Amlodipine and Atorvastatin Tablets

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

1 DEFINITION

Amlodipine and Atorvastatin Tablets contain an amount of amlodipine besylate equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) and an amount of atorvastatin calcium equivalent to NLT 94.5% and NMT 105.0% of the labeled amount of atorvastatin (C₃₃H₃₅FN₂O₅). It may contain suitable antioxidants.

2 IDENTIFICATION

A. The UV spectrum of the major peaks of the Sample solution exhibits maxima and minima at the same wavelengths as that of the Standard solution, as obtained in the Assay.

B. The retention times 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:

3.1 PROCEDURE

Solution A: Dissolve 1.54 g of ammonium acetate in 1000 mL of water and add 2 mL of triethylamine. Adjust with acetic acid to a pH of 5.0.

Mobile phase: Acetonitrile, methanol, and Solution A (38:15:47)

Buffer: Transfer 7 mL of triethylamine to a 1000-mL volumetric flask containing 900 mL of water and mix. Adjust with dilute phosphoric acid (1 in 100) to a pH of 3.0 and dilute with water to volume.

Diluent: Acetonitrile, methanol, and Buffer (3:7:10)

Standard stock solution 1: 0.35 mg/mL of USP Amlodipine Besylate RS in methanol

Standard stock solution 2: 0.44 mg/mL of USP Atorvastatin Calcium RS in methanol

Standard solution: Prepare solutions of USP Amlodipine Besylate RS and USP Atorvastatin Calcium RS in Mobile phase at concentrations given in Table 1 from Standard stock solution 1 and Standard stock solution 2.

Table 1

Sample solution: Transfer NLT 10 Tablets to a suitable volumetric flask. Add about 20% of the final volume of the volumetric flask size in Diluent and sonicate to disperse the Tablets. Add about 40% of the final volume of the volumetric flask size in Diluent, sonicate for 20 min, and dilute with Diluent to volume. Centrifuge and transfer a suitable quantity of the supernatant to an appropriate suitable volumetric flask. Dilute with Mobile phase to volume to obtain the nominal concentrations of amlodipine and atorvastatin similar to that of the Standard 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: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 3.5 times the retention time of amlodipine

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for both peaks

Relative standard deviation: NMT 2.0% for both 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 s

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 atorvastatin (C₃₃H₃₅FN₂O₅) in the portion of Tablets taken:

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

r_U = peak response of atorvastatin from the Sample solution

r_S = peak response of atorvastatin from the Standard solution

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

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

M_r1 = number of moles of atorvastatin per mole of atorvastatin calcium, 2

M_r1 = molecular weight of atorvastatin, 558.65 (CN 1-May-2024)

M_r2 = molecular weight of atorvastatin calcium, 1155.36 (CN 1-May-2024)

3.5 Acceptance criteria

Amlodipine: 90.0%-110.0%

Atorvastatin: 94.5%-105.0 %

4 PERFORMANCE TESTS

Change to read:

4.1 DISSOLUTION (711)

4.1.1 Test 1

Solution A, Mobile phase, Standard stock solution 1, Standard stock solution 2, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Medium: 0.1% Polysorbate 80 in pH 6.8 phosphate buffer; 900 mL

Apparatus 2: 75 rpm

Time: 20 min

Standard solution: (L₁/900) mg/mL of amlodipine and (L₂/900) mg/mL of atorvastatin in Medium from Standard stock solution 1 and Standard stock solution 2, where L₁ is the label claim of amlodipine in mg/Tablet and L₂, is the label claim of atorvastatin in mg/Tablet

Sample solution: Centrifuge the solution under test and use the supernatant.

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 atorvastatin (C₃₃H₃₅FN₂O₅) dissolved:

Result = (r_U/r_S) x C_S x V x [M x ((M_r1/M_r2)] x (1/L) x 100

r_U = peak response of atorvastatin from the Sample solution

r_S = peak response of atorvastatin from the Standard solution

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

V = volume of Medium, 900 mL

M = number of moles of atorvastatin per mole of atorvastatin calcium, 2

M_r1 = molecular weight of atorvastatin, 558.65 (CN 1-May-2024)

M_r2 = molecular weight of atorvastatin calcium, 1155.36 (CN 1-May-2024)

L = label claim of atorvastatin (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) and atorvastatin (C₃₃H₃₅FN₂O₅) 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: 0.05 M phosphate buffer prepared as follows. Dissolve 40.8 g of potassium phosphate, monobasic and 5 g of sodium hydroxide in 6 L of water. Adjust with 1 N sodium hydroxide or phosphoric acid to a pH of 6.8; 900 mL.

Apparatus 2: 75 rpm

Time: 30 min

Buffer: Dissolve 4.0 g of sodium phosphate, monobasic in 1200 mL of water and add 6 mL of triethylamine. Adjust with phosphoric acid to a pH of 2.5.

