Felodipine

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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C₁₈H₁₉CI₂NO₄ 384.25

3,5-Pyridinedicarboxylic acid 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-, ethyl methyl ester, (±)-;

Ethyl methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate CAS RN^®: 72509-76-3.

1 DEFINITION

Felodipine contains NLT 98.0% and NMT 101.0% of felodipine (C₂H₂CI₂NO₄), calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K or 197A

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 PROCEDURE

Buffer: Dissolve 6.9 g of sodium phosphate monobasic dihydrate in 400 mL of water, add 8.0 mL of 1 M phosphoric acid, and dilute with water to 1 L. [NOTE-The pH of this solution is around 3.0.]

Mobile phase: Acetonitrile, methanol, and Buffer (40:20:40)

System suitability stock solution: 0.05 mg/mL of USP Felodipine RS and 0.1 mg/mL of USP Felodipine Related Compound A RS in Mobile phase

System suitability solution: 0.5 µg/mL of USP Felodipine RS and 1 µg/mL of USP Felodipine Related Compound A RS in Mobile phase from the System suitability stock solution. [NOTE-Pass the solution through a suitable filter of 0.2-µm pore size.]

Standard solution: 0.3 mg/mL of USP Felodipine RS in Mobile phase. [NOTE-Prepare fresh before analysis. Pass the solution through a suitable filter of 0.2-µm pore size.]

Sample solution: 0.3 mg/mL of Felodipine in Mobile phase. [NOTE-Prepare fresh before analysis. Pass the solution through a suitable filter of 0.2-µm pore size.]

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Flow rate: 1 mL/min

Injection volume: 20 µL for the System suitability solution and 40 µL for the Standard solution and the Sample solution

Run time: NLT 2 times the retention time of felodipine

3.3 System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for felodipine related compound A and felodipine are 0.83 and 1.00, respectively.]

Suitability requirements

Resolution: NLT 2.5 between felodipine related compound A and felodipine, System suitability solution

Tailing factor: NMT 1.5, Standard solution

Relative standard deviation: NMT 0.37%, Standard solution

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of felodipine (C₁₈H₁₉CI₂NO₄) in the portion of Felodipine taken:

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

r_U = peak response of felodipine from the Sample solution

r_S = peak response of felodipine from the Standard solution

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

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

Acceptance criteria: 98.0%-101.0% on the dried basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.1%

4.2 LIMIT OF ETHYL 3-AMINOCROTONATE

Buffer: 2.84 g/L of sodium phosphate, dibasic, anhydrous in water prepared as follows. Dissolve 2.84 g of sodium phosphate, dibasic, anhydrous in 1000 mL of water. Adjust with phosphoric acid to a pH of 7.0.

Mobile phase: Acetonitrile and Buffer (57:43)

Standard solution: 30 µg/mL of USP Ethyl 3-Aminocrotonate RS in Mobile phase. Prepare fresh before analysis.

Sample solution: 20 mg/mL of Felodipine in Mobile phase. Sonicate the solution for 10 min. Prepare fresh before analysis. [NOTE-Pass the solution through a suitable filter of 0.2-um pore size.]

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

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

Temperatures

Column: 35°

Detector: 35°

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 4 times the retention time of ethyl 3-aminocrotonate for the Standard solution; NLT 8 times the retention time of ethyl 3-aminocrotonate for the Sample solution

4.3 System suitability

Sample: Standard solution

Requirements

Relative standard deviation: NMT 3.0%

4.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ethyl 3-aminocrotonate in the portion of Felodipine taken:

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

r_U = peak response of ethyl 3-aminocrotonate from the Sample solution

r_S = peak response of ethyl 3-aminocrotonate from the Standard solution

C_S = concentration of USP Ethyl 3-Aminocrotonate RS in the Standard solution (mg/mL)

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

Acceptance criteria: NMT 