Chlorthalidone

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

Chlorthalidone contains NLT 98.0% and NMT 102.0% of chlorthalidone (C₁₄H₁₁ClN₂O₄S), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS 〈197〉 , Infrared Spectroscopy: 197A or (USP 1-May-2023) 197M

Delete the following:

B. SPECTROSCOPIC IDENTIFICATION TESTS 〈197〉 , Ultraviolet-Visible Spectroscopy (USP 1-M  -2023)

Add the following:

B. 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-May-2023)

Delete the following:

C. (USP 1-M -2023)

3 ASSAY

Change to read:

3.1 PROCEDURE

Solution A: 69 mL/L of phosphoric acid in water Solution B: 2 g/L of sodium hy droxide in water

Solution C: Dissolve 1.32 g of ammonium phosphate, dibasic in about 900 mL of water. Adjust with Solution A to a pH of 5.5. Dilute with water to 1000 mL.

Mobile phase: See Table 1.

Table 1

Diluent: Methanol, Solution C, and Solution B (48:50:2)

Standard solution: 0.1 mg/mL of USP Chlorthalidone RS in Diluent. Sonicate to dissolve as needed. Sample solution: 0.1 mg/mL of Chlorthalidone in Diluent. Sonicate to dissolve as needed.

3.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.) Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 5-µm packing L7 Column temperature: 40°

Flow rate: 1.4 mL/min Injection volume: 10 µL

3.1.2 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

3.1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of chlorthalidone (C₁₄H₁₁ClN₂O₄S) in the portion of Chlorthalidone taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of chlorthalidone from the Sample solution

r_s = peak response of chlorthalidone from the Standard solution

C_s = concentration of USP Chlorthalidone RS in the Standard solution (mg/mL)

C_u = concentration of Chlorthalidone in the Sample solution (mg/mL) (USP 1-May-2023)

Acceptance criteria: 98.0%–102.0% on the dried basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION 〈281〉

NMT 0.1%

4.2 CHLORIDE AND SULFATE 〈221〉 , Chloride

Standard solution: 0.50 mL of 0.020 N hy drochloric acid

Sample solution: Shake 1.0 g with 40 mL of water for 5 min, and pass through chloride-free filter paper previously rinsed with water. Use the filtrate.

Acceptance criteria: NMT 0.035%

Change to read:

4.3 ORGANIC IMPURITIES

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

System suitability solution: 1 mg/mL of USP Chlorthalidone RS and 5 μg/mL of USP Chlorthalidone Related Compound A RS in Diluent. Sonicate to dissolve as needed.

Standard solution: 10 μg/mL of USP Chlorthalidone RS in Diluent. Sonicate to dissolve as needed. Sensitivity solution: 0.5 μg/mL of USP Chlorthalidone RS from the Standard solution in Diluent Sample solution: 1 mg/mL of Chlorthalidone in Diluent. Sonicate to dissolve as needed.

4.3.1 System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution [NOTE—See Table 2 for the relative retention times.]

Suitability requirements

Resolution: NLT 5.0 between chlorthalidone related compound A and chlorthalidone, System suitability solution Relative standard deviation: NMT 5.0%, Standard solution

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

4.3.2 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any specified or unspecified impurity in the portion of Chlorthalidone taken:

Result = (r_u/r_s) × (C_s/C_u) × (1/F) × 100

r_u = peak response of any specified or unspecified impurity from the Sample solution

r_s = peak response of chlorthalidone from the Standard solution

C_s = concentration of USP Chlorthalidone RS in the Standard solution (mg/mL)

C_u = concentration of Chlorthalidone in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

Table 2

^a  3-(3,4-Dichlorophenyl)-2,3-dihydro-3-hydroxy-1H-isoindolin-1-one.

5 SPECIFIC TESTS

LOSS ON DRYING 〈731〉

Sample: 2 g

Analysis: Dry at 105° for 4 h.

Acceptance criteria: NMT 0.4%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers. Change to read:

USP REFERENCE STANDARDS 〈11〉

USP Chlorthalidone RS

USP Chlorthalidone Related Compound A RS

2-(4-Chloro-3-sulfamoylbenzoyl)benzoic acid;

Also known as (USP 1-May-2023) 4′-Chloro-3′-sulfamoyl-2-benzophenone carboxylic acid.