Irbesartan and Hydrochlorothiazide Tablets
DEFINITION
Irbesartan and Hydrochlorothiazide Tablets contain NLT 90.0% and NMT 110.0% of the labeled amounts of irbesartan (C25H28N6O) and hydrochlorothiazide (C7H8ClN3O4S2).
IDENTIFICATION
• A. Infrared Absorption 
197K
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.
• B.
The relative retention times of the major peaks from the Sample solution correspond to those of the Standard solution, as obtained in the Assay.
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
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
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C25H28N6O and C7H8ClN3O4S2 in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak area of irbesartan or hydrochlorothiazide from the Sample solution |
| rS | = | = peak area of irbesartan or hydrochlorothiazide from the Standard solution |
| CS | = | = concentration of USP Irbesartan RS or USP Hydrochlorothiazide RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of irbesartan or hydrochlorothiazide in the Sample solution (mg/mL) |
Acceptance criteria:
90.0%–110.0%
PERFORMANCE TESTS
• Dissolution 711
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:
| Label Claim of Irbesartan/ Hydrochlorothiazide (mg/Tablet) |
Volume of the Irbesartan standard stock solution (mL) |
Volume of the Hydrochlorothiazide standard stock solution (mL) |
Final Volume (mL) |
|---|---|---|---|
| 75/12.5 | 15 | 12.5 | 100 |
| 150/12.5 | 30 | 12.5 | 100 |
| 300/12.5 | 60 | 12.5 | 100 |
| 300/25 | 60 | 25.0 | 100 |
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
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 = (rU/rS) × (CS/L) × V × 100
| rU | = | = peak response for irbesartan or hydrochlorothiazide from the Sample solution |
| rS | = | = peak response for irbesartan or hydrochlorothiazide from the Standard solution |
| CS | = | = 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
905:
Meet the requirements
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 = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of irbesartan related compound A from the Sample solution |
| rS | = | = peak response of irbesartan from the Standard solution |
| CS | = | = concentration of USP Irbesartan RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of irbesartan in the Sample solution (mg/mL) |
Calculate the percentage of benzothiadiazine related compound A in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 1/F × 100
| rU | = | = peak response of benzothiadiazine related compound A from the Sample solution |
| rS | = | = peak response of hydrochlorothiazide from the Standard solution |
| CS | = | = concentration of USP Hydrochlorothiazide RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of hydrochlorothiazide in the Sample solution (mg/mL) |
| F | = | = relative response factor (see Impurity Table 1) |
Calculate the percentage of any other individual impurity in the portion of Tablets taken:
Result = (rU/rT) × 100
| rU | = | = peak response of each other impurity in the Sample solution |
| rT | = | = 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
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| Benzothiadiazine related compound A | 0.15 | 1.3 | 1.0 |
| Hydrochlorothiazide | 0.18 | — | — |
| Irbesartan related compound A | 0.86 | 1.0 | 0.3 |
| Irbesartan | 1.00 | — | — |
| Any other individual, unidentified impurity | — | 1.0 | 0.2 |
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in well-closed containers.
• USP Reference Standards 11
11
USP Hydrochlorothiazide RS 
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USP Irbesartan RS
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USP Irbesartan Related Compound A RS
1-Pentanoylamino-cyclopentanecarboxylic acid [2¢-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amide.
C25H30N6O2 446.54
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 285.73
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4-Amino-6-chloro-1,3-benzenedisulfonamide.
C6H8ClN3O4S2 285.73
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Sujatha Ramakrishna, Ph.D.
Senior Scientific Liaison 1-301-816-8349 |
(SM22010) Monographs - Small Molecules 2 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 3558
Pharmacopeial Forum: Volume No. 36(2) Page 409