Amlodipine, Valsartan, 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

Amlodipine, Valsartan, and Hydrochlorothiazide Tablets contain NLT 92.5% and NMT 107.5% each of the labeled amounts of amlodipine (C₂₀H₂₅ClN₂O₅), valsartan (C₂₄H₂₉N₅O₃), and hydrochlorothiazide (C₇H₈ClN₃O₄S₂).

2 IDENTIFICATION

A. The UV absorption spectra of the amlodipine, valsartan, and hydrochlorothiazide peaks of Sample solution A, Sample solution B, andSample solution C, and those of the Standard solution exhibit maxima and minima at the same wavelengths, as obtained in the Assay.

B. The retention times of the amlodipine, valsartan, and hydrochlorothiazide peaks of Sample solution A, Sample solution B, and Sample solution C correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Procedure

Use amber glassware for all solutions containing drug substances.

Solution A: Acetonitrile, water, and phosphoric acid (50:950:1)

Solution B: Acetonitrile, water, and phosphoric acid (950:50:1)

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and water (500:500)

0.1% Phosphoric acid: Water and phosphoric acid (1000:1)

Standard solution: 0.14 mg/mL of USP Amlodipine Besylate RS, 0.064 mg/mL of USP Valsartan RS, and 0.025 mg/mL of USP Hydrochlorothiazide RS in Diluent

Sample stock solution: Transfer NLT 10 Tablets into a suitable volumetric flask. Add 0.1% Phosphoric acid to 4% of the total volume to disperse the Tablets. Sonicate for 10 min. Add 4% of the total volume of acetonitrile, swirl to mix, and add 60% of the total volume of Diluent. Sonicate for 20 min. Dilute with Diluent to volume to obtain solutions of nominal concentrations stated in Table 2. Centrifuge, and use the clear supernatant.

Table 2

Sample solution A: Nominally equivalent to 0.1 mg/mL of amlodipine in Diluent from Sample stock solution

Sample solution B: Nominally equivalent to 0.064 mg/mL of valsartan in Diluent from Sample stock solution

Sample solution C: Nominally equivalent to 0.025 mg/mL of hydrochlorothiazide in Diluent from Sample stock solution

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm. For Identification A, use a diode array detector in the range of 200–400 nm.

Column: 4.6-mm × 15-cm; 3-μm packing L1

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

3.3 System suitability

Sample: Standard solution

3.4 Suitability requirements

Tailing factor: NMT 2.0 for amlodipine, valsartan, and hydrochlorothiazide

Relative standard deviation: NMT 2.0% for amlodipine, valsartan, and hydrochlorothiazide

3.5 Analysis

Samples: Standard solution, Sample solution A, Sample solution B, and Sample solution C

Calculate the percentage of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O₅) 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 amlodipine from Sample solution A

r_S = peak response of amlodipine from the Standard solution

C_U = concentration of USP Amlodipine Besylate RS in the Standard solution (mg/mL)

C_S = nominal concentration of amlodipine in Sample solution A (mg/mL)

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05

Calculate the percentage of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S /C_U) × 100

r_U = peak response of valsartan from Sample solution B

r_S = peak response of valsartan from the Standard solution

C_S = concentration of USP Valsartan RS in the Standard solution (mg/mL)

C_U = nominal concentration of valsartan in Sample solution B (mg/mL)

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S /C_U) × 100

r_U = peak response of hydrochlorothiazide from Sample solution C

r_S = peak response of hydrochlorothiazide from the Standard solution

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

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

Acceptance criteria: 92.5%–107.5%

4 PERFORMANCE TESTS

Dissolution 〈711〉

4.1 Test 1

Buffer: Dissolve 6.805 g of monobasic potassium phosphate and 0.896 g of sodium hydroxide in 1000 mL of water. Adjust with 0.2 N sodium hydroxide or 1 M phosphoric acid to a pH of 6.8.

