Chlorothiazide

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

1 DEFINITION

Chlorothiazide contains NLT 98.0% and NMT 102.0% of chlorothiazide (C₇H₆ClN₃O₄S₂), calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS 〈197〉 , Infrared Spectroscopy: 197M Analysis: Previously dried at 105° for 1 h

Acceptance criteria: Meets the requirements Delete the following:

B. SPECTROSCOPIC IDENTIFICATION TESTS 〈197〉 , Ultraviolet-Visible Spectroscopy: 197U Medium: sodium hydroxide solution (1 in 250)

Standard solution: 10 µg/mL of USP Chlorothiazide RS in Medium Sample solution: 10 µg/mL of Chlorothiazide in Medium

Acceptance criteria: Absorptivities at 292 nm, calculated on the dried basis, differ by NMT 3.0%. (USP 1-Aug-2022)

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-Aug-2022)

3 ASSAY

Change to read:

3.1 PROCEDURE

Mobile phase: Acetonitrile and 0.1 M monobasic sodium phosphate (10:90). Adjust with phosphoric acid to a pH of 3.0 ± 0.1.

System suitability solution: 0.15 mg/mL of USP Chlorothiazide RS and 1.5 µg/mL of USP Benzothiadiazine Related Compound A RS in Mobile phase

Standard solution: 0.15 mg/mL of USP Chlorothiazide RS in Mobile phase. [NOTE—A volume of acetonitrile not exceeding 10% of the total volume of the solution may be used to dissolve the Reference Standard. The Standard solution should be injected immediately upon preparation.]

Sample solution: 0.15 mg/mL of Chlorothiazide prepared as follows. Transfer about 30 mg of Chlorothiazide to a 200-mL volumetric flask, and dissolve in a small volume of acetonitrile not exceeding 10% of the total volume of the solution. Dilute with Mobile phase to volume. [NOTE—The Sample solution should be injected immediately upon preparation.]

3.1.1 Chromatographic system

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

Detector: UV 254 nm

Column: 4.6-mm × 25-cm; 5-μm (USP 1-Aug-2022) packing L1 Flow rate: 1.2 mL/min

Injection volume: 20 µL

3.1.2 System suitability

Samples: System suitability solution and Standard solution

[NOTE—The relative retention times are about 0.9 and 1.0 for benzothiadiazine related compound A and chlorothiazide, respectively.]

Suitability requirements

Resolution: NLT 3.5 between benzothiadiazine related compound A and chlorothiazide, System suitability solution Relative standard deviation: NMT 1.5%, Standard solution

3.1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of chlorothiazide (C₇H₆ClN₃O₄S₂) in the portion of Chlorothiazide taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of chlorothiazide from the Sample solution

r_s = peak response of chlorothiazide from the Standard solution

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

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

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

4 IMPURITIES

4.1 RESIDUE ON IGNITION 〈281〉

NMT 0.1%

4.2 CHLORIDE

Titrimetric system Mode: Direct titration

Titrant: 0.050 N silver nitrate Endpoint detection: Potentiometric

Analysis: Dissolve 1.00 g of Chlorothiazide in a mixture of 10 mL of water and 10 mL of sodium hydroxide solution (1 in 10). Cool in an ice bath, and add 20 mL of water and 5 mL of nitric acid. A flocculent, white precipitate is formed. Titrate with Titrant, using a silver–silver chloride electrode system.

Acceptance criteria: NMT 0.28 mL of Titrant is required (0.05%). Delete the following:

4.3 SELENIUM 〈291〉

NMT 0.003% (USP 1-Aug-2022)

4.4 ORGANIC IMPURITIES

Mobile phase, System suitability solution, Standard solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Standard solution A: 1.5 µg/mL of USP Benzothiadiazine Related Compound A RS in Mobile phase

4.4.1 System suitability

Samples: System suitability solution and Standard solution

[NOTE—The relative retention times are about 0.9 and 1.0 for benzothiadiazine related compound A and chlorothiazide, respectively.] Suitability requirements

Resolution: NLT 3.5 between benzothiadiazine related compound A and chlorothiazide, System suitability solution Relative standard deviation: NMT 1.5%, Standard solution

4.4.2 Analysis

Samples: Standard solution A and Sample solution

Calculate the percentage of benzothiadiazine related compound A in the portion of Chlorothiazide taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of benzothiadiazine related compound A from the Sample solution

r_s = peak response of benzothiadiazine related compound A from Standard solution A

C_s = concentration of USP Benzothiadiazine Related Compound A RS in Standard solution A (µg/mL)

C_u = concentration of Chlorothiazide in the Sample solution (µg/mL)

Acceptance criteria: NMT 1.0%

5 SPECIFIC TESTS

LOSS ON DRYING 〈731〉

Analysis: Dry at 105° for 1 h.

Acceptance criteria: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers. Store at 25°; excursions permitted between 15° and 30°.

USP REFERENCE STANDARDS 〈11〉

USP Benzothiadiazine Related Compound A RS

USP Chlorothiazide RS