Telmisartan and Hydrochlorothiazide Tablets
DEFINITION
Telmisartan and Hydrochlorothiazide Tablets contain NLT 95.0% and NMT 105.0% of the labeled amount of telmisartan (C33H30N4O2) and NLT 90.0% and NMT 107.5% of the labeled amount of hydrochlorothiazide (C7H8ClN3O4 S2).
IDENTIFICATION
• A. Ultraviolet Absorption 
197U
:
The spectrum of the solution under test corresponds to that of the Standard solution, as obtained in Assay.
197U:
The spectrum of the solution under test corresponds to that of the Standard solution, as obtained in Assay.
• B.
The retention time of the two major peaks of the Sample solution corresponds to that of the two major peaks in Standard solution A, as obtained in the Assay.
ASSAY
• Procedure
Diluent:
0.005 M methanolic solution of sodium hydroxide
Buffer:
2.0 g/L of ammonium dihydrogen phosphate. Adjust with phosphoric acid to a pH of 3.0.
Solution A:
Methanol and acetonitrile (1:1)
Mobile phase:
See the gradient table below.
| Time (min) |
Buffer (%) |
Solution A (%) |
|---|---|---|
| 0 | 85 | 15 |
| 3.50 | 85 | 15 |
| 3.51 | 45 | 55 |
| 7.70 | 45 | 55 |
| 7.71 | 20 | 80 |
| 12.0 | 20 | 80 |
| 12.1 | 85 | 15 |
| 15.5 | 85 | 15 |
Standard stock solution 1:
0.025 mg/mL of USP Benzothiadiazine Related Compound A RS in Diluent
Standard stock solution 2:
1.6 mg/mL or 3.2 mg/mL (required for analyzing the Tablet strength of 80 mg/12.5 mg) of USP Telmisartan RS, 0.5 mg/mL of USP Hydrochlorothiazide RS, and 2.5 µg/mL of USP Benzothiadiazine Related Compound A RS (from Standard stock solution 1) in Diluent
Standard solution A:
Dilute Standard stock solution 2 with a 1:1 solution of Buffer and Solution A to prepare 0.32 mg/mL of telmisartan, 0.1 mg/mL of hydrochlorothiazide, and 0.5 µg/mL of benzothiadiazine related compound A for Tablet strengths of 80 mg/25 mg and 40 mg/12.5 mg. The final concentrations for analyzing the Tablet strength of 80 mg/12.5 mg are 0.32 mg/mL of telmisartan, 0.05 mg/mL of hydrochlorothiazide solution, and 0.25 µg/mL of benzothiadiazine related compound A.
Sample stock solution:
Transfer NLT 10 Tablets into a suitable volumetric flask, add 0.1 N sodium hydroxide solution (5% of the total volume of the flask), and shake until the Tablets have completely disintegrated. Add methanol (80% of the total volume of the flask). Sonicate for 10 min and stir vigorously for 30 min. Allow to cool to room temperature, dilute with methanol to volume, and mix. The concentration of the Sample stock solution is about 1.6 mg/mL of telmisartan. [Note—The hydrochlorothiazide concentration may vary depending on the ratio of telmisartan to hydrochlorothiazide in the Tablet. ] Centrifuge a portion of the solution at 4000 rpm. [Note—To prevent heat from degrading the sample, do not extend the sonication time and also maintain the bath temperature at NMT 22
by adding ice. ]
by adding ice. ]
Sample solution:
Dilute 1 mL of the Sample stock solution to 5 mL in a 1:1 solution of Buffer and Solution A.
