Losartan Potassium and Hydrochlorothiazide Tablets
DEFINITION
Losartan Potassium and Hydrochlorothiazide Tablets contain NLT 95.0% and NMT 105.0% of the labeled amounts of losartan potassium (C22H22ClKN6O) and hydrochlorothiazide (C7H8ClN3O4S2).
IDENTIFICATION
• The retention times of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
Buffer A:
2.76 g/L of monobasic sodium phosphate in water. Adjust with phosphoric acid to a pH of 2.5.
Buffer B:
1.25 g/L of monobasic potassium phosphate and 1.5 g/L of dibasic sodium phosphate in water. The pH of the resulting solution is about 7.0–7.5.
Diluent:
Acetonitrile and Buffer A (3:2)
Solution A:
Acetonitrile and Buffer B (7:93)
Solution B:
Use acetonitrile.
Mobile phase:
See the gradient table below.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 100 | 0 |
| 12 | 92 | 8 |
| 28 | 38 | 62 |
| 30 | 100 | 0 |
| 35 | 100 | 0 |
Standard solution:
Transfer USP Losartan Potassium RS and USP Hydrochlorothiazide RS into a suitable volumetric flask, and dissolve in Diluent (50% of the volume of the flask). Dilute with Buffer A to volume to obtain a solution having concentrations as directed in the table below. Pass a portion of the solution through a PTFE or equivalent filter of 0.45-µm pore size.
| Tablet Strength Losartan Potassium/Hydrochlorothiazide (mg) |
Concentration of USP Losartan Potassium RS (mg/mL) |
Concentration of USP Hydrochlorothiazide RS (mg/mL) |
|---|---|---|
| 50/12.5 | 0.4 | 0.1 |
| 100/12.5 | 0.4 | 0.05 |
| 100/25 | 0.4 | 0.1 |
Sample stock solution:
Transfer 10 Tablets into a suitable volumetric flask and add Diluent as directed in the table below. Mix well and mechanically shake or stir until the solid is dispersed. Dilute with Buffer A to volume, and sonicate.
| Tablet Strength Losartan Potassium/Hydrochlorothiazide (mg) |
Flask Size (mL) |
Volume of Diluent (mL) |
|---|---|---|
| 50/12.5 | 250 | 210 |
| 100/12.5 | 500 | 420 |
| 100/25 | 500 | 420 |
Sample solution:
Dilute a portion of the Sample stock solution first with acetonitrile (20% of the volume of the flask) and then with Buffer A, to obtain a solution having nominal concentrations as directed in the table below. Pass a portion of this solution through a PTFE or equivalent filter of 0.45-µm pore size, and use the filtrate.
| Tablet Strength Losartan Potassium/Hydrochlorothiazide (mg) |
Concentration of USP Losartan Potassium RS (mg/mL) |
Concentration of USP Hydrochlorothiazide RS (mg/mL) |
|---|---|---|
| 50/12.5 | 0.4 | 0.1 |
| 100/12.5 | 0.4 | 0.05 |
| 100/25 | 0.4 | 0.1 |
Chromatographic system
Mode:
LC
Detector:
UV 280 nm
Column:
3.9-mm × 15-cm; 5-µm packing L7
Column temperature:
35
Flow rate:
1 mL/min
Injection size:
20 µL
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
Less than 2.5 for the losartan peak
Relative standard deviation:
Less than 2.0% for both hydrochlorothiazide and losartan peaks
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C22H22ClKN6O or C7H8ClN3O4S2 in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of losartan or hydrochlorothiazide from the Sample solution |
| rS | = | = peak response of losartan or hydrochlorothiazide from the Standard solution |
| CS | = | = concentration of USP Losartan Potassium RS or USP Hydrochlorothiazide RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of losartan potassium or hydrochlorothiazide in the Sample solution (mg/mL) |
Acceptance criteria:
95.0%–105.0%
PERFORMANCE TESTS
• Dissolution 
711
711
Medium:
Water; 900 mL, deaerated
Apparatus 1:
100 rpm
Time:
30 min for both losartan and hydrochlorothiazide
Buffer:
Dissolve 1.36 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 2.5.
Mobile phase:
Acetonitrile and Buffer (2:3)
Losartan potassium stock solution:
0.44 mg/mL of USP Losartan Potassium RS in Medium
Hydrochlorothiazide stock solution:
0.14 mg/mL of USP Hydrochlorothiazide RS prepared by dissolving in methanol (10% of the volume of the flask). Dilute with Medium to volume.
