Amlodipine and Olmesartan Medoxomil 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 Olmesartan Medoxomil Tablets contain an amount of Amlodipine Besylate equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) and NLT 90.0% and NMT 110.0% of the labeled amount of olmesartan medoxomil (C₂₉H₃₀N₆O₆).

2 IDENTIFICATION

A. The UV spectra of the amlodipine and olmesartan medoxomil peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

B. The retention times of the amlodipine and olmesartan medoxomil peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 PROCEDURE

Solution A: 6.9 g/L of sodium phosphate, monobasic. Adjust with phosphoric acid to a a pH of 2.5.

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and water (50:50)

Standard stock solution: 0.28 mg/mL of USP Amlodipine Besylate RS and 0.8 mg/mL of USP Olmesartan Medoxomil RS in Diluent

Standard solution: 0.056 mg/mL of USP Amlodipine Besylate RS and 0.16 mg/mL of USP Olmesartan Medoxomil RS in Diluent from Standard stock solution

Sample stock solution: Nominal concentrations given in Table 2 are prepared as follows.

For Tablet strength 5/20, transfer NLT 5 Tablets equivalent to 25 mg of amlodipine and 100 mg of olmesartan medoxomil into a suitable volumetric flask. Add water to 20% of the total volume and sonicate for 5 min. Add acetonitrile to 20% of the total volume and sonicate for 5 min. Add Diluent to 30% of the total volume and sonicate for 15 min. Dilute with Diluent to volume. Centrifuge a portion of the solution for 10 min and pass through a filter of 0.45-µm pore size.

For Tablet strength 5/40, 10/20, or 10/40, transfer NLT 5 Tablets equivalent to 25 mg of amlodipine and 200 mg of olmesartan medoxomil, 50 mg of amlodipine and 100 mg of olmesartan medoxomil, or 50 mg of amlodipine and 200 mg of olmesartan medoxomil into a suitable volumetric flask. Add water to 10% of the total volume and sonicate for 5 min. Add acetonitrile to 10% of the total volume and sonicate for 5 min. Add Diluent to 30% of the total volume and sonicate for 15 min. Dilute with Diluent to volume. Centrifuge a portion of the solution for 10 min and pass through a filter of 0.45-µm pore size.

Table 2

Sample solution: Nominal concentrations in Diluent from Sample stock solution are given in Table 3.

Table 3

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm. For Identification A, use a diode array detector in the range of 200-400 nm.

Column: 4.6-mm x 25-cm; 5-µm packing L11

Temperatures

Autosampler: 5°

Column: 60°

Flow rate: 2 mL/min

Injection volume: 10 µL

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for amlodipine and olmesartan medoxomil peaks

Relative standard deviation: NMT 2.0% for amlodipine and olmesartan medoxomil peaks

3.4 Analysis

Samples: Standard solution and Sample solution

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 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)

C_U = nominal concentration of amlodipine in the Sample solution (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 olmesartan medoxomil (C₂₉H₃₀N₆O₆) in the portion of Tablets taken:

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

r_U = peak response of olmesartan medoxomil from the Sample solution

r_S = peak response of olmesartan medoxomil from the Standard solution

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

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

3.5 Acceptance criteria

Amlodipine: 90.0%-110.0%

Olmesartan medoxomil: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

4.1 DISSOLUTION (711).

4.1.1 Test 1

Medium: 6.8 g/L of potassium phosphate, monobasic. Adjust with 0.2 N sodium hydroxide solution to a pH of 6.8; 900 mL.

Apparatus 2: 50 rpm

Times

Amlodipine: 30 min

Olmesartan medoxomil: 45 min

Buffer: 4.08 g/L of potassium phosphate, monobasic. Adjust with phosphoric acid to a pH of 2.5.

Mobile phase: Acetonitrile and Buffer (40:60)

Standard stock solution A: 0.16 mg/mL of USP Amlodipine Besylate RS in Mobile phase

Standard stock solution B: 0.44 mg/mL of USP Olmesartan Medoxomil RS in Mobile phase

Standard solution: 0.016 mg/mL of USP Amlodipine Besylate RS and 0.044 mg/mL of USP Olmesartan Medoxomil RS in Medium from Standard stock solution A and Standard stock solution B

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size and discard the first 2-3 mL of the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Autosampler temperature: 5°

Flow rate: 1.2 mL/min

Injection volume: 10 µL

Run time: NLT 1.4 times the retention time of olmesartan medoxomil

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for amlodipine and olmesartan medoxomil peaks.