Medium: Buffer; 900 mL

4.1.1 Apparatus 2

For 5/160/12.5, 10/160/12.5, 5/160/25, and 10/160/25 (mg/mg/mg) of Tablet strengths (amlodipine/valsartan/hydrochlorothiazide): 50 rpm

For 10/320/25 (mg/mg/mg) of Tablet strengths (amlodipine/valsartan/hydrochlorothiazide): 55 rpm

Time: 30 min

Solution A: Acetonitrile, water, and phosphoric acid (50:950:1)

Solution B: Acetonitrile, water, and phosphoric acid (950:50:1)

Mobile phase: See Table 3.

Table 3

Diluent: 1 mg/mL of Polysorbate 80 in Buffer

Standard stock solution A: 0.07 mg/mL of USP Amlodipine Besylate and 0.124 mg/mL of USP Hydrochlorothiazide RS. Initially dissolve with 4% of the total volume of methanol, and dilute with Diluent to volume.

Standard stock solution B: 3.2 mg/mL of USP Valsartan RS in methanol

Standard solution: 0.014 mg/mL of USP Amlodipine Besylate RS, 0.16 mg/mL of USP Valsartan RS, and 0.0248 mg/mL of USP Hydrochlorothiazide RS in Diluent from Standard stock solution A and Standard stock solution B, respectively

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size. Discard at least the first 10 mL of the filtrate.

4.1.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 250 nm

Column: 4.6-mm × 5-cm; 3-μm packing L1

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume

For 10/320/25 (mg/mg/mg) of Tablet strengths (amlodipine/valsartan/hydrochlorothiazide): 5 μL

For 5/160/12.5, 10/160/12.5, 5/160/25, and 10/160/25 (mg/mg/mg) of Tablet strengths (amlodipine/valsartan/hydrochlorothiazide): 10 μL

4.1.3 System suitability

Sample: Standard solution

4.1.4 Suitability requirements

Resolution: NLT 3.0 between amlodipine and valsartan

Tailing factor: NMT 2.0 for amlodipine, valsartan, and hydrochlorothiazide

Relative standard deviation: NMT 2.0% for amlodipine, valsartan, and hydrochlorothiazide

4.1.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O₅) dissolved:

Result = (r_U/r_S) × C_S× V × (M_r1/M_r2) × (1/L₁) × 100

r_U = peak response of amlodipine from the Sample solution

r_S = peak response of amlodipine from the Standard solution

C_S = concentration of USP Amlodipine Besylate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05

L₁ = label claim of amlodipine (mg/Tablet)

Calculate the percentage of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L₂) × 100

r_U = peak response of valsartan from the Sample solution

r_S = peak response of valsartan from the Standard solution

C_S = concentration of USP Valsartan RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L₂ = label claim of valsartan (mg/Tablet)

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L₃) × 100

r_U = peak response of hydrochlorothiazide from the Sample solution

r_S = peak response of hydrochlorothiazide from the Standard solution

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

V = volume of Medium, 900 mL

L₃ = label claim of hydrochlorothiazide (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O₅) is dissolved, NLT 80% (Q) of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) is dissolved, and NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) is dissolved.

4.2 Test 2

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

Medium: Proceed as directed under Dissolution Test 1; 900 mL.

4.2.1 Apparatus 2

For Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 5/160/12.5, 10/160/12.5, 5/160/25, 10/160/25, and 5/80/12.5 (mg/mg/mg): 50 rpm

For Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 10/320/25 (mg/mg/mg): 55 rpm

Times

For valsartan and hydrochlorothiazide: 30 min

For amlodipine: 45 min

Buffer: Mix 7.0 mL of triethylamine with 1000 mL of water. Adjust with phosphoric acid to a pH of 3.0.

Solution A: Acetonitrile and Buffer (10:90)

Solution B: Acetonitrile and Buffer (90:10)

Mobile phase: See Table 4.

Table 4

Standard stock solution A: 0.35 mg/mL of USP Amlodipine Besylate RS, prepared as follows. Initially dissolve in 10% of the final volume of methanol and dilute with Medium to volume.

Standard stock solution B: 1.6 mg/mL of USP Valsartan RS in methanol

Standard stock solution C: 0.7 mg/mL of USP Hydrochlorothiazide RS, prepared as follows. Initially dissolve in 25% of the final volume of methanol and dilute with Medium to volume.

