Losartan Potassium 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

Losartan Potassium and Hydrochlorothiazide Tablets contain NLT 95.0% and NMT 105.0% of the labeled amount of losartan potassium (C₂₂H₂₂ClKN₆O) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂).

2 IDENTIFICATION

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

B. The UV spectra of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

Change to read:

Procedure

Buffer A: 2.76 g/L of monobasic sodium phosphate (ERR 1-Nov-2020) 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.

Solution A: Acetonitrile and Buffer B (7:93)

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and Buffer A (60:40)

Standard solution: Transfer appropriate amounts of 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 Table 2. Pass a portion of the solution through a PTFE or equivalent filter of 0.45-μm pore size.

Table 2

Sample stock solution: Transfer 10 Tablets into a suitable volumetric flask and add Diluent as directed in Table 3. Mix well and mechanically shake or stir until the solid is dispersed. Dilute with Buffer A to volume, and sonicate.

Table 3

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 of losartan potassium and hydrochlorothiazide similar to those of the Standard solution.

Pass a portion of this solution through a PTFE or equivalent filter of 0.45-μm pore size, and use the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm. For Identification B, use a diode array detector in the range of 190–400 nm.

Column: 3.9-mm × 15-cm; 5-μm packing L7

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 20 μL

System suitability

Sample: Standard solution

[Note—The relative retention times for hydrochlorothiazide and losartan are 1.0 and 3.0, respectively.]

Suitability requirements

Tailing factor: NMT 2.5 for the losartan peak

Relative standard deviation: NMT 2.0% for both hydrochlorothiazide and losartan peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of losartan potassium (C₂₂H₂₂ClKN₆O) or hydrochlorothiazide (C₇H₈ClN₃O₄S₂) in the

portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of losartan or hydrochlorothiazide from the Sample solution

r_S = peak response of losartan or hydrochlorothiazide from the Standard solution

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

C_U = nominal concentration of losartan potassium or hydrochlorothiazide in the Sample solution (mg/mL)

Acceptance criteria: 95.0%–105.0%

4 PERFORMANCE TESTS

Dissolution 〈711〉

Test 1

Medium: Water; 900 mL, deaerated

Apparatus 1: 100 rpm

Time: 30 min for both losartan and hydrochlorothiazide

Buffer: 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 (40:60)

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 Table 4. Dilute with Medium to volume.

Table 4

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

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 volume: 20 μL

Run time: NLT 2 times the retention time of the losartan peak

System suitability

Sample: Standard solution

[Note—The relative retention times for hydrochlorothiazide and losartan are 1.0 and 2.7, respectively.]

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 the labeled amount of losartan potassium (C₂₂H₂₂ClKN₆O) or hydrochlorothiazide (C₇H₈ClN₃O₄S₂)

dissolved:

Result = (r_U/r_S) × C_S × V × (1/L) × 100

r_U = peak response of losartan or hydrochlorothiazide from the Sample solution

r_S = peak response of losartan or hydrochlorothiazide from the Standard solution

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: NLT 85% (Q) of the labeled amount of losartan potassium (C₂₂H₂₂ClKN₆O) and NLT 75% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) is dissolved.

Test 2: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 2.

Medium, Apparatus 1, and Time: Proceed as directed in Test 1.

Buffer: 1.78 g/L of dibasic sodium phosphate dihydrate in water. Adjust with phosphoric acid to a pH of 6.5.

Mobile phase: Acetonitrile and Buffer (32:68)

Diluent: Acetonitrile and water (40:60)

Standard stock solution 1: 1.1 mg/mL of USP Losartan Potassium RS in Diluent. Sonication may be necessary for complete dissolution.

Standard stock solution 2: 0.28 mg/mL of USP Hydrochlorothiazide RS in Diluent. Sonication may be necessary for complete dissolution.

Standard solution: Transfer appropriate volumes of Standard stock solution 1 and Standard stock solution 2 to a 100-mL volumetric flask according to the dilution schemes in Table 5. Dilute with Medium to volume.

