to read:

Procedure

Solution A: 0.5% (v/v) formic acid in water prepared as follows. To a 1-L volumetric flask, add 5 mL of formic acid and dilute with water to volume.

Solution B: Methanol

Mobile phase: See Table 1.

Standard stock solution: 0.2 mg/mL of USP Bumetanide RS in methanol

Standard solution: 0.1 mg/mL of USP Bumetanide RS from the Standard stock solution in water

Sample stock solution: Nominally 0.2 mg/mL of bumetanide from Tablets (NLT 10) in a suitable amount of methanol. Initially mix well until the Tablets are disintegrated, centrifuge for about 10 min, and use the supernatant. Sonication may be necessary for complete disintegration.

Sample solution: Nominally 0.1 mg/mL of bumetanide from the Sample stock solution in water

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.

Column: 4.6-mm × 15-cm; 3.5-µm packing L1

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of bumetanide (C₁₇H₂₀N₂O₅S) in the portion of Tablets taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

where

rᵤ = peak response of bumetanide from the Sample solution

rₛ = peak response of bumetanide from the Standard solution

Cₛ = concentration of USP Bumetanide RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of bumetanide in the Sample solution (mg/mL)

▲ (USP 1-May-2024)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Solution A: 7.505 g/L of glycine and 5.85 g/L of sodium chloride in water

Solution B: Solution A, 0.1 N hydrochloric acid, and water (4:1:45). Adjust, if necessary, with 0.1 N hydrochloric acid or 0.1 N sodium hydroxide to a pH of 2.9.

Standard solution: USP Bumetanide RS at a known concentration in Medium

Sample solution: Dilute with Solution B as needed.

Instrumental conditions

Mode: Fluorescence

Detectors

Excitation wavelength: 350 nm

Emission wavelength: 450 nm

Analysis

Samples: Standard solution and Sample solution

▲Calculate the percentage of the labeled amount of bumetanide (C₁₇H₂₀N₂O₅S) dissolved:

Result = (Iᵤ / Iₛ) × [Cₛ × V × (1/L)] × 100

where

Iᵤ = fluorescence intensity of the Sample solution

Iₛ = fluorescence intensity of the Standard solution

Cₛ = concentration of the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

▲ (USP 1-May-2024)

Tolerances: NLT 85% (Q) of the labeled amount of bumetanide (C₁₇H₂₀N₂O₅S) is dissolved

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

Medium, Apparatus 2, and Time: Proceed as directed in Test 1.

Buffer: 2.72 g/L of potassium phosphate, monobasic in water. Adjust with 1.8 N potassium hydroxide to a pH of 7.0.

Mobile phase: Acetonitrile and Buffer (30:70)

Diluent: Acetonitrile and water (50:50)

Standard stock solution: 55.5 µg/mL of USP Bumetanide RS in Diluent

Standard solution: (L/1000) µg/mL of USP Bumetanide RS in Medium, from Standard stock solution, 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.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 222 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 35°

Flow rate: 1.5 mL/min

Injection volume: 100 µL

Run time: NLT 1.7 times the retention time of bumetanide

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 bumetanide (C₁₇H₂₀N₂O₅S) dissolved:

Result = (rᵤ / rₛ) × Cₛ × V × (1/L) × 100

where

rᵤ = peak response of bumetanide from the Sample solution

rₛ = peak response of bumetanide from the Standard solution

Cₛ = concentration of USP Bumetanide 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 bumetanide (C₁₇H₂₀N₂O₅S) is dissolved

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

Organic Impurities

Solution A, Solution B, and Mobile phase: Prepare as directed in the Assay.

Diluent: Methanol and water (40:60)

Standard stock solutions:

0.1 mg/mL each of USP Bumetanide RS, USP Bumetanide Related Compound A RS, and USP Bumetanide Related Compound B RS individually prepared as follows. Transfer suitable amounts each of USP Bumetanide RS, USP Bumetanide Related Compound A RS, and USP Bumetanide Related Compound B RS to separate suitable volumetric flasks. Add methanol to about 40% of the total volume of each flask to dissolve the solids. Dilute with water to volume.

System suitability solution: 0.25 µg/mL each of USP Bumetanide RS, USP Bumetanide Related Compound A RS, and USP Bumetanide Related Compound B RS from the corresponding Standard stock solutions in Diluent

Standard solution: 0.25 µg/mL each of USP Bumetanide RS and USP Bumetanide Related Compound A RS from the corresponding Standard stock solutions in Diluent

Sensitivity solution: 0.125 µg/mL each of USP Bumetanide RS and USP Bumetanide Related Compound A RS from the Standard solution in Diluent

Sample solution: Nominally 250 µg/mL of bumetanide prepared as follows. To Tablets (NLT 10), in a suitable volumetric flask, add about 40% of the total volume of methanol. Shake well until the Tablets disintegrate, and dilute with water to volume. Centrifuge for NLT 10 min and use the supernatant.

Chromatographic system:

Proceed as directed in the Assay, except for the Injection volume.

Injection volume: 50 µL

System suitability

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

[Note—The relative retention time for bumetanide related compound B with respect to bumetanide is 0.7.]

Suitability requirements

Resolution: NLT 20 between bumetanide related compound A and bumetanide related compound B, System suitability solution

Relative standard deviation: NMT 5.0% for each peak, Standard solution

Signal-to-noise ratio: NLT 10 for each peak, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of bumetanide related compound A in the portion of Tablets taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

where

rᵤ = peak response of bumetanide related compound A from the Sample solution

rₛ = peak response of bumetanide related compound A from the Standard solution

Cₛ = concentration of USP Bumetanide Related Compound A RS in the Standard solution (µg/mL)

Cᵤ = nominal concentration of bumetanide in the Sample solution (µg/mL)

Calculate the percentage of any unspecified impurity in the portion of Tablets taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

where

rᵤ = peak response of any unspecified impurity from the Sample solution

rₛ = peak response of bumetanide from the Standard solution

Cₛ = concentration of USP Bumetanide RS in the Standard solution (µg/mL)

Cᵤ = nominal concentration of bumetanide in the Sample solution (µg/mL)

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

ᵃ Bumetanide related compound A is not included in the total impurities.

▲ (USP 1-May-2024)

6 ADDITIONAL REQUIREMENTS

Change to read:

Packaging and Storage: Preserve in tight, light-resistant containers. ▲Store at controlled room temperature.▲ (USP 1-May-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 Bumetanide RS

USP Bumetanide Related Compound A RS

3-Amino-4-phenoxy-5-sulfamoylbenzoic acid.

C₁₃H₁₂N₂O₄S 308.31

▲ USP Bumetanide Related Compound B RS

3-Nitro-4-phenoxy-5-sulfamoylbenzoic acid.

C₁₃H₁₀N₂O₇S 338.29▲ (USP 1-May-2024)