Standard solution: (L /1000) mg/mL of amlodipine, (L /1000) mg/mL of valsartan, and (L /1000) mg/mL of hydrochlorothiazide in Medium from Standard stock solution A, Standard stock solution B, and Standard stock solution C, where L is the label claim of amlodipine in mg/Tablet, L is the label claim of valsartan in mg/Tablet, and L is the label claim of hydrochlorothiazide in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 1-μm pore size.

4.2.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 237 nm

Column: 4.6-mm × 15-cm; 5-μm packing L1

Temperatures

Autosampler: 10°

Column: 50°

Flow rate: 1.5 mL/min

Injection volume: 20 μL

4.2.3 System suitability

Sample: Standard solution

4.2.4 Suitability requirements

Tailing factor: NMT 2.0 for each peak

Relative standard deviation: NMT 2.0% for each peak

4.2.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O₅) dissolved:

Result = (r_U/r_S) × C_S× V × (M_r1/M_r2) × (1/L₁) × 100

r_U = peak response of amlodipine from the Sample solution

r_S = peak response of amlodipine from the Standard solution

C_S = concentration of USP Amlodipine Besylate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05

L₁ = label claim of amlodipine (mg/Tablet)

Calculate the percentage of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L₂) × 100

r_U = peak response of valsartan from the Sample solution

r_S = peak response of valsartan from the Standard solution

C_S = concentration of USP Valsartan RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L₂ = label claim of valsartan (mg/Tablet)

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L₃) × 100

r_U = peak response of hydrochlorothiazide from the Sample solution

r_S = peak response of hydrochlorothiazide from the Standard solution

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

V = volume of Medium, 900 mL

L₃ = label claim of hydrochlorothiazide (mg/Tablet)

Tolerances:NLT 75% (Q) of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O₅) is dissolved, NLT 80% (Q) of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) is dissolved, and NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) is dissolved.

4.3 Test 3

If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 3.

Medium: Dissolve 6.80 g of monobasic potassium phosphate in 1000 mL of water. Adjust with 10% sodium hydroxide solution to a pH of 6.8; 1000 mL for valsartan and hydrochlorothiazide; 900 mL for amlodipine.

4.3.1 Apparatus 2

For valsartan and hydrochlorothiazide: 50 rpm

For amlodipine in Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 10/320/25 (mg/mg/mg): 55 rpm

For amlodipine in Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 5/160/12.5, 10/160/12.5, 5/160/25, 10/160/25, and 5/80/12.5 (mg/mg/mg): 50 rpm

Times

For valsartan and hydrochlorothiazide: 30 min

For amlodipine: 45 min

Solution A: Acetonitrile, trifluoroacetic acid and water (10:0.1:90)

Solution B: Acetonitrile, trifluoroacetic acid and water (90:0.1:10)

Mobile phase: See Table 5.

Table 5

Diluent: Acetonitrile and water (50:50)

Standard stock solution A: 0.15 mg/mL of USP Amlodipine Besylate RS in Medium, prepared as follows. Initially dissolve and sonicate in 5% of the final volume of Diluent, and dilute with Medium to volume.

Standard stock solution B: 1.6 mg/mL of USP Valsartan RS in Medium, prepared as follows. Initially dissolve and sonicate in 20% of the final volume of Diluent, and dilute with Medium to volume.

Standard stock solution C: 0.25 mg/mL of USP Hydrochlorothiazide RS in Medium, prepared as follows. Initially dissolve and sonicate in 10% of the final volume of Diluent, and dilute with Medium to volume.

Standard solution: (L /1000) mg/mL of amlodipine, (L /1000) mg/mL of valsartan, and (L /1000) mg/mL of hydrochlorothiazide in Diluent from Standard stock solution A, Standard stock solution B, and Standard stock solution C, where L is the label claim of amlodipine in mg/Tablet, L is the label claim of valsartan in mg/Tablet, and L is the label claim of hydrochlorothiazide in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size. Discard at least the first few milliliters of the filtrate.