Relative standard deviation: NMT 2.0% for amlodipine and olmesartan medoxomil peaks

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/L) 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, 900 mL

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05

L = label claim of amlodipine (mg/Tablet)

Calculate the concentration (C₁ or C₂) of olmesartan medoxomil (C₂₉H₃₀N₆O₆) in the sample withdrawn from the vessel at the 30- or 45-min time point:

Result = (r_U/r_S) x C_S

r_U = peak response of olmesartan medoxomil from the Sample solution at the 30- or 45-min time point

r_S = peak response of olmesartan medoxomil from the Standard solution

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

Calculate the percentage of the labeled amount of olmesartan medoxomil (C₂₉H₃₀N₆O₆) dissolved:

Result = {[C₂ x (V - V_S)] + (C₁ x V_S)} x (1/L) x 100

C₂ = concentration of olmesartan medoxomil in the Sample solution at the 45-min time point (mg/mL)

V = volume of Medium, 900 mL

V_S = volume of the Sample solution withdrawn at the 30-min time point (mL)

C₁ = concentration of olmesartan medoxomil in the Sample solution at the 30-min time point (mg/mL)

L = label claim of olmesartan medoxomil (mg/Tablet)

Tolerances: NLT 80.0% (Q) of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) at 30 min and NLT 70.0% (Q) of the labeled amount of olmesartan medoxomil (C₂₉H₃₀N₆O₆) at 45 min are dissolved.

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

Medium: 6.8 g/L of potassium phosphate monobasic and 0.9 g/L of sodium hydroxide. Adjust with 10% sodium hydroxide solution to a pH of 6.8; 900 mL.

Apparatus 2: 50 rpm

Times

Amlodipine: 30 min

Olmesartan medoxomil: 30 min

Buffer: Add 2 mL of triethylamine in 1000 mL of water. Adjust with phosphoric acid to a pH of 2.5.

Mobile phase: Acetonitrile and Buffer (30:70)

Standard stock solution A: 0.15 mg/mL of USP Amlodipine Besylate RS in methanol

Standard stock solution B: 0.44 mg/mL of USP Olmesartan Medoxomil RS in methanol

Standard solution: Known concentrations of USP Amlodipine Besylate RS and USP Olmesartan Medoxomil RS in Medium from Standard stock solution A and Standard stock solution B, prepared per Table 4.

Table 4

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 236 nm

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

Temperatures

Autosampler: 5°

Column: 30°

Flow rate: 1.0 mL/min

Injection volume: 10 µL

Run time: NLT 1.5 times the retention time of olmesartan medoxomil

System suitability

Sample: Standard solution

[NOTE-The relative retention times for olmesartan, amlodipine, and olmesartan medoxomil are 0.29, 0.68, and 1.00, respectively.]

Suitability requirements

Tailing factor: NMT 2.0 for amlodipine and olmesartan medoxomil peaks

Relative standard deviation: NMT 2.0% for amlodipine and olmesartan medoxomil peaks

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/L) 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, 900 mL

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05

L = label claim of amlodipine (mg/Tablet)

Calculate the percentage of the labeled amount of olmesartan medoxomil (C₂₉H₃₀N₆O₆) dissolved:

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

r_U = sum of peak responses of olmesartan and olmesartan medoxomil from the Sample solution

r_S = sum of peak responses of olmesartan and olmesartan medoxomil from the Standard solution

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

V = volume of Medium, 900 mL

L = label claim of olmesartan medoxomil (mg/Tablet/

Tolerances: NLT 75.0% (Q) of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) and NLT 70.0% (Q) of the labeled amount of olmesartan medoxomil (C₂₉H₃₀N₆O₆) are dissolved.

4.1.3 Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.

Medium: pH 6.8 phosphate buffer (3.4 g/L of potassium phosphate monobasic and 3.55 g/L of sodium phosphate, dibasic, anhydrous in water) and water (50:50); 900 mL

Apparatus 2: 50 rpm

Times

Amlodipine: 15 min

Olmesartan medoxomil: 45 min

Solution A: Dissolve 2.72 g of potassium phosphate monobasic in 1000 mL of water. Add 5 mL of triethylamine and adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Acetonitrile and Solution A (35:65)

Standard stock solution A: 0.31 mg/mL of USP Amlodipine Besylate RS in acetonitrile. Sonicate to dissolve if necessary.

Standard stock solution B: 0.90 mg/mL of USP Olmesartan Medoxomil RS in acetonitrile. Sonicate to dissolve if necessary.

Standard solution: Known concentrations of USP Amlodipine Besylate RS and USP Olmesartan Medoxomil RS in Medium from Standard stock solution A and Standard stock solution B, prepared per Table 5

Table 5

Sample solution: At the end of the specified time, withdraw 10 mL of the solution under test, pass through a suitable filter and discard the first 5 mL of the filtrate. Replace the aliquot withdrawn with equal volumes of pre-equilibrated Medium. For Tablets with strengths of 5/20, 5/40, and 10/20 mg/mg, use the filtrate. For Tablets with a strength of 10/40 mg/mg, dilute 5 mL of the filtrate with Medium to 10 mL.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 250 nm

Column: 4.6-mm × 15-cm; 5-µm packing L7

Temperatures

Autosampler: 5°

Column: 30°

Flow rate: 1.2 mL/min

Injection volume: 20 µL

Run time: NLT 1.5 times the retention time of olmesartan medoxomil

System suitability

Sample: Standard solution

[NOTE-The relative retention times for olmesartan, amlodipine, and olmesartan medoxomil are 0.32, 0.74, and 1.00, respectively.]

