Valsartan and Hydrochlorothiazide Tablets
DEFINITION
Valsartan and Hydrochlorothiazide Tablets contain NLT 90.0% and NMT 110.0% of the labeled amounts of valsartan (C24H29N5O3) and hydrochlorothiazide (C7H8ClN3O4S2).
IDENTIFICATION
• A. Thin-Layer Chromatographic Identification Test 
201
201
Sample solution:
To an amount of ground Tablets, equivalent in weight to a single Tablet, add 2.0 mL of acetone, sonicate for 15 min, and centrifuge.
Application volume:
2 µL
Developing solvent system:
Ethyl acetate, dehydrated alcohol, and 3.6 M of ammonium hydroxide (8:2:1)
Analysis:
Proceed as directed in the chapter, except to develop the plate in a paper-lined chromatographic chamber equilibrated with Developing solvent system for 15 min before use. Allow the chromatogram to develop until the solvent front has moved at least 7 cm. After removing the plate and marking the solvent front, dry the plate under a current of warm air. The RF values of the principal spots obtained from the Sample solution correspond to those from the Standard solution.
• B.
The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
Diluent:
Acetonitrile and water (1:1)
Solution A:
Acetonitrile, water, and trifluoroacetic acid (10:90:0.1)
Solution B:
Acetonitrile, water, and trifluoroacetic acid (90:10:0.1)
Mobile phase:
See the gradient table below.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 90 | 10 |
| 25 | 10 | 90 |
| 27 | 90 | 10 |
| 40 | 90 | 10 |
Standard solution:
Transfer 12.5 mg of USP Hydrochlorothiazide RS to a 200-mL volumetric flask, and add 12.5J mg of USP Valsartan RS, J being the ratio of the labeled amount, in mg, of valsartan to the labeled amount, in mg, of hydrochlorothiazide per Tablet. Add 100 mL of Diluent, sonicate for 15 min, dilute with Diluent to 250 mL, and mix. Transfer 25.0 mL of this solution to a 50-mL volumetric flask, dilute with Diluent to volume, and mix. Dilute with Diluent to obtain a solution having a concentration of 0.2 mg/mL of USP Valsartan RS in Diluent.
Sample stock solution:
To the equivalent of 62.5 mg of hydrochlorothiazide from a number of Tablets add 5 mL of water, and allow to stand for 5 min. Then add 100 mL of Diluent, sonicate for 15 min, and shake for 30 min. Dilute with Diluent to 250 mL, and centrifuge a portion of this solution at 3000 rpm. Dilute 25.0 mL of the clear supernatant with Diluent to 200.0 mL.
Sample solution:
0.2 mg/mL of valsartan, from Sample stock solution in Diluent
Chromatographic system
Mode:
LC
Detector:
UV 265 nm
Column:
3.0-mm × 12.5-cm; 5-µm packing L1
Flow rate:
0.4 mL/min
Injection size:
10 µL
System suitability
Sample:
Standard solution
Suitability requirements
Relative standard deviation:
NMT 2.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C24H29N5O3 and C7H8ClN3O4S2 in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of the appropriate USP Reference Standard in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of the corresponding analyte in the Sample solution (mg/mL) |
Acceptance criteria:
90.0%–110.0%
PERFORMANCE TESTS
• Dissolution 711
711
Medium:
pH 6.8 phosphate buffer; 1000 mL
Apparatus 2:
50 rpm
Time:
30 min
Analytical wavelength:
250 nm for valsartan and 272 nm for hydrochlorothiazide
Cell path length:
0.2 cm quartz
Standard solution:
USP Hydrochlorothiazide RS and USP Valsartan RS in Medium
Sample solutions:
Pass a portion of the solution under test through a suitable glass fiber filter of 1-µm pore size. Dilute with Medium, if necessary, to a concentration similar to that of the Standard solution.