Standard solution:
Transfer the appropriate volumes of Losartan potassium stock solution and Hydrochlorothiazide stock solution to a 100-mL volumetric flask according to the dilution schemes in the table below. Dilute with Medium to volume.
| Tablet Strength Losartan Potassium/Hydrochlorothiazide (mg) |
Aliquot of Losartan potassium stock solution (mL) |
Aliquot of Hydrochlorothiazide stock solution (mL) |
|---|---|---|
| 50/12.5 | 12.5 | 10.0 |
| 100/12.5 | 25.0 | 10.0 |
| 100/25 | 25.0 | 20.0 |
Sample solution:
Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size.
Chromatographic system
Mode:
LC
Detector:
UV 230 nm
Column:
4.6-mm × 25-cm; 10-µm packing L7
Column temperature:
35
Flow rate:
2.3 mL/min
Injection size:
20 µL
System suitability
Sample:
Standard solution
Suitability requirements
Resolution:
NLT 2 between the hydrochlorothiazide and losartan peaks
Relative standard deviation:
NMT 2.0% for both the hydrochlorothiazide and losartan peaks
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C22H22ClKN6O or C7H8ClN3O4S2 dissolved:
Result = (rU/rS) × (CS/L) × V × 100
| rU | = | = peak response of losartan or hydrochlorothiazide from the Sample solution |
| rS | = | = peak response of losartan or hydrochlorothiazide from the Standard solution |
| CS | = | = concentration of USP Losartan Potassium RS or USP Hydrochlorothiazide RS in the Standard solution (mg/mL) |
| L | = | = Tablet label claim (mg) |
| V | = | = volume of Medium, 900 mL |
Tolerances:
NLT 85% (Q) of the labeled amount of C22H22ClKN6O and NLT 75% (Q) of the labeled amount of C7H8ClN3O4S2 is dissolved.
• Uniformity of Dosage Units 905
905
Procedure for content uniformity
Buffer A:
Prepare as directed in the Assay.
Buffer B:
Dissolve 1.36 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 2.5.
Diluent:
Prepare a mixture of acetonitrile and Buffer A (3:2).
Mobile phase:
Acetonitrile and Buffer B (2:3)
Standard stock solution 1:
0.46 mg/mL of USP Losartan Potassium RS prepared by dissolving in Diluent (50% of the total volume of the flask). Mechanically shake for 15 min or until dissolved. Dilute with Buffer A to volume.
Standard stock solution 2:
0.35 mg/mL of USP Hydrochlorothiazide RS prepared by dissolving in Diluent (50% of the total volume of the flask). Mechanically shake for 15 min or until dissolved. Dilute with Buffer A to volume.
Standard solution:
Transfer aliquots of Standard stock solution 1 and Standard stock solution 2 into a suitable volumetric flask, and add Diluent, up to 42% of the total volume of the flask. Dilute with Buffer A to volume, mix well, and sonicate for 2 min to obtain a solution having concentrations based on Tablet strength as listed in the table below. Pass a portion of the solution through a PTFE or equivalent filter of 0.45-µm pore size, and use the filtrate.
| Tablet Strength Losartan Potassium/Hydrochlorothiazide (mg) |
Concentration of USP Losartan Potassium RS (mg/mL) |
Concentration of USP Hydrochlorothiazide RS (mg/mL) |
|---|---|---|
| 50/12.5 | 0.06 | 0.014 |
| 100/12.5 | 0.06 | 0.007 |
| 100/25 | 0.06 | 0.014 |
Sample stock solution:
Transfer 1 Tablet into a suitable volumetric flask, and add Diluent as directed in the table below. Mix well, and mechanically shake for 30 min or until the solid is finely dispersed. Dilute with Buffer A to volume, and mix well.
| Tablet Strength Losartan Potassium/Hydrochlorothiazide (mg) |
Flask Size (mL) |
Volume of Diluent (mL) |
|---|---|---|
| 50/12.5 | 100 | 50 |
| 100/12.5 | 200 | 100 |
| 100/25 | 200 | 100 |
Sample solution:
Dilute 10 mL of the Sample stock solution in a 100-mL volumetric flask, with 45 mL of Diluent, and then dilute with Buffer A to volume. Pass an aliquot of the solution through a PTFE or equivalent filter of 0.45-µm pore size, and use the filtrate.