Mobile phase: Acetonitrile and Buffer (40:60)

Diluent: Acetonitrile and water (50:50)

Standard stock solution 1: 155 µg/mL of USP Amlodipine Besylate RS in Diluent

Standard stock solution 2: 460 µg/mL of USP Atorvastatin Calcium RS in Diluent

Standard solution: Prepare solutions of USP Amlodipine Besylate RS and USP Atorvastatin Calcium RS at concentrations given in Table 2 from Standard stock solution 1 and Standard stock solution 2.

Table 2

Sample solution: Pass a portion of the solution under test through a suitable filter. Discard the first few milliliters of filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm x 5-cm; 1.8-µm packing L1

Column temperature: 50°

Flow rate: 2 mL/min

Injection volume: 20 µL

Run time: NLT 1.8 times the retention time of atorvastatin

System suitability

Sample: Standard solution

[NOTE-The relative retention times for amlodipine and atorvastatin are 0.12 and 1.0, respectively.]

Suitability requirements

Tailing factor: NMT 1.5 for amlodipine

Relative standard deviation: NMT 2.0% for amlodipine and atorvastatin

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 atorvastatin (C₃₃H₃₅FN₂O₅) dissolved:

Result = (r_U/r_S) x C_S x V x [M x ((M_r1/M_r2)] x (1/L) x 100

r_U = peak response of atorvastatin from the Sample solution

r_S = peak response of atorvastatin from the Standard solution s

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

V = volume of Medium, 900 mL

M = number of moles of atorvastatin per mole of atorvastatin calcium, 2

M_r1 = molecular weight of atorvastatin, 558.65 (CN 1-May-2024)

M_r2 = molecular weight of atorvastatin calcium, 1155.36 (CN 1-May-2024)

L = label claim of atorvastatin (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of amlodipine (C₂₀H₂₅CIN₂O₅) and atorvastatin (C₃₃H₃₅FN₂O₅) are dissolved.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

5.1 ORGANIC IMPURITIES RELATED TO AMLODIPINE

Buffer 1: Add 7 mL of triethylamine in 1000 mL of water and adjust with phosphoric acid to a pH of 2.5. Add 1.8 g of tetrabutylammonium hydrogen sulfate and mix well.

Solution A: Methanol and Buffer 1 (40:60)

Solution B: Acetonitrile, methanol, and Buffer 1 (40:40:20)

Mobile phase: See Table 3.

Table 3

Buffer 2: Add 7 mL of triethylamine in 1000 mL of water. Adjust with phosphoric acid to a pH of 3.0.

Diluent 1: Methanol and water (50:50)

Diluent 2: Methanol and Buffer 2 (50:50)

Standard stock solution: 0.7 mg/mL of USP Amlodipine Besylate RS in Diluent 2, prepared as follows. Transfer a suitable amount of USP Amlodipine Besylate RS to a suitable volumetric flask and dissolve in a quantity of methanol, about 20% of the volume of the flask. Dilute with Diluent 2 to volume.

Standard solution 1: 5 µg/mL of USP Amlodipine Related Compound A RS in Diluent 1

Standard solution 2: 3.5 µg/mL of USP Amlodipine Besylate RS from Standard stock solution in Diluent 2

Sample solution: Nominally 0.5 mg/mL of amlodipine in Diluent 2, prepared as follows. Finely powder NLT 25 Tablets and transfer a portion of the powder, equivalent to 50 mg of amlodipine to a 100-mL volumetric flask. Add about 40 mL of methanol, shake to disperse, and sonicate for 15 min. Add about 40 mL of Buffer 2 and sonicate for another 10 min. Dilute with Diluent 2 to volume, centrifuge, and use the supernatant. Pass a portion of the solution through a suitable filter of 0.22-um pore size. Prepare this solution fresh.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 270 nm for amlodipine related compound A; 360 nm for all other impurities

Column: 2.1-mm × 15-cm; 1.8-µm packing L1

Column temperature: 40°

Flow rate: 0.3 mL/min

Injection volume: 5 µL

System suitability

Sample: Standard solution 2

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 5.0%

Analysis

Samples: Standard solution 1, Standard solution 2, and Sample solution

Calculate the percentage of amlodipine related compound A 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 Standard solution 1

C_S = concentration of USP Amlodipine Related Compound A RS in Standard solution 1 (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 fumarate, 522.94

Calculate the percentage of atorvastatin-amlodipine adduct or any 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 (1/F) x 100

r_U = peak response of each degradation product from the Sample solution

r_S = peak response of amlodipine from Standard solution 2

C_S = concentration of USP Amlodipine Besylate RS in Standard solution 2 (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

F = relative response factor (see Table 4)

Acceptance criteria: See Table 4. Disregard peaks at the relative retention times of 2.18, 2.47 (atorvastatin), and 2.79 min.

Table 4

^a 3-Ethyl 5-methyl 4-(2-chlorophenyl)-2-[(2-{(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanamido}ethoxy)methyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.