Calculate the percentage of C24H29N5O3 dissolved:
Result = [(AT2 × D) 
(AT1 × E)/(C × D) (B × E)] × 12,500
(AT1 × E)/(C × D) (B × E)] × 12,500Calculate the percentage of C7H8ClN3O4S2 dissolved:
Result = [(AT1 × C) (AT2 × B)/(D × C) (E ×B)] × 80,000
(AT2 × B)/(D × C) (E ×B)] × 80,000| AT1 | = | = absorbance of the Sample solution at 272 nm |
| AT2 | = | = absorbance of the Sample solution at 250 nm |
| B | = | = A1%V272, absorptivity (1%, 0.2 cm, 272 nm) of valsartan in Medium |
| C | = | = A1%V250, absorptivity (1%, 0.2 cm, 250 nm) of valsartan in Medium |
| D | = | = A1%H272, absorptivity (1%, 0.2 cm, 272 nm) of hydrochlorothiazide in Medium |
| E | = | = A1%H250, absorptivity (1%, 0.2 cm, 250 nm) of hydrochlorothiazide in Medium |
Tolerances:
NLT 80% (Q) of the labeled amounts of C24H29N5O3 and C7H8ClN3O4S2 is dissolved.
• Uniformity of Dosage Units 905
905
Procedure for content uniformity
Diluent, Solution A, Solution B, Mobile phase, Standard solution, and Chromatographic system:
Proceed as directed in the Assay.
Sample solution:
Transfer 1 Tablet to a 200-mL volumetric flask, add 5 mL of water, and allow to stand for 5 min. Add 100 mL of Diluent, and sonicate for 15 min. Dilute with Diluent to 250 mL, mix, and centrifuge a portion of this solution at 3000 rpm. Dilute a volume of the clear supernatant with Diluent to obtain a solution having a concentration of 0.2 mg/mL of valsartan.
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of valsartan (C24H29N5O3) and hydrochlorothiazide (C7H8ClN3O4S2) in the Tablet taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rs | = | = peak response from the Standard solution |
| CS | = | = concentration of the appropriate USP Reference Standard in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of the corresponding analyte in the Sample solution (mg/mL) |
Acceptance criteria:
Meet the requirements
IMPURITIES
Organic Impurities
• Procedure
Diluent, Solution A, Solution B, Mobile phase, Sample solution, and Chromatographic system:
Proceed as directed in the Assay.
Standard stock solution:
0.03 mg/mL of USP Benzothiadiazine Related Compound A RS, 0.06 mg/mL of USP Hydrochlorothiazide RS, 0.08 mg/mL of USP Valsartan RS, and 0.2 mg/mL of USP Valsartan Related Compound B RS in Diluent
System suitability solution:
Dilute 5.0 mL of the Standard stock solution with Diluent to 100 mL.
Standard solution:
Dilute 10.0 mL of System suitability solution in 100.0 mL of Diluent
System suitability
Samples:
System suitability solution and Standard solution
Suitability requirements
Resolution:
NLT 1.4 between valsartan related compound B and valsartan and NLT 1.4 between benzothiadiazine related compound A and hydrochlorothiazide, System suitability solution
Relative standard deviation:
NMT 10.0% for the valsartan and hydrochlorothiazide peaks, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Disregard the peak, if any, with a retention time of 22 min.
Calculate the percentage of benzothiadiazine related compound A in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of benzothiadiazine related compound A from the Sample solution |
| rS | = | = peak response of benzothiadiazine related compound A from the Standard solution |
| CS | = | = concentration of benzothiadiazine related compound A in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of hydrochlorothiazide in the Sample solution (mg/mL) |
Calculate the percentage of each other impurity in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of each other impurity from the Sample solution |
| rS | = | = peak response of valsartan from the Standard solution |
| CS | = | = concentration of valsartan in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of valsartan (for calculating other impurities) in the Sample solution (mg/mL) |
Acceptance criteria:
NMT 1.0% of benzothiadiazine related compound A; NMT 0.2% of any other impurity, excluding valsartan related compound A; NMT 1.3% of total impurities, excluding valsartan related compound A. [Note—Valsartan related compound A is the enantiomer of valsartan and coelutes with valsartan in this test. ]
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers, and protect from moisture and heat. Store at controlled room temperature.
• USP Reference Standards 11
11
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
USP Hydrochlorothiazide RS
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USP Valsartan RS
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USP Valsartan Related Compound B RS
(S-N-Butyryl-N-([2¢-(1H-tetrazole-5-yl)biphen-4-yl]methyl)-valine.
C23H27N5O3 421.49
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(S-N-Butyryl-N-([2¢-(1H-tetrazole-5-yl)biphen-4-yl]methyl)-valine.
C23H27N5O3 421.49
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 4998
Pharmacopeial Forum: Volume No. 37(4)