Irbesartan and Hydrochlorothiazide 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 

Irbesartan and Hydrochlorothiazide Tablets contain NLT 90.0% and NMT 110.0% of the labeled amounts of irbesartan (C₂₅H₂₈N₆O) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂). 

2 IDENTIFICATION 

Change to read: 

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

Sample solution: Transfer the contents of 1 Tablet, previously crushed with a mortar and pestle, to a suitable vial. Add 5 mL of acetone, sonicate for 10 min, and pass through a membrane filter of 0.45-µm pore size. Evaporate the filtrate to dryness. 

The relative retention times of the major peaks from the Sample solution correspond to those of the Standard solution, as obtained in the Assay. 

3 ASSAY

Procedure 

Buffer: Dissolve 1.36 g of monobasic potassium phosphate in 900 mL of water, add 2 mL of triethylamine, and adjust with phosphoric acid to a pH of 3.0 ± 0.1. Dilute further with water to 1 L. 

Mobile phase: Acetonitrile, methanol, and Buffer (13:20:67) 

Acidified water: Adjust with phosphoric acid (or sodium hydroxide, if necessary) to a pH of 2.0 ± 0.1. 

Extraction solution: Methanol and Acidified water (7:3) 

Irbesartan standard stock solution: Dissolve USP Irbesartan RS in a suitable volumetric flask in methanol (1/5 of the volume of the flask), and dilute with Extraction solution to prepare a 0.6 mg/mL solution. Sonicate for 2 min. 

Hydrochlorothiazide standard stock solution: Dissolve USP Hydrochlorothiazide RS in methanol (1/20 of the volume of the flask), and dilute with Extraction solution to prepare a 0.1 mg/mL solution. Sonicate for 2 min. 

Irbesartan related compound A standard stock solution: 0.1 mg/mL of USP Irbesartan Related Compound A RS in methanol. Sonicate for 2 min. 

Benzothiadiazine related compound A standard stock solution: 0.05 mg/mL of USP Benzothiadiazine Related Compound A RS in methanol. Sonicate for 2 min. 

Standard solution: 0.24 mg/mL of irbesartan and 0.02 mg/mL of hydrochlorothiazide from the Irbesartan standard stock solution and the Hydrochlorothiazide standard stock solution in the Extraction solution 

System suitability solution: Prepare 0.05 mg/mL of USP Irbesartan RS, 0.005 mg/mL of USP Hydrochlorothiazide RS, 1.0 µg/mL of USP Irbesartan Related Compound A RS, and 3.0 µg/mL of USP Benzothiadiazine Related Compound A RS in the Extraction solution from the respective Standard stock solutions 

Sample stock solution: 0.75 mg/mL of irbesartan from NLT 5 Tablets in a suitable volumetric flask. Add Acidified water up to 30% of the volume of the flask, and sonicate until the Tablets disintegrate. Add methanol to fill the flask up to 90% of the total volume. Sonicate for 5 min, and stir. Dilute with methanol to volume, and pass through a filter of 0.45-µm pore size. 

Sample solution: 0.225 mg/mL of irbesartan in the Extraction solution from the Sample stock solution. [Note—The hydrochlorothiazide concentration may vary depending on the ratio of irbesartan to hydrochlorothiazide in the Tablet.] 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 220 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L10 

Flow rate: 1.5 mL/min 

Injection volume: 10 µL 

System suitability 

Samples: Standard solution and System suitability solution 

Suitability requirements 

Resolution: NLT 1.7 between irbesartan and irbesartan related compound A; NLT 1.7 between hydrochlorothiazide and benzothiadiazine related compound A, System suitability solution 

Relative standard deviation: NMT 1.5% for both the irbesartan and hydrochlorothiazide peaks, Standard solution 

Samples: Standard solution and Sample solution 

Calculate the percentage of C₂₅H₂₈N₆O and C₇H₈ClN₃O₄S₂ in the portion of Tablets taken: 

Result = (r_U/r_S) × (C_S/C_U) x 100 

r_U = peak area of irbesartan or hydrochlorothiazide from the Sample solution

r_S = peak area of irbesartan or hydrochlorothiazide from the Standard solution

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

C_U = concentration of irbesartan or hydrochlorothiazide in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0% 

4 PERFORMANCE TESTS 

Dissolution 〈711〉 

Medium: 0.1 N hydrochloric acid; 1000 mL 

Apparatus 2: 50 rpm 

Time: 30 min 

pH 3.0 phosphate buffer: 1.36 g/L of monobasic potassium phosphate in water. Adjust with 10% phosphoric acid to a pH of 3.0 ± 0.1. This solution is stable for 3 months. 