Change to read:

5.2 ORGANIC IMPURITIES RELATED TO ATORVASTATIN

Buffer 1: Dissolve 6.8 g of potassium dihydrogen phosphate in 1000 mL of water and adjust with dilute phosphoric acid (1 in 10) to a pH of 3.4

Buffer 2: Dissolve 6.8 g of potassium dihydrogen phosphate in 1000 mL of water and adjust with triethylamine to a pH of 7.0.

Solution A: Tetrahydrofuran, acetonitrile, and Buffer 1 (5:25:70)

Solution B: Tetrahydrofuran, acetonitrile, and Buffer 2 (5:70:25)

Mobile phase: See Table 5.

Table 5

Diluent: Acetonitrile and water (50:50)

System suitability solution: Heat a suitable amount of USP Atorvastatin Calcium RS at 60° for 1 h for degradation; 0.55 mg/mL of degraded USP Atorvastatin Calcium RS, 3 µg/mL each of USP Atorvastatin Related Compound A RS, USP Atorvastatin Related Compound B RS, USP Atorvastatin Related Compound C RS, and USP Atorvastatin Related Compound H. RS in Diluent. Sonication may be necessary for complete dissolution.

Standard solution: 2.7 µg/mL of USP Atorvastatin Calcium RS in Diluent

Sample solution: Nominally 0.5 mg/mL of atorvastatin in Diluent, prepared as follows. Transfer an amount equivalent to 50 mg of atorvastatin from a portion of NLT 20 finely powdered Tablets to a 100-mL volumetric flask. Add about 10 mL of acetonitrile, shake to disperse, and sonicate for 5 min. Add about 70 mL of Diluent and sonicate for another 20 min. Dilute with Diluent to volume and centrifuge. Prepare this solution fresh.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 246 nm

Column: 4.6-mm x 25-cm; 4-um packing L11

Column temperature: 45°

Flow rate: 1.2 mL/min

Injection volume: 20 µL

System suitability

Suitability requirements

Resolution: NLT 1.0 between atorvastatin pyrrolidone analog and atorvastatin related compound A, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each atorvastatin specified or unspecified degradation product in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) x [M x ((M_r1/M_r2)] x (1/F) x 100

r_U = peak response of each atorvastatin degradation product from the Sample solution

r_S = peak response of atorvastatin from the Standard solution

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

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

M = number of moles of atorvastatin per mole of atorvastatin calcium, 2

M_r1 = molecular weight of atorvastatin, 558.65 (CN 1-May-2024)

M_r2 = molecular weight of atorvastatin calcium, 1155.36 (CN 1-May-2024)

F = relative response factor (see Table 6)

Acceptance criteria: See Table 6. Disregard any impurity peaks less than 0.05% and the peaks from amlodipine related impurities.

Table 6

^a (3R,5R)-7-[(5-(4-Fluorophenyl)-3-isopropyl-2-oxo-4-phenyl-3-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid.

^b 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.

^c 4-(6-(4-Fluorophenyl)-7,8-epoxy-6-hydroxy-8a-isopropyl-7-phenyl-8-(phenylcarbamoyl) hexahydro-2H-pyrrolo [2,1-b] [1,3]oxazin-2-yl)-3-hydroxybutanoic acid.

^d (3R)-4-(1b-(4-Fluorophenyl)-7-hydroxy-7-isopropyl-1a-phenyl-7a-(phenylcarbamoyl) hexahydro-1aH-oxireno [2',3':3,4]pyrrolo[2,1-b] [1,3]oxazin-3-yl)-3-hydroxybutanoic acid.

^e 4-(4-Fluorophenyl)-2,4-dihydroxy-2-isopropyl-N,5-diphenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxamide.

^f 3-(4-Fluorobenzoyl)-2-isobutyryl-N,3-diphenyloxirane-2-carboxamide.

^g Sum of atorvastatin epoxy tetrahydrofuran analog and atorvastatin oxirane.

^h (3R,5R)-tert-Butyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate.

ⁱ Sum of the total degradation products for amlodipine from the test for Organic Impurities Related to Amlodipine and the total degradation products for atorvastatin from the test for Organic Impurities Related to Atorvastatin.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers. 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.

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.

C₂₀H₂₃CIN₂O₅·C₄H₄O₄ 522.94

USP Atorvastatin Calcium RS

USP Atorvastatin Related Compound A RS

Calcium (3R,5R)-7-[2-isopropyl-4,5-diphenyl-3-(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate (1:2).

C₆₆H₇₀CaN₄O₁₀ 1119.38

USP Atorvastatin Related Compound B RS

Calcium (3S,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate (1:2); also known as (3S,5R)-7-[3-(Phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid calcium salt.

C₆₆H₆₈CaF₂N₄O₁₀ 1155.36 (CN 1-May-2024)

USP Atorvastatin Related Compound C RS

Calcium (3R,5R)-7-[2,3-Bis(4-fluorophenyl)-5-isopropyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate (1:2).

C₆₆H₆₆CaF₄N₄O₁₀ 1191.34

USP Atorvastatin Related Compound H RS

5-(4-Fluorophenyl)-1-(2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide.

C₃₃H₃₃FN₂O₄ 540.64