Chromatographic system
Mode:
LC
Detector:
UV 230 nm
Column:
4.6-mm × 25-cm; 10-µm packing L7
Column temperature:
35
Flow rate:
2.3 mL/min
Injection size:
20 µL
System suitability
Sample:
Standard solution
Suitability requirements
Resolution:
NLT 2 between the hydrochlorothiazide and losartan peaks
Relative standard deviation:
NMT 2.0% for both the hydrochlorothiazide and losartan peaks
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C22H22ClKN6O or C7H8ClN3O4S2 in the Tablet taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of losartan or hydrochlorothiazide from the Sample solution |
| rS | = | = peak response of losartan or hydrochlorothiazide from the Standard solution |
| CS | = | = concentration of USP Losartan Potassium RS or USP Hydrochlorothiazide RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of losartan potassium or hydrochlorothiazide in the Sample solution (mg/mL) |
Acceptance criteria:
Meet the requirements
IMPURITIES
Organic Impurities
• Procedure
Buffer A, Buffer B, Diluent, Solution A, Solution B, Mobile phase, Standard solution, Sample solution, and Chromatographic system:
Prepare as directed in the Assay.
Chlorothiazide standard solution:
0.1 mg/mL of USP Chlorothiazide RS prepared by dissolving in Diluent (50% of the volume of the flask). Dilute with Buffer A to volume, and sonicate.
Benzothiadiazine related compound A standard solution:
0.1 mg/mL of USP Benzothiadiazine Related Compound A RS prepared by dissolving in Diluent (50% of the volume of the flask). Dilute with Buffer A to volume, and sonicate.
Stressed losartan solution:
[Note—This solution contains the degradates 1-H-dimer and 2-H-dimer and losartan potassium. ] Weigh 12 mg of the USP Losartan Potassium RS into a 50-mL flask. Dissolve in 5 mL of water. Pipet 5.0 mL of 0.1 N hydrochloric acid into this solution, and place it in an oven at 105 for 1–2 h. Remove from the oven and allow to cool to room temperature. Pipet 5.0 mL of 0.1 N sodium hydroxide into the flask, and dilute with water to volume.
for 1–2 h. Remove from the oven and allow to cool to room temperature. Pipet 5.0 mL of 0.1 N sodium hydroxide into the flask, and dilute with water to volume.
Diluted standard solution:
Dilute portions of the Standard solution and Benzothiadiazine related compound A standard solution first with acetonitrile (30% of the volume of the flask), and then with Buffer A to obtain a solution having nominal concentrations based on Tablet strength as listed in the table below.
| Tablet Strength Losartan Potassium/Hydrochlorothiazide (mg) |
Concentration of USP Losartan Potassium RS (µg/mL) |
Concentration of USP Hydrochlorothiazide RS (µg/mL) |
Concentration of USP Benzothiadiazine Related Compound A RS (µg/mL) |
|---|---|---|---|
| 50/12.5 | 4 | 1 | 1 |
| 100/12.5 | 4 | 0.5 | 1 |
| 100/25 | 4 | 1 | 1 |
System suitability solution:
Dissolve weighed quantities of USP Losartan Potassium RS and USP Hydrochlorothiazide RS in a suitable volumetric flask in Diluent (50% of the volume of the flask). Add the Stressed losartan solution, about 25% of the volume of the flask, into the same flask. Transfer appropriate amounts of Chlorothiazide standard solution and Benzothiadiazine related compound A standard solution into the same flask, and dilute with Buffer A to volume to obtain a solution having a known concentration of about 0.4 mg/mL of losartan, 0.1 mg/mL of hydrochlorothiazide, and 0.001 mg/mL each of benzothiadiazine related compound A and chlorothiazide. Adjust with phosphoric acid to a pH of 2.5, and mix well. Pass an aliquot of the solution through a PTFE or equivalent filter of 0.45-µm pore size, and use the filtrate.
Limit of quantitation solution:
Pipet 5.0 mL of the Diluted standard solution into a 50-mL volumetric flask. Add 15 mL of acetonitrile, dilute with Buffer A to volume, and mix well.
