Metolazone

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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C₁₆H₁₆CIN₃O₃S             365.83

6-Quinazolinesulfonamide, 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-;

7-Chloro-1,2,3,4-tetrahydro-2-methyl-4-oxo-3-o-tolyl-6-quinazolinesulfonamide CAS RN^®: 17560-51-9; UNII: TZ7V40X7VX.

1 DEFINITION

Metolazone contains NLT 97.0% and NMT 102.0% of metolazone (C₁₆H₁₆CIN₃O₃S), calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K

B. SPECTROSCOPIC IDENTIFICATION TESTS (197), Ultraviolet-Visible Spectroscopy: 1970

Sample solution: 5 µg/mL in methanol

Acceptance criteria: Meets the requirements

C. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 PROCEDURE

Protect all solutions of Metolazone from light.

Buffer: 5.4 g/L of monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Acetonitrile, methanol, and Buffer (10:25:65)

Standard stock solution: 0.5 mg/mL of USP Metolazone RS in tetrahydrofuran

Standard solution: 0.05 mg/mL of USP Metolazone RS in alcohol from the Standard stock solution

Sample stock solution: 1 mg/mL of Metolazone in tetrahydrofuran

Sample solution: 0.05 mg/mL of Metolazone in alcohol from the Sample stock solution

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm x 25-cm; 10-µm packing L1

Flow rate: 1.5 mL/min

Injection volume: 15 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.4

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of metolazone (C₁₆H₁₆CIN₃O₃S) in the portion of sample taken:

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

r_U = peak response of metolazone from the Sample solution

r_S = peak response of metolazone from the Standard solution

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

C_U = concentration of Metolazone in the Sample solution (µg/mL)

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

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.1%

Change to read:

ORGANIC IMPURITIES

Buffer and Mobile phase: Proceed as directed in the Assay.

Standard stock solution: 0.48 mg/mL of USP Metolazone RS in tetrahydrofuran

Standard solution: 6 µg/mL of USP Metolazone RS in alcohol from the Standard stock solution

Sample solution: 0.6 mg/mL of Metolazone, prepared as follows. Dissolve a suitable amount of Metolazone with tetrahydrafuran in 50% of the total volume, and dilute with alcohol to volume.

Chromatographic system: Proceed as directed in the Assay, except for the following:

Column: 4.6-mm x 25-cm; 5-um packing ^▲L1_{▲(ERR 1-Mar-2024)}

Run time: NLT 3.5 times the retention time of metolazone

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.4

Relative standard deviation: NMT 5.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of sample taken:

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

r_U = peak response of each individual impurity from the Sample solution

r_S = peak response of metolazone from the Standard solution S

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

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

F = relative response factor of each individual impurity (see Table 1)

Acceptance criteria: See Table 1.

Table 1

^a 7-Chloro-2-methyl-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinazoline-6-sulfonamide.

^b 2-Amino-4-chloro-5-sulfamoyl-N-(o-tolyl)benzamide.

^c 7-Chloro-2-methyl-4-oxo-3-(m-tolyl)-1,2,3,4-tetrahydroquinazoline-6-sulfonamide.

^d 7-Chloro-2-methyl-4-oxo-3-(p-tolyl)-1,2,3,4-tetrahydroquinazoline-6-sulfonamide.

^e 7-Chloro-2-methyl-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-sulfonamide.

^f Sum of all individual impurities. Disregard any peaks less than 0.05%.

5 SPECIFIC TESTS

LOSS ON DRYING (731)

Analysis: Dry a sample at 105° for 2 h.

Acceptance criteria: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers.

USP REFERENCE STANDARDS (11).

USP Metolazone RS

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