Metolazone 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

Metolazone Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of metolazone (C₁₆H₁₆ClN₃O₃S).

2 IDENTIFICATION

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

Sample solution: Dilute 3 mL of the Sample solution in the Assay with methanol to 25 mL.

Acceptance criteria: Meet the requirements

3 ASSAY

Change to read:

Procedure

[Note—Use low-actinic glassware throughout the Assay.]

Buffer: 1.38 g of ▲monobasic sodium phosphate▲ (ERR 1-Jan-2023) in 900 mL of water. Adjust with phosphoric acid to a pH of 3.0, and dilute

with water to 1000 mL.

Mobile phase: Methanol, acetonitrile, and Buffer (28:7:65)

Standard stock solution: 0.25 mg/mL of USP Metolazone RS in methanol

Standard solution: 5 µg/mL of USP Metolazone RS in Mobile phase from Standard stock solution

Sample stock solution: Transfer 10 Tablets to a 200-mL volumetric flask. Add 3 mL of water and 100 mL of methanol, and sonicate for 30

min. If disintegration is not complete, sonicate for an additional 30 min. Shake by mechanical means for 30 min. Dilute with methanol to

volume.

Sample solution: Nominally equivalent to 5 µg/mL of metolazone in Mobile phase from the Sample stock solution

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 235 nm

Column: 3.9-mm × 15-cm; packing L1

Flow rate: 1.1 mL/min

Injection volume: 100 µL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of metolazone (C₁₆H₁₆ClN₃O₃S) in the portion of Tablets taken:

Result = (r₁ / r₂) × (C₁ / C₂) × 100

r₁ = peak response from the Sample solution

r₂ = peak response from the Standard solution

C₁ = concentration of USP Metolazone RS in the Standard solution (µg/mL)

C₂ = nominal concentration of the Sample solution (µg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Dissolution 〈711〉

[Note—Protect all solutions from light.]

Test 1

Medium: 2% w/v sodium lauryl sulfate in 0.05 M monobasic sodium phosphate. Heat the mixture to about 37° to dissolve the sodium lauryl

sulfate, and adjust with 10 N sodium hydroxide to a pH of 7.5; 900 mL, deaerated

Apparatus 2: 75 rpm

Time: 120 min

Buffer: 0.05 M monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 3.00.

Mobile phase: Acetonitrile, methanol, and Buffer (270:50:680)

Standard stock solution: 0.28 mg/mL of USP Metolazone RS. Initially add methanol to 2% of the volume of the flask. Sonicate to dissolve,

and dilute with Medium to volume.

Standard solution: (L/900) mg/mL in Medium from the 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 254 nm

Column: 4.6-mm × 15-cm; 5-µm packing L7

Column temperature: 30°

Flow rate: 1.2 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Column efficiency: NLT 2000 theoretical plates

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of metolazone (C₁₆H₁₆ClN₃O₃S) dissolved:

Result = (r₁ / r₂) × (C / L) × V × 100

r₁ = peak response from the Sample solution

r₂ = peak response from the Standard solution

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

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 75% (Q) of the labeled amount of metolazone (C₁₆H₁₆ClN₃O₃S) is dissolved.

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

Medium: Prepare a solution of 0.05 M dibasic sodium phosphate in a suitable flask, and adjust with phosphoric acid to a pH of 7.5.

Dissolve a suitable amount of sodium lauryl sulfate to obtain a 20-g/L solution; 900 mL

Apparatus 2: 75 rpm

Time: 120 min

Standard stock solution: 0.275 mg/mL of USP Metolazone RS. Initially add methanol to 10% of the volume of the flask. Sonicate to

dissolve, and dilute with Medium to volume.

Standard solution: (L/900) mg/mL in Medium from the 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.

Detector: UV 238 nm

Path length: 1 cm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of metolazone (C₁₆H₁₆ClN₃O₃S) dissolved:

Result = (A₁ / A₂) × (C / L) × V × 100

A₁ = absorbance of the Sample solution

A₂ = absorbance of the Standard solution

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

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 75% (Q) of the labeled amount of metolazone (C₁₆H₁₆ClN₃O₃S) is dissolved.

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

Medium: 0.05 M phosphate buffer pH 7.5 with 2% sodium lauryl sulfate. (Dissolve 6.9 g of monobasic sodium phosphate monohydrate in

1000 mL of water. Adjust with 10 N sodium hydroxide solution to a pH of 7.5. Dissolve 20 g of sodium lauryl sulfate in the solution.

Sonicate for defoaming and deaeration.); 900 mL

Apparatus 2: 75 rpm

Times: 30 and 90 min

Buffer: Dissolve 6.8 g of monobasic potassium phosphate in 1000 mL of water. Adjust with diluted phosphoric acid to a pH of 3.0.

Solution A: Acetonitrile, methanol, and Buffer (27:5:68)

Solution B: Methanol and water (80:20)

Mobile phase: See Table 1.

Table 1

Standard stock solution: 0.28 mg/mL of USP Metolazone RS prepared as follows. Transfer a suitable amount of USP Metolazone RS into a

suitable volumetric flask. Add methanol to 2% of the volume of the flask. Sonicate to dissolve, and dilute with Medium to volume.

Standard solution: (L/900) mg/mL of USP Metolazone RS in Medium from the 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. Replace the portion withdrawn with

an equal volume of Medium at the specified time point.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 15-cm; 5-µm packing L7

Column temperature: 30°

Flow rate: 1.2 mL/min

Injection volume: 50 µL

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 concentration (Cᵢ) of metolazone (C₁₆H₁₆ClN₃O₃S) in the sample withdrawn from the vessel at each time point (i):

Result = (rᵢ / rₛ) × Cₛ

rᵢ = peak response of metolazone from the Sample solution

rₛ = peak response of metolazone from the Standard solution

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

Calculate the percentage of the labeled amount of metolazone (C₁₆H₁₆ClN₃O₃S) dissolved at each time point (i):

Result = Cᵢ × V × (1 / L) × 100

Result = [(Cᵢ × V) + (Cᵢ₋₁ × Vₛ)] × (1 / L) × 100

Cᵢ = concentration of metolazone in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn at each time point, 10 mL

Tolerances: See Table 2

Table 2

The percentages of the labeled amount of metolazone (C₁₆H₁₆ClN₃O₃S) dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers, and store below 30°.

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

USP Reference Standards 〈11〉

USP Metolazone RS