System suitability
Samples:
Standard solution, Diluted standard solution, System suitability solution, and Limit of quantitation solution
Suitability requirements
Resolution:
Greater than 1.5 between chlorothiazide and benzothiadiazine related compound A and greater than 1.5 between the benzothiadiazine related compound A and hydrochlorothiazide peak, System suitability solution
Tailing factor:
Less than 2.5 for the losartan peak, Standard solution
Relative standard deviation:
Less than 2.0% for both the hydrochlorothiazide and losartan peaks, Standard solution; and less than 10.0% for both the hydrochlorothiazide and losartan peaks, Diluted standard solution
Signal-to-noise ratio:
NLT 10 for each component from the first injection. If this is not met, then the signal-to-noise ratio must be greater than 3 with a relative standard deviation of area counts less than 25% for three replicate injections, Limit of quantitation solution
Analysis
Samples:
Sample solution and Diluted standard solution [Note—The runtime is about 1.6 times the retention time of the losartan peak. Identify the peaks using the relative retention times provided in Impurity Table 1. ]
Calculate the percentage of benzothiadiazine related compound A (expressed as hydrochlorothiazide equivalent) in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
| rU | = | = peak response of benzothiadiazine related compound A from the Sample solution |
| rS | = | = peak response of benzothiadiazine related compound A from the Diluted standard solution |
| CS | = | = concentration of USP Benzothiadiazine Related Compound A RS in the Diluted standard solution (mg/mL) |
| CU | = | = concentration of hydrochlorothiazide in the Sample solution (mg/mL) |
| Mr1 | = | = molecular weight of hydrochlorothiazide, 298 |
| Mr2 | = | = molecular weight of benzothiadiazine related compound A, 286 |
Calculate the percentage of each specified impurity in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of each individual impurity from the Sample solution |
| rS | = | = peak response of losartan from the Diluted standard solution |
| CS | = | = concentration of USP Losartan Potassium RS in the Diluted standard solution (mg/mL) |
| CU | = | = nominal concentration of losartan potassium in the Sample solution (mg/mL) |
For Tablet strengths of 50/12.5 and 100/25 for losartan potassium/hydrochlorothiazide, respectively, calculate the percentage of any other impurity in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of each individual impurity from the Sample solution |
| rS | = | = peak response of losartan from the Diluted standard solution |
| CS | = | = concentration of USP Losartan Potassium RS in the Diluted standard solution (mg/mL) |
| CU | = | = nominal concentration of losartan potassium in the Sample solution (mg/mL) |
For a Tablet strength of 100/12.5 for losartan potassium/hydrochlorothiazide, calculate the percentage of any other impurity in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of each individual impurity from the Sample solution |
| rS | = | = peak response of hydrochlorothiazide from the Diluted standard solution |
| CS | = | = concentration of USP Hydrochlorothiazide RS in the Diluted standard solution (mg/mL) |
| CU | = | = nominal concentration of hydrochlorothiazide in the Sample solution (mg/mL) |
Acceptance criteria
Individual impurities:
See Impurity Table 1.
Total impurities:
NMT 2.0%. [Note—The Total impurities include the sum of all the specified impurities and the sum of all the unspecified impurities that are equal to or greater than 0.1%. ]
Impurity Table 1
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|---|---|---|
| Chlorothiazidea | 0.57 | — |
| Benzothiadiazine related compound A | 0.69 | 1.0 |
| Hydrochlorothiazide | 1.0 | — |
| Losartan | 2.7 | — |
| 1-H-Dimerb | 3.3 | 0.5 |
| 2-H-Dimerc | 3.5 | 0.5 |
|
a
This process impurity (not a degradation product) is related to hydrochlorothiazide and is controlled in the drug substance.
b
Related to losartan potassium: 5-[4¢-([2-butyl-5-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]biphenyl-2-yl]-1H-tetrazol-1-yl]methyl]-4-chloro-1H-imidazol-1-yl)methyl]biphenyl-2-yl]tetrazol, potassium salt.
c
Related to losartan potassium: 5-[4¢-([2-butyl-5-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]biphenyl-2-yl]-2H-tetrazol-2-yl]methyl]-4-chloro-1H-imidazol-1-yl)methyl]biphenyl-2-yl]tetrazol, potassium salt.
|
||
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tightly closed containers protected from light, 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
') + '&img=../../images/v35300/c11rs1396.gif',600,500);)
4-Amino-6-chloro-1,3-benzenedisulfonamide.
C6H8ClN3O4S2 285.73
USP Chlorothiazide RS
') + '&img=../../images/v35300/cas-58-94-6.gif',600,500);)
USP Hydrochlorothiazide RS
') + '&img=../../images/v35300/cas-58-93-5.gif',600,500);)
USP Losartan Potassium RS
') + '&img=../../images/v35300/cas-124750-99-8.gif',600,500);)
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 3725
Pharmacopeial Forum: Volume No. 34(6) Page 1455