Mobile phase: pH 3.0 phosphate buffer, methanol, and acetonitrile (45:35:20) 

Irbesartan standard stock solution: Transfer 50 mg of USP Irbesartan RS to a 100-mL volumetric flask. Add 15 mL of methanol, and sonicate for 5 min. Dilute with Medium to volume. This solution is stable for 14 days when stored at 4°. 

Hydrochlorothiazide standard stock solution: Transfer 20 mg of USP Hydrochlorothiazide RS to a 200-mL volumetric flask. Add 5 mL of methanol, and sonicate for 5 min. Dilute with Medium to volume. This solution is stable for 14 days when stored at 4°. Standard solution: Prepare on day of use dilutions of the Irbesartan standard stock solution and Hydrochlorothiazide standard stock solution in Medium as directed in the table below: 

System suitability solution: Transfer 10 mg of USP Irbesartan Related Compound A RS to a 100-mL volumetric flask. Add 5 mL of methanol, and sonicate to dissolve. Dilute with Medium to volume. Transfer 10.0 mL of this solution, 5.0 mL of the Irbesartan standard stock solution, and 12.5 mL of the Hydrochlorothiazide standard stock solution to a 100-mL volumetric flask. Dilute with Medium to volume. 

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding the first few mL. Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 272 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L10 

Column temperature: 40° 

Flow rate: 1.4 mL/min 

Injection volume: 25 µL 

System suitability 

Samples: Standard solution and System suitability solution 

Suitability requirements 

Resolution: NLT 2.0 between irbesartan and irbesartan related compound A, System suitability solution 

Relative standard deviation: NMT 2.0% for both the irbesartan and hydrochlorothiazide peaks, Standard solution 

Calculate the percentage of irbesartan and hydrochlorothiazide dissolved: 

Result = (r_U/r_S) × (C_S/C_U) × V x 100 

r_U = peak response for irbesartan or hydrochlorothiazide from the Sample solution

r_S = peak response for irbesartan or hydrochlorothiazide from the Standard solution

C_S = concentration of irbesartan or hydrochlorothiazide in the Standard solution

L = label claim for irbesartan or hydrochlorothiazide (mg/Tablet) 

V = volume of Medium (mL), 1000 

Tolerances: NLT 80% (Q) of the labeled amounts of irbesartan (C₂₅H₂₈N₆O) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂) are dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements 

5 IMPURITIES 

Organic Impurities 

Procedure 

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

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of irbesartan related compound A in the portion of Tablets taken: 

Result = (r_U/r_S) × (C_S/C_U) x 100 

r_U = peak response of irbesartan related compound A from the Sample solution

r_S = peak response of irbesartan from the Standard solution

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

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

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

Result = (r_U/r_S) × (C_S/C_U) x 100 

r_U = peak response of benzothiadiazine related compound A 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) 

Calculate the percentage of any other individual impurity in the portion of Tablets taken: 

(r_U/r_T) × 100 

r_U = peak response of each other impurity in the Sample solution 

r_T = sum of the peak responses excluding hydrochlorothiazide and benzothiadiazine related compound A from the Sample solution

Acceptance criteria 

Individual impurities: See Impurity Table 1. 

Total impurities: NMT 1.5% (sum of all the individual unknown impurities, irbesartan related compound A, and benzothiadiazine related compound A) 

Impurity Table 1 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in well-closed containers. 

USP Reference Standards 〈11〉 

USP Hydrochlorothiazide RS 

USP Irbesartan RS 

USP Irbesartan Related Compound A RS 

1-Pentanoylamino-cyclopentanecarboxylic acid [2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amide. 

C₂₅H₃₀N₆O₂     446.54 

USP Benzothiadiazine Related Compound A RS 

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

C₆H₈ClN₃O₄S₂ 285.7