Hydrochlorothiazide

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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C₇H₈ClN₃O₄S₂   297.74 

2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-, 1,1-dioxide; 

6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide CAS RN®: 58-93-5; UNII: 0J48LPH2TH. 

1 DEFINITION 

Hydrochlorothiazide contains NLT 98.0% and NMT 102.0% of hydrochlorothiazide (C₇H₈ClN₃O₄S₂), calculated on the dried basis.

2 IDENTIFICATION 

Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K 

Sample: Potassium bromide–hydrochlorothiazide mixture, previously heated at 105° for 2 h 

Acceptance criteria: Meets the requirements 

Delete the following: 

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

Sample solution: 10 µg/mL in methanol 

Acceptance criteria: Meets the requirements  

Add the following: 

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 

Change to read: 

Procedure 

Buffer: 2.76 g of sodium phosphate, monobasic in a 1000-mL volumetric ask. Add 990 mL of water. Adjust with phosphoric acid to a pH of 2.7 ± 0.1, and dilute with water to volume. 

Diluent: Acetonitrile and Buffer (30:70) 

Solution A: Acetonitrile and methanol (75:25) 

Solution B: 0.5% formic acid, anhydrous solution in water 

Mobile phase: See Table 1. 

Table 1 

System suitability solution: 0.32 mg/mL of USP Hydrochlorothiazide RS, 0.0032 mg/mL of USP Chlorothiazide RS, and 0.0032 mg/mL of USP Benzothiadiazine Related Compound A RS in Diluent. Sonicate if necessary to dissolve. Pass a portion through a filter of 0.45-µm or finer pore size. 

Standard solution: 0.32 mg/mL of USP Hydrochlorothiazide RS in Diluent. Sonicate if necessary to dissolve. Pass a portion through a filter of 0.45-µm or finer pore size. 

Sample solution: 0.32 mg/mL of Hydrochlorothiazide in Diluent, prepared as follows. Transfer 32 mg of Hydrochlorothiazide into a 100-mL volumetric ask. Add 70 mL of Diluent, sonicate for 10 min if necessary to dissolve, and allow to cool to ambient temperature. Dilute with Diluent to volume. Pass a portion through a filter of 0.45-µm or finer pore size. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 275 nm 

Column: 4.6-mm × 5-cm; 3.5-µm packing L1 

Column temperature: 35° 

Flow rate: 1 mL/min Injection volume: 10 µL System suitability  

Samples: System suitability solution and Standard solution 

[Note—See Table 2 for the relative retention times.] 

  Suitability requirements 

Resolution: NLT 2.0 between benzothiadiazine related compound A and chlorothiazide and NLT 1.5 between chlorothiazide and hydrochlorothiazide, System suitability solution 

Tailing factor: NMT 1.5, Standard solution  

Relative standard deviation: NMT 1.0%, Standard solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) in the portion of Hydrochlorothiazide taken: 

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

4 IMPURITIES 

Residue on Ignition 〈281〉: NMT 0.1% 

Chloride and Sulfate 〈221〉, Chloride 

Sample solution: Shake 0.50 g with 40 mL of water for 5 min, and filter. 

Acceptance criteria: 0.035%; the filtrate shows no more chloride than corresponds to 0.25 mL of 0.020 N hydrochloric acid. Delete the following: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of hydrochlorothiazide from the Sample solution  

r_S = peak response of hydrochlorothiazide from the Standard solution 

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

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

Selenium 〈291〉 

Sample: 200 mg 

Acceptance criteria: NMT 30 ppm  

Change to read: 

Organic Impurities 

Buffer,  Diluent, Solution A, Solution B, Mobile phase, System suitability solution, Sample solution,  and Chromatographic system: Proceed as directed in the Assay. 

Sensitivity solution: 0.16 µg/mL of USP Hydrochlorothiazide RS in Diluent. Sonicate if necessary to dissolve. 

System suitability 

Samples: System suitability solution and Sensitivity solution 

[Note—See Table 2 for the relative retention times.] 

Suitability requirements 

Resolution: NLT 2.0 between benzothiadiazine related compound A and chlorothiazide and NLT 1.5 between chlorothiazide and hydrochlorothiazide, System suitability solution 

  Relative standard deviation: NMT 5.0% for benzothiadiazine related compound A and chlorothiazide, System suitability solution; NMT 25% for hydrochlorothiazide, based on 3 replicate injections, Sensitivity solution 

Analysis 

Samples: Diluent and  Sample solution 

[Note—Injection(s) of Diluent can be made to correctly identify system peaks, which should be excluded from quantitation.]

Calculate the percentage of each impurity in the portion of Hydrochlorothiazide taken: 

Result =｛(r_U/F)/[r_S+ Σ(r_U/F)]｝× 100  

r_U = peak response of each impurity from Sample solution 

F = relative response factor of each impurity (see Table 2) 

r_S = peak response of hydrochlorothiazide from the Sample solution   

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

Table 2 

^a 5,6-Dichloro-3,4-dihydro-2H-benzothiadiazine-7-sulfonamide 1,1-dioxide. 

^b 6-Chloro-N-[(6-chloro-7-sulfamoyl-2,3-dihydro-4H-1,2,4-benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide 1,1-dioxide. 

^c Excluding benzothiadiazine related compound A. 

5 SPECIFIC TESTS 

Loss on Drying 〈731〉 

Analysis: Dry at 105° for 1 h. 

Acceptance criteria: NMT 0.5% 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in well-closed containers. 

USP Reference Standards 〈11〉 

USP Benzothiadiazine Related Compound A RS 

4-Amino-6-chloro-1,3-benzenedisulfonamide. 

C₇H₈ClN₃O₄S₂ 285.73 

USP Chlorothiazide RS 

USP Hydrochlorothiazide RS