Amlodipine and Valsartan 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 and Valsartan Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) and valsartan (C₂₄H₂₉N₅O₃).

2 IDENTIFICATION

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

3 ASSAY

3.1 PROCEDURE

Solution A: Water and triethylamine (1000:10). Adjust with phosphoric acid to a pH of 2.8.

Solution B: Methanol and acetonitrile (700:300)

Mobile phase: See Table 1.

Table 1

Diluent: Solution A and Solution B (50:50)

Standard solution: 0.14 mg/mL of USP Amlodipine Besylate RS and 0.16 mg/mL of USP Valsartan RS. Add methanol to 5% of the final volume to dissolve, and dilute with Diluent to volume.

Sample stock solution: Transfer NLT 10 Tablets into a suitable volumetric flask. Initially add water to 10% of the final volume, and sonicate to disperse as needed. Add Diluent, using about 70% of the final volume, and shake for up to 45 min to disperse. Following dispersion, sonicate for 15 min, and shake for 30 min. Dilute with Diluent to volume to obtain a solution containing known nominal concentrations of 0.1-0.2 mg/mL of amlodipine and 1.6-6.4 mg/mL of valsartan. Centrifuge the solution for about 10 min at 3000 rpm.

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

Sample solution B: Nominally equivalent to 0.16 mg/mL of valsartan in Diluent from the Sample stock solution

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 237 nm. For Identification A, use a diode array detector in the range of 200-400 nm.

Column: 3.9-mm x 15-cm; 5-µm packing L1

Temperatures

Autosampler: 10°

Column: 30°

Flow rate: 1.0 mL/min

Injection volume: 10 µL

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5 for both amlodipine and valsartan

Relative standard deviation: NMT 2.0% for amlodipine and valsartan

3.4 Analysis

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

Calculate the percentage of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) in the portion of Tablets taken:

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

r_U = peak response of amlodipine 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

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

Result = (r_U/r_S) x (C_S/C_U) x 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)

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

4.1.1 Test 1

Buffer: Dissolve 6.805 g of monobasic potassium phosphate and 0.896 g of sodium hydroxide in water, and dilute with water to 1000 mL.

Adjust with 0.2 N sodium hydroxide or 1 M phosphoric acid to a pH of 6.8.

Medium: Buffer, 1000 mL

Apparatus 2: 75 rpm

Time: 30 min

Mobile phase: Acetonitrile, water, and trifluoroacetic acid (500:500:2)

Diluent: 1 mg/mL of Polysorbate 80 in Buffer

System suitability solution: 0.4 mg/mL each of USP Amlodipine Besylate RS and USP Valsartan RS, prepared as follows. Initially dissolve in methanol to 40% of the total volume, and dilute with Buffer to volume.

Standard stock solution A: 0.072 mg/mL of USP Amlodipine Besylate RS, prepared as follows. Initially dissolve in methanol to 4% of the final volume, and dilute with Diluent to volume.

Standard stock solution B: 2.2 mg/mL of USP Valsartan RS in methanol

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

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

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm x 15-cm; 4-µm packing L11

Column temperature: 40°

Flow rate: 1.2 mL/min

Injection volume: 10 µL

Run time: NLT 2 times the retention time of amlodipine

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2.0 between amlodipine and valsartan, System suitability solution

Tailing factor: NMT 2.0 for amlodipine and valsartan, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) dissolved:

Result = (r_U/r_S) x C_S x V x (M_r1/M_r2) x (1/L₁) x 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, 1000 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) x C_S x V x (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, 1000 mL

L₂ = label claim of valsartan (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) and valsartan (C₂₄H₂₉N₅O₃) is dissolved.

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

Medium and Time: Proceed as directed in Dissolution Test 1; 1000 mL.

Apparatus 2: 50 rpm

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 2.

Table 2

Standard stock solution A: 0.14 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

2 Standard solution: (L₁/1000) mg/mL of amlodipine and (L₂/1000) mg/mL of valsartan in Medium from Standard stock solution A and Standard stock solution B, where L₁ is the label claim of amlodipine in mg/Tablet, and L₂ is the label claim of valsartan in mg/Tablet

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

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 237 nm

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

Temperatures

Autosampler: 10°

Column: 50°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for amlodipine and valsartan

Relative standard deviation: NMT 2.0% for amlodipine and valsartan

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) dissolved:

Result = (r_U/r_S) x C_S x V x (M_r1/M_r2) x (1/L₁) x 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, 1000 mL V

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05 12

L₁ = label claim of amlodipine ( mg/Tablet)

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

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

r_S = peak response of valsartan from the Sample solution

r_U = peak response of valsartan from the Standard solution

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

V = volume of Medium, 1000 mL

L₂ = label claim of valsartan (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) is dissolved and NLT 80% (Q) of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) is dissolved.

