Hydrochlorothiazide Capsules

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 

Hydrochlorothiazide Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂).

2 IDENTIFICATION 

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

3 ASSAY 

Procedure 

Buffer: 13.8 g/L of monobasic sodium phosphate 

Mobile phase: Acetonitrile and Buffer (10:90). Adjust with 10% (v/v) phosphoric acid to a pH o

System suitability solution: 0.15 mg/mL each of USP Hydrochlorothiazide RS and USP Chlorothiazide RS in Mobile phase. Sonicate to completely dissolve. 

Standard stock solution: 0.50 mg/mL of USP Hydrochlorothiazide RS prepared as follows. To a suitable amount of USP Hydrochlorothiazide RS in a suitable volumetric flask add acetonitrile to 10% of the final volume and sonicate to dissolve. Dilute with Buffer to volume. Standard solution: 50 µg/mL of USP Hydrochlorothiazide RS in Mobile phase from the Standard stock solution 

Sample stock solution: Nominally 0.25 mg/mL of hydrochlorothiazide prepared as follows. Transfer NLT 10 Capsules into a suitable volumetric flask. Add water to 10% of the final volume, and sonicate for 10 min with vigorous shaking. Add Buffer to 20% of the final volume, and again sonicate for 10 min. Add acetonitrile up to 40% of the final volume, and sonicate for 30 min. Dilute with Buffer to volume, and pass through a suitable filter of 0.45-µm pore size. 

Sample solution: 50 µg/mL of hydrochlorothiazide in Mobile phase from the Sample stock solution 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 272 nm. For Identification B, use a diode array detector in the range of 200–400 nm. 

Column: 4.6-mm × 25-cm; 5-µm packing L1 

Flow rate: 2 mL/min 

Injection volume: 20 µL 

Run time: NLT 1.5 times the retention time of hydrochlorothiazide 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—The relative retention times for chlorothiazide and hydrochlorothiazide are 0.80 and 1.0, respectively.] 

Suitability requirements 

Resolution: NLT 2.0 between chlorothiazide and hydrochlorothiazide, System suitability solution 

Tailing factor: NMT 2.0, Standard solution 

Relative standard deviation: NMT 2.0%, Standard solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) in the portion of Capsules taken:

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) 

Acceptance criteria: 90.0%–110.0% 

4 PERFORMANCE TESTS 

Change to read: 

Dissolution 〈711〉 

Test 1 

Medium: 0.1 N hydrochloric acid; 900 mL 

Apparatus 1: 100 rpm 

Time: 30 min 

Standard solution: 6.75 µg/mL of USP Hydrochlorothiazide RS prepared as follows. Dissolve a quantity of USP Hydrochlorothiazide RS in 10% of the flask volume of acetonitrile, and dilute with Medium. Sonicate to completely dissolve. 

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Dilute with Medium to a concentration similar to that of the Standard solution. 

Instrumental conditions 

Mode: UV 

Analytical wavelength: 272 nm 

Cell: 1 cm 

Blank: Medium 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) dissolved: 

Result = (A_U/A_S) × (C_S/L) × D × V × 100 

A_U = absorbance of the Sample solution 

A_S = absorbance of the Standard solution  

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

L = label claim (mg/Capsule) 

D = dilution factor for the Sample solution 

V = volume of Medium, 900 mL 

Tolerances: NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) is dissolved. 

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2. 

Medium: 0.01 N hydrochloric acid; 900 mL 

Apparatus 1: 100 rpm 

Time: 30 min 

Standard stock solution: 0.35 mg/mL of USP Hydrochlorothiazide RS in Medium. An amount of acetonitrile, not exceeding 25% of the final volume, may be used to help solubilize hydrochlorothiazide. 

Standard solution: (L/900) mg/mL of USP Hydrochlorothiazide RS in Medium, from the Standard stock solution, where L is the label claim in mg/Capsule 

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. 

Empty capsules solution: Place 10 empty capsules into a 900-mL volumetric flask. Slowly add 800 mL of Medium preheated to 37°, and stir until dissolved. Cool to room temperature, and dilute with Medium to volume. 

Instrumental conditions 

Mode: UV 

Analytical wavelength: 272 nm 

Cell: 1 cm 

Blank: Medium 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) dissolved: 

Result = [(A_U− A_EC)/A_S] × (C_S/L) × V × 100 

A_U = absorbance of the Sample solution 

A_EC = absorbance of the Empty capsules solution 

A_S = absorbance of the Standard solution 

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

L = label claim (mg/Capsule) 

V = volume of Medium, 900 mL 

Tolerances: NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) is dissolved. 

Uniformity of Dosage Units 〈905〉: Meet the requirements 

5 IMPURITIES 

Organic Impurities 

Buffer, Mobile phase, and System suitability solution: Prepare as directed in the Assay. 

Standard stock solution: 0.25 mg/mL of USP Hydrochlorothiazide RS prepared as follows. To a suitable amount of USP Hydrochlorothiazide RS in a suitable volumetric flask add acetonitrile to 10% of the final volume, and sonicate to dissolve. Dilute with Buffer to volume. Standard solution: 0.25 µg/mL of USP Hydrochlorothiazide RS in Mobile phase from the Standard stock solution 

Sample solution: Use the Sample stock solution as prepared in the Assay. 

Chromatographic system: Proceed as directed in the Assay except for the Run time. 

Run time: NLT 4 times the retention time of hydrochlorothiazide 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—See Table 1 for the relative retention times for chlorothiazide and hydrochlorothiazide.] 

Suitability requirements 

Resolution: NLT 2.0 between chlorothiazide and hydrochlorothiazide, System suitability solution 

Tailing factor: NMT 2.0, Standard solution 

Relative standard deviation: NMT 5.0%, Standard solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of benzothiadiazine related compound A and any unspecified impurity in the portion of Capsules taken: 

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

r_U = peak response of benzothiadiazine related compound A or any unspecified impurity 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)

F = relative response factor (see Table 1) 

Acceptance criteria: See Table 1. 

Table 1 

^a4-Amino-6-chloro-1,3-benzenedisulfonamide.

^b Process impurity included in the table for Identification only. Process impurities are controlled in the drug substance and are not to be reported or included in the total impurities for the drug product. 

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

^d Total impurities include benzothiadiazine related compound A and all unspecified impurities. 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in well-closed containers, and store at controlled room temperature. 

DOI ref: a0del 

Labeling: The labeling states the Dissolution test used only if Test 1 is not used. 

USP Reference Standards 〈11〉 

USP Chlorothiazide RS 

USP Hydrochlorothiazide RS