Chromatographic system
Mode:
LC
Detector:
UV 270 nm for hydrochlorothiazide and 298 nm for telmisartan
Column:
4.0-mm × 12.5-cm; 5-µm packing L7
Column temperature:
40
Flow rate:
1.2 mL/min
Injection size:
10 µL
System suitability
Sample:
Standard solution A
Suitability requirements
Resolution:
NLT 2.0 between hydrochlorothiazide and benzothiadiazine related compound A
Relative standard deviation:
NMT 2.0% for both the telmisartan and hydrochlorothiazide peaks
Analysis
Samples:
Standard solution A and Sample solution
Calculate the percentages of the labeled amount of telmisartan (C33H30N4O2) and hydrochlorothiazide (C7H8ClN3O4 S2) in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of telmisartan or hydrochlorothiazide from the Sample solution |
| rS | = | = peak response of telmisartan or hydrochlorothiazide from Standard solution A |
| CS | = | = concentration of USP Telmisartan RS or the hydrochlorothiazide peak in Standard solution A (mg/mL) |
| CU | = | = nominal concentration of telmisartan or hydrochlorothiazide in the Sample solution (mg/mL) |
Acceptance criteria:
95.0%–105.0% of telmisartan and 90.0%–107.5% of hydrochlorothiazide
PERFORMANCE TESTS
• Dissolution 711
711
Telmisartan
Medium:
pH 7.5 phosphate buffer (13.61 g/L of potassium dihydrogen phosphate in water. Adjust with 2 M sodium hydroxide to a pH of 7.5); 900 mL
Apparatus 2:
75 rpm
Time:
30 min
Hydrochlorothiazide
Medium:
0.1 N hydrochloric acid; 900 mL
Apparatus 1:
100 rpm
Time:
30 min
Analysis:
Determine the amounts of telmisartan and hydrochlorothiazide dissolved by the following method.
Solution A:
5.0 g/L of ammonium dihydrogen phosphate in water. Adjust with phosphoric acid to a pH of 3.0.
Solution B:
Acetonitrile
Standard stock solution:
Appropriate amounts of USP Telmisartan RS and USP Hydrochlorothiazide RS in methanol
Telmisartan standard solution:
Dilute the Standard stock solution with Telmisartan Medium to obtain a solution having a known concentration of telmisartan similar to that expected in the Sample solution.
Hydrochlorothiazide standard solution:
Dilute the Standard stock solution with Hydrochlorothiazide Medium to obtain a solution having a known concentration of hydrochlorothiazide similar to that expected in the Sample solution.
Sample solution:
Pass a portion of the solution through a suitable filter of 0.45-µm pore size, discard the first few mL, and dilute with appropriate Medium, if necessary.
Chromatographic system
Mode:
LC
Detector:
UV 270 nm for hydrochlorothiazide and 298 nm for telmisartan
Column:
3.0-mm × 6-cm; 5-µm packing L7
Column temperature:
40
Flow rate:
0.6 mL/min from 0–5.00 min and 1.0 mL/min from 5.01–6.20 min. The flow rate goes back to 0.6 mL from 6.21–9.70.
Injection size:
4 µL
Mobile phase:
See the gradient table below.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 85 | 15 |
| 1.50 | 85 | 15 |
| 1.51 | 60 | 40 |
| 5.00 | 60 | 40 |
| 5.01 | 20 | 80 |
| 6.20 | 20 | 80 |
| 6.21 | 85 | 15 |
| 9.70 | 85 | 15 |
System suitability
Samples:
Telmisartan standard solution or Hydrochlorothiazide standard solution
[Note—The relative retention times for hydrochlorothiazide and telmisartan are 0.33 and 1.0, respectively. ]
Suitability requirements
Tailing factor:
NMT 2.5 for both hydrochlorothiazide and telmisartan
Relative standard deviation:
NMT 2%
Calculate the percentage of telmisartan or hydrochlorothiazide dissolved:
Result = (rU/rS) × (CS/L) × V × 100
| rU | = | = peak response of telmisartan or hydrochlorothiazide in the Sample solution |
| rS | = | = peak response of telmisartan in the Telmisartan standard solution or hydrochlorothiazide in the Hydrochlorothiazide standard solution |
| CS | = | = concentration of telmisartan in the Telmisartan standard solution or hydrochlorothiazide in the Hydrochlorothiazide standard solution (mg/mL) |
| L | = | = Tablet label claim for telmisartan or hydrochlorothiazide (mg) |
| V | = | = volume of Medium, 900 mL |
Tolerances:
NLT 80% (Q) of the labeled amount of telmisartan and hydrochlorothiazide is dissolved.