Suitability requirements

Resolution: NLT 3.0 between amlodipine and olmesartan medoxomil

Tailing factor: NMT 2.0 for amlodipine and olmesartan medoxomil

Relative standard deviation: NMT 2.0% for amlodipine and olmesartan medoxomil

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) dissolved at time point 1:

Result = (r_U/r_S) x C_S x V x D x (M_r1/M_r2) x (1/L) x 100

r_U = peak response of amlodipine from the Sample solution withdrawn at time point 1

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

D = dilution factor for the Sample solution withdrawn at time point 1, if needed

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05 12

L = label claim of amlodipine (mg/Tablet)

Calculate the concentration (C_i) of olmesartan medoxomil (C₂₉H₃₀N₆O₆) in the portion of sample withdrawn from the vessel at each time point (i):

Result_i = (r_i/r_S) x C_S x D

r_i = peak response of olmesartan medoxomil from the Sample solution withdrawn at time point i

r_S = peak response of olmesartan medoxomil from the Standard solution

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

D = dilution factor for the Sample solution withdrawn at time point i, if needed

Calculate the percentage of the labeled amount of olmesartan medoxomil (C₂₉H₃₀N₆O₆) dissolved at time point 2:

Result = [(C₂ x V) + (C₁ x V_S)] x (1/L) x 100

C₂ = concentration of olmesartan medoxomil in the portion of sample withdrawn at time pointi (mg/mL)

V = volume of Medium, 900 mL

V_S = volume of the Sample solution withdrawn at each time point and replaced with Medium, 10 mL

L = label claim of olmesartan medoxomil (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) and NLT 70% (Q) of the labeled amount of olmesartan medoxomil (C₂₀H₂₅CIN₂O₅) are dissolved. (See Table 6.)

Table 6

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

Change to read:

ORGANIC IMPURITIES

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

Standard stock solution A: 28 µg/mL of USP Amlodipine Besylate RS and 80 µg/mL of USP Olmesartan Medoxomil RS in Diluent from Standard stock solution

Standard stock solution B: 50 µg/mL of USP Amlodipine Related Compound A RS in Diluent

Standard solution: 1.4 µg/mL of USP Amlodipine Besylate RS, 2.5 µg/mL of USP Amlodipine Related Compound A RS, and 4 µg/mL of USP Olmesartan Medoxomil RS in Diluent from Standard stock solution A and Standard stock solution B

Sensitivity solution: 0.28 µg/mL of USP Amlodipine Besylate RS, 0.5 µg/mL of USP Amlodipine Related Compound A RS, and 0.8 µg/mL of USP Olmesartan Medoxomil RS in Diluent from Standard solution

Sample solution: Use the Sample stock solution, prepared as directed in the Assay.

System suitability

Samples: Standard solution and Sensitivity solution

[NOTE-See Table Z (RB 1-Apr-2021) for relative retention times.]

Suitability requirements

Tailing factor: NMT 2.0 for amlodipine related compound A, amlodipine, and olmesartan medoxomil peaks, Standard solution

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

Signal-to-noise ratio: NLT 10 for amlodipine related compound A, amlodipine, and olmesartan medoxomil peaks, Sensitivity solution

Analysis

Samples: Standard solution and Sample 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 the Sample solution

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 the Sample solution (mg/mL)

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

M_r2 = molecular weight of amlodipine related compound A, 522.94

Calculate the percentage of any unspecified amlodipine related impurity 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 any unspecified amlodipine related impurity 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)

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

M_r1 = molecular weight of amlodipine, 408.88

M_r2 = molecular weight of amlodipine besylate, 567.05

Calculate the percentage of olmesartan or any unspecified olmesartan medoxomil related impurity in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of olmesartan or any unspecified olmesartan medoxomil related impurity from the Sample solution

r_S = peak response of olmesartan medoxomil from the Standard solution

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

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

Acceptance criteria: See Table 2.

Table 7 (RB 1-Apr-2021)

^a This peak is due to the counterion and is not to be reported or included in the total impurities.

^b 1-[2'-(1H-Tetrazol-5-yl)biphenyl-4-yl]methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid.

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

^d 1-[2'-(1H-Tetrazol-5-yl)biphenyl-4-yl]methyl)-4,4-dimethyl-2-propyl-1H-furo[3,4-dimidazol-6(4H)-one.

^e Process impurity included in the table for identification only. Process impurities are controlled in the drug substance and are not to be reported or included in the total impurities for the drug product.

^f (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(prop-1-en-2-yl)-2-propyl-1H-imidazole-5-carboxylate.

^g (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate.

^h The relative retention times for unspecified amlodipine related impurities are up to 1.0. The relative retention times for unspecified olmesartan medoxomil related impurities are after 1.0 and also at 0.45, 0.60, 0.76, 0.79, and 0.92.

ⁱ Excluding olmesartan.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers, 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 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

USP Olmesartan Medoxomil RS