Chlorthalidone 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

Chlorthalidone Tablets contain NLT 92.0% and NMT 108.0% of the labeled amount of chlorthalidone (C₁₄H₁₁ClN₂O₄S).

2 IDENTIFICATION

A. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. 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

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 stock solution: Nominally 1 mg/mL of chlorthalidone in Diluent prepared as follows. Weigh and finely powder Tablets (NLT 20). Transfer an amount of powder, equivalent to about 50 mg of chlorthalidone, into a 50-mL volumetric flask. Add Diluent to about 60% of the flask volume and sonicate. [NOTE—Sonicating for NLT 10 min is recommended.] Dilute with Diluent to volume. Centrifuge a portion and use the supernatant.

Sample solution: Nominally 0.1 mg/mL of chlorthalidone from the Sample stock solution in Diluent

3.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm. For Identification A, use a diode array detector in the range of 190–400 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 1.0%

3.1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of chlorthalidone (C₁₄H₁₁ClN₂O₄S) in the portion of Tablets 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 = nominal concentration of chlorthalidone in the Sample solution (mg/mL)

Acceptance criteria: 92.0%–108.0%

4 PERFORMANCE TESTS

Change to read:

4.1 DISSOLUTION 〈711〉

Test 1 (RB 1-Oct-2024) Medium: Water; 900 mL Apparatus 2: 75 rpm

Time: 60 min

Standard stock solution: 5 mg/mL of USP Chlorthalidone RS in methanol Standard solution: A known concentration of USP Chlorthalidone RS in water

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with water to a concentration that is similar to that of the Standard solution.

Instrumental conditions Mode: UV

Analytical wavelength: 275 nm

4.1.1 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of chlorthalidone (C₁₄H₁₁ClN₂O₄S) 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 Chlorthalidone RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

D = dilution factor, if needed

L = label claim (mg/Tablet)

Tolerances: NLT 70% (Q) of the labeled amount of chlorthalidone (C14H11ClN2O4S) is dissolved.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2. Medium: 0.25% sodium dodecyl sulfate in water. Heat to dissolve, if necessary; 900 mL.

Apparatus 2: 75 rpm

Time: 45 min

Standard stock solution: 5 mg/mL of USP Chlorthalidone RS in methanol. Sonicate to dissolve, if necessary. Standard solution:

For Tablets labeled to contain 25 mg/Tablet: 0.025 mg/mL of USP Chlorthalidone RS in Medium from the Standard stock solution For Tablets labeled to contain 50 mg/Tablet: 0.05 mg/mL of USP Chlorthalidone RS in Medium from the Standard stock solution

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding an appropriate volume of filtrate so that a consistent result can be obtained.

4.1.2 Instrumental conditions

Mode: UV

Analytical wavelength: 275 nm Cell: 2 cm

Blank: Medium Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of chlorthalidone (C₁₄H₁₁ClN₂O₄S) 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 Chlorthalidone 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 chlorthalidone (C₁₄H₁₁ClN₂O₄S) is dissolved. (RB 1-Oct-2024)

4.2 UNIFORMITY OF DOSAGE UNITS 〈905〉

Meet the requirements

5 IMPURITIES

5.1 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: 1 μg/mL of USP Chlorthalidone RS from the Standard solution in Diluent

Sample solution: Nominally 1 mg/mL of chlorthalidone in Diluent prepared as follows. Weigh and finely powder Tablets (NLT 20). Transfer an amount of powder, equivalent to about 50 mg of chlorthalidone, into a 50-mL volumetric flask. Add Diluent to about 60% of the flask volume and sonicate. [NOTE—Sonicating for NLT 10 min is recommended.] Dilute with Diluent to volume. Centrifuge a portion and use the supernatant.

5.1.1 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

5.1.2 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any specified or unspecified impurity in the portion of Tablets 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 = nominal 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 0.1%.

Table 2

^aExcluding chlorthalidone related compound A.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers. Store at controlled room temperature. Protect from light.

Add the following:

LABELING: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used. (RB 1-Oct-2024)

USP REFERENCE STANDARDS 〈11〉

USP Chlorthalidone RS

USP Chlorthalidone Related Compound A RS

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

Also known as 4′-Chloro-3′-sulfamoyl-2-benzophenone carboxylic acid.