4.3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detectors

For amlodipine: UV 237 nm

For valsartan and hydrochlorothiazide: UV 270 nm

Column: 4.6-mm × 10-cm; 5-μm packing L1

Flow rate: 1.5 mL/min

Injection volume: 10 μL

4.3.3 System suitability

Sample: Standard solution

4.3.4 Suitability requirements

Tailing factor: NMT 2.0 for each peak

Relative standard deviation: NMT 2.0% for each peak

4.3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O₅) dissolved:

Result = (r_U/r_S) × C_S× V × (M_r1/M_r2) × (1/L₁) × 100

r_U = peak response of amlodipine from the Sample solution

r_S = peak response of amlodipine from the Standard solution

C_S = concentration of USP Amlodipine Besylate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05

L₁ = label claim of amlodipine (mg/Tablet)

Calculate the percentage of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L₂) × 100

r_U = peak response of valsartan from the Sample solution

r_S = peak response of valsartan from the Standard solution

C_S = concentration of USP Valsartan RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L₂ = label claim of valsartan (mg/Tablet)

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L₃) × 100

r_U = peak response of hydrochlorothiazide from the Sample solution

r_S = peak response of hydrochlorothiazide from the Standard solution

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

V = volume of Medium, 900 mL

L₃ = label claim of hydrochlorothiazide (mg/Tablet)

Tolerances

For Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 5/160/12.5, 10/160/12.5, 5/160/25, and 10/160/25 (mg/mg/mg): NLT 75% (Q) of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O₅) is dissolved, NLT 80% (Q) of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) is dissolved, and NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) is dissolved.

For Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 5/160/25, and 10/320/25 (mg/mg/mg): NLT 70% (Q) of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O₅) is dissolved, NLT 80% (Q) of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) is dissolved, and NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) is dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

5.1 Organic Impurities

Use amber glassware for all solutions containing drug substances.

Mobile phase, Diluent, Sample solution A, Sample solution B, Sample solution C, and Chromatographic system: Proceed as directed in the Assay.

System suitability solution: 0.02 mg/mL each of USP Benzothiadiazine Related Compound A RS and USP Valsartan Related Compound B RS, 0.005 mg/mL of USP Amlodipine Related Compound A RS, 0.14 mg/mL of USP Amlodipine Besylate RS, 0.064 mg/mL of USP Valsartan RS, and 0.025 mg/mL of USP Hydrochlorothiazide RS in Diluent

Sensitivity solution: 0.14 μg/mL of USP Amlodipine Besylate RS, 0.064 μg/mL of USP Valsartan RS, and 0.025 μg/mL of USP Hydrochlorothiazide RS in Diluent

Standard solution: 0.0005 mg/mL of USP Amlodipine Related Compound A RS, 0.0001 mg/mL of USP Benzothiadiazine Related Compound A RS, 0.0003 mg/mL of USP Amlodipine Besylate RS, 0.00015 mg/mL of USP Valsartan RS, and 0.00005 mg/mL of USP Hydrochlorothiazide RS in Diluent

5.1.1 System suitability

Samples: System suitability solution, Sensitivity solution, and Standard solution

5.1.2 Suitability requirements

Resolution: NLT 2.0 between any adjacent peaks of benzothiadiazine related compound A, hydrochlorothiazide, amlodipine related compound A, amlodipine, valsartan related compound B, and valsartan, System suitability solution

Relative standard deviation: NMT 5.0% for amlodipine related compound A, benzothiadiazine related compound A, amlodipine, valsartan, and hydrochlorothiazide, Standard solution

Signal-to-noise ratio: NLT 10 for amlodipine, valsartan, and hydrochlorothiazide, Sensitivity solution

5.1.3 Analysis

Samples: Sample solution A, Sample solution B, Sample solution C, and Standard solution

Calculate the percentage of amlodipine related compound A 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 amlodipine related compound A from Sample solution A

r_S = peak response of amlodipine related compound A from the Standard solution

C_S = concentration of USP Amlodipine Related Compound A RS in the Standard solution (mg/mL)

C_U = nominal concentration of amlodipine in Sample solution A (mg/mL)

M_r1 = molecular weight of amlodipine related compound A free base, 406.86

M_r2 = molecular weight of amlodipine related compound A fumarate, 522.94 (CN 1-Dec-2023)

Calculate the percentage of any valsartan related degradation product in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of any valsartan related degradation product from Sample solution B

r_S = peak response of valsartan from the Standard solution

C_S = concentration of USP Valsartan RS in the Standard solution (mg/mL)