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

Medium, Apparatus 2, and Time: Proceed as directed in Dissolution Test 1.

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 3.

Table 3

Diluent: Acetonitrile and water (50:50)

Standard stock solution A: 0.14 mg/mL of USP Amlodipine Besylate RS, prepared as follows. Initially dissolve in Diluent about 4% of the final volume, and dilute with Medium to volume.

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

Standard solution: (L₁/1000) mg/mL of amlodipine and (L₂/1000) mg/mL of valsartan in Medium from Standard stock solution A and Standard stock solution B, where L₁ is the label claim of amlodipine in mg/Tablet, and L₂ is the label claim of valsartan in mg/Tablet

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

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 237 nm for amlodipine and UV 270 nm for valsartan

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

Flow rate: 1.5 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for amlodipine and valsartan

Relative standard deviation: NMT 2.0% for amlodipine and valsartan

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) dissolved:

Result = (r_U/r_S) x C_S x V x (M_r1/M_r2) x (1/L₁) x 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, 1000 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) x C_S x V x (1/L₂) x 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, 1000 mL

L₂ = label claim of valsartan (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) is dissolved and NLT 80% (Q) of the labeled amount of valsartan (C₂₄H₂₉N₅O₃) is dissolved.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

Change to read:

5.1 ORGANIC IMPURITIES

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

Standard stock solution A: Prepare as directed for the Standard solution in the Assay.

System suitability solution: Dissolve a suitable quantity of USP Valsartan Related Compound B RS in Standard stock solution A to obtain a solution containing 0.08 mg/mL of USP Valsartan Related Compound B RS, 0.14 mg/mL of USP Amlodipine Besylate RS, and 0.16 mg/mL of USP Valsartan RS.

Sensitivity solution: 0.14 µg/mL of USP Amlodipine Besylate RS and 0.16 µg/mL of USP Valsartan RS in Diluent from Standard stock solution A

Standard stock solution B: 0.1 mg/mL of USP Amlodipine Related Compound A RS as free base, prepared as follows. Add methanol to 5% of the final volume to dissolve, and dilute with Diluent to volume.

Standard solution: 0.0005 mg/mL of USP Amlodipine Related Compound A RS as free base, and 0.0003 mg/mL each of USP Amlodipine Besylate RS and USP Valsartan RS in Diluent from Standard stock solution A and Standard stock solution B, respectively

System suitability

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

Suitability requirements

Resolution: More than 4.0 between amlodipine and valsartan related compound B and more than 4.0 between valsartan related compound B and valsartan, System suitability solution

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

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

Analysis

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

Calculate the percentage of amlodipine related compound A free base in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) x (M_r1/M_r2) x 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 valsartan related degradation products other than valsartan related compound A in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of 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 each unspecified degradation product in the portion of Tablets taken:

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

r_U = peak response of each unspecified degradation product from Sample solution A

r_S = peak response of amlodipine from the Standard solution s

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 4. Disregard valsartan related compound B, the benzenesulfonic acid peak at relative retention time 0.19, and any peaks below 0.1%.

Table 4

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

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

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

^d N-Butyryl-N-{[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl)-L-valine.

^e N-Valeryl-N-{[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl)-L-valine ethyl ester.

^f If valsartan related compound A is a potential degradation product, the total degradation products limit does not include valsartan related compound A and amlodipine related compound A.

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.

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

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for valsartan related compound A and valsartan are about 0.7 and 1.0, respectively.]

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

Analysis

Samples: Standard solution and Sample solution

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

Result = (r_U/r_S) x (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

6.1 PACKAGING AND STORAGE

Store at controlled room temperature, in tight containers, and in a dry place.

6.2 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:

6.3 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.

C₂₀H₂₃CIN₂O₅·C₄H₄O₄ 522.94 (Sunday 1-Dec-2023)

USP Valsartan RS

USP Valsartan Related Compound A RS

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

C₂₄H₂₉N₅O₃ 435.53(Sunday 1-Dec-2023)

USP Valsartan Related Compound B RS

N-Butyryl-N-{[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-L-valine.

C₂₃H₂₇N₅O₃ 421.50(Sunday 1-Dec-2023)