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
IMPURITIES
Organic Impurities
• Procedure
Diluent, Buffer, Solution A, Mobile phase, Standard stock solution 1, Standard solution A, Sample solution, and Chromatographic system:
Proceed as directed in the Assay.
Standard solution B:
1.25 µg/mL of USP Benzothiadiazine Related Compound A RS in Diluent from Standard stock solution 1. Dilute further with a 1:1 solution of Buffer and Solution A to prepare a 0.25-µg/mL solution for a Tablet strength of 80 mg/12.5 mg, and a 0.5-µg/mL solution for Tablet strengths of 40 mg/12.5 mg and 80 mg/25 mg.
Standard stock solution 3:
1.6 mg/mL of USP Telmisartan RS and 0.5 mg/mL of USP Hydrochlorothiazide RS in Diluent for Tablet strengths of 40 mg/12.5 mg and 80 mg/25 mg. For the Tablet strength of 80 mg/12.5 mg, the concentrations are 1.6 mg/mL of USP Telmisartan RS and 0.25 mg/mL of USP Hydrochlorothiazide RS in Diluent.
Sensitivity solution:
Dilute 10 mL of Standard stock solution 3 with Diluent to 100 mL. Combine 1.0 mL of this solution with 2.0 mL of Standard stock solution 1 and dilute with Diluent to 100 mL. Dilute 1 mL of this solution to 5 mL with a 1:1 solution of Buffer and Solution A.
System suitability
Samples:
Standard solution A and Sensitivity solution
Suitability requirements
Resolution:
NLT 2.0 between hydrochlorothiazide and benzothiadiazine related compound A, Standard solution A
Relative standard deviation:
NMT 2.0% for both the telmisartan and hydrochlorothiazide peaks, Standard solution A
Signal-to-noise ratio:
NLT 3.0 for the telmisartan, hydrochlorothiazide, and benzothiadiazine related compound A peaks from the Sensitivity solution
Analysis
Samples:
Standard solution A, Standard solution B, and Sample solution
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 Standard solution B |
| CS | = | = concentration of USP Benzothiadiazine Related Compound A RS in Standard solution B (mg/mL) |
| CU | = | = concentration of hydrochlorothiazide in the Sample solution (mg/mL) |
Calculate the percentage of each unspecified degradation impurity related to hydrochlorothiazide in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of each unspecified degradation impurity at 270 nm from the Sample solution |
| rS | = | = peak response of hydrochlorothiazide from Standard solution A |
| CS | = | = concentration of USP Hydrochlorothiazide RS in Standard solution A (mg/mL) |
| CU | = | = concentration of hydrochlorothiazide in the Sample solution (mg/mL) |
Calculate the percentage of each unspecified degradation impurity related to telmisartan in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of each unspecified degradation impurity at 298 nm from the Sample solution |
| rS | = | = peak response of telmisartan from Standard solution A |
| CS | = | = concentration of USP Telmisartan RS in Standard solution A (mg/mL) |
| CU | = | = concentration of telmisartan in the Sample solution (mg/mL) |
Acceptance criteria
Individual impurities:
NMT 1.0% of benzothiadiazine related compound A and NMT 0.2% of each individual unspecified degradation impurity related to hydrochlorothiazide or telmisartan
Total impurities:
NMT 0.2% of the sum of all degradation products related to telmisartan and NMT 1.5% of the sum of all hydrochlorothiazide degradation products
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in well-closed containers and 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
4-Amino-6-chloro-1,3-benzenedisulfonamide.
C6H8ClN3O4S2 285.73
USP Hydrochlorothiazide RS
USP Telmisartan RS
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 4777
Pharmacopeial Forum: Volume No. 36(3) Page 683