Table 5

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 25-cm; 5-μm packing L1

Autosampler temperature: 8°

Flow rate: 1.2 mL/min

Injection volume: 10 μL

Run time: NLT 2 times the retention time of the losartan peak

System suitability

Sample: Standard solution

[Note—The relative retention times for hydrochlorothiazide and losartan are 1.0 and 1.4, respectively.]

Suitability requirements

Relative standard deviation: NMT 2.0% for both the hydrochlorothiazide and losartan peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of losartan potassium (C₂₂H₂₂ClKN₆O) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂) dissolved:

Result = (r_U/r_S) × C_S × (1/L) × V × 100

r_U = peak response of losartan or hydrochlorothiazide from the Sample solution

r_S = peak response of losartan or hydrochlorothiazide from the Standard solution

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

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 85% (Q) of the labeled amount of losartan potassium (C₂₂H₂₂ClKN₆O) and NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) is dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Organic Impurities

Buffer A, Buffer B, Solution A, Solution B, Mobile phase, Diluent, Standard solution, Sample solution, and Chromatographic system: Proceed 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 in 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.

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), then with Buffer A to obtain a solution having nominal concentrations based on Tablet strength as listed in Table 6.

Table 6

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.

Sensitivity 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, andSensitivity solution

[Note—The run time is about 1.6 times the retention time of the losartan peak. See Table 7 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between chlorothiazide and benzothiadiazine related compound A; NLT 1.5 between benzothiadiazine related compound A and hydrochlorothiazide, System suitability solution

Tailing factor: NMT 2.5 for the losartan peak, Standard solution

Relative standard deviation: NMT 2.0% for both the hydrochlorothiazide and losartan peaks, Standard solution; NMT 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 3 replicate injections, Sensitivity solution

Analysis

Samples: Sample solution and Diluted standard solution

Calculate the percentage of benzothiadiazine related compound A (expressed as hydrochlorothiazide equivalent) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100

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

r_S = peak response of benzothiadiazine related compound A from the Diluted standard solution

C_S = concentration of USP Benzothiadiazine Related Compound A RS in the Diluted standard solution (mg/mL)

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

M_r1 = molecular weight of hydrochlorothiazide, 298

M_r2 = molecular weight of benzothiadiazine related compound A, 286

Calculate the percentage of each specified impurity in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of each individual impurity from the Sample solution

r_S = peak response of losartan from the Diluted standard solution

C_S = concentration of USP Losartan Potassium RS in the Diluted standard solution (mg/mL)

C_U = nominal concentration of losartan potassium in the Sample solution (mg/mL)

For Tablet strengths of 50/12.5 and 100/25 mg for losartan potassium/hydrochlorothiazide, respectively, calculate the percentage of any other impurity in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of each individual impurity from the Sample solution

r_S = peak response of losartan from the Diluted standard solution

C_S = concentration of USP Losartan Potassium RS in the Diluted standard solution (mg/mL)

C_U = nominal concentration of losartan potassium in the Sample solution (mg/mL)

For a Tablet strength of 100/12.5 mg for losartan potassium/hydrochlorothiazide, calculate the percentage of any other impurity in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of each individual impurity from the Sample solution

r_S = peak response of hydrochlorothiazide from the Diluted standard solution

C_S = concentration of USP Hydrochlorothiazide RS in the Diluted standard solution (mg/mL)

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

Acceptance criteria See Table 7.

Table 7

^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-[(5-{4'-[(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-[(5-{4'-[(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.

^d Total impurities include the sum of all the specified impurities and the unspecified impurities that are equal to or greater than 0.1%.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tightly closed containers protected from light, and store at controlled room temperature.

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

USP Reference Standards 〈11〉

USP Benzothiadiazine Related Compound A RS

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

C₆H₈ClN₃O₄S₂ 285.73

USP Chlorothiazide RS

USP Hydrochlorothiazide RS

USP Losartan Potassium RS