C_U = nominal concentration of valsartan in Sample solution B (mg/mL)

Calculate the percentage of benzothiadiazine related compound A in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

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

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

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

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

Calculate the percentage of chlorothiazide and hydrochlorothiazide dimer in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of chlorothiazide or hydrochlorothiazide dimer from Sample solution C

r_S = peak response of hydrochlorothiazide from the Standard solution

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

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

Calculate the percentage of each unspecified degradation product 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 each unspecified degradation product from Sample solution A

r_S = peak response of amlodipine from the Standard solution

C_S = concentration of USP Amlodipine Besylate RS in the Standard solution (mg/mL)

C_U = nominal concentration of amlodipine in Sample solution A (mg/mL)

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05

Acceptance criteria: See Table 6. Disregard the amlodipine ethyl analog peak, the valsartan related compound B peak, and any peaks below 0.1%.

Table 6

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

^b 6-Chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

^c N-{[2'-(1H-Tetrazole-5-yl)biphenyl-4-yl]methyl}-l-valine.

^d 6-Chloro-N-[(6-chloro-7-sulfamoyl-2,3-dihydro-4H-1,2,4-benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

^e 3-Ethyl 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxylate].

^f These are specified unidentified degradation products. No information is available about chemical structures or chemical names for these impurities.

^g Diethyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate. Process related impurity given for information only.

^h N-Butyryl-N-{[2′-(1H-tetrazole-5-yl)biphenyl-4-yl]-methyl}-l-valine. Process related impurity given for information only.

ⁱ Benzenesulfonic acid is the counter ion to the amlodipine, and peaks at RRT of 0.33 and 0.42 are not considered as degradation products.

5.2 Limit of Valsartan Related Compound A

[Note-Valsartan related compound A is a process impurity and a formulation specific degradation product.]

Mobile phase: n-Hexane, 2-propanol, and trifluoroacetic acid (850:150:1)

System suitability solution: 0.04 mg/mL each of USP Valsartan Related Compound A and USP Valsartan RS in Mobile phase

Standard solution: 0.001 mg/mL of USP Valsartan Related Compound A RS in Mobile phase

Sample solution: Nominally 0.5 mg/mL of valsartan in Mobile phase from a suitable amount of finely crushed powder from NLT 20 Tablets.

Sonication may be necessary for complete dissolution. Pass through a suitable filter of 0.45-μm pore size.

5.2.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 25-cm; 5-μm packing L40

Temperatures

Autosampler: 10°

Column: 30°

Flow rate: 0.8 mL/min

Injection volume: 20 μL

Run time: NLT 3.5 times the retention time of valsartan related compound A

5.2.2 System suitability

Samples: System suitability solution and Standard solution

[Note-The relative retention times of valsartan related compound A and valsartan are about 0.65 and 1.0, respectively.]

5.2.3 Suitability requirements

Resolution: NLT 2.0 between valsartan and valsartan related compound A, System suitability solution

Relative standard deviation: NMT 5.0% for valsartan related compound A, Standard solution

5.2.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the valsartan related compound A in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U)× 100

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

r_S = peak response of valsartan related compound A from the Standard solution

C_S = concentration of USP Valsartan Related Compound A RS in the Standard solution (mg/mL)

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

Acceptance criteria: NMT 1.0 %

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Store at controlled room temperature in tight containers in a dry place.

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

Change to read:

USP Reference Standards 〈11〉

USP Amlodipine Besylate RS

USP Amlodipine Related Compound A RS

3-Ethyl 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxylate] fumarate.

C₂₀H₂₃ClN₂O₅ · C₄H₄O₄ 522.94 (CN 1-Dec-2023)

USP Benzothiadiazine Related Compound A RS

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

C₆H₈ClN₃O₄S₂ 285.72 (CN 1-Dec-2023)

USP Hydrochlorothiazide RS

USP Valsartan RS

USP Valsartan Related Compound A RS

N-{[2’-(1H-Tetrazol-5-yl)biphenyl-4-yl]methyl}-N-pentanoyl-D-valine. (CN 1-Dec-2023)

C₂₄H₂₉N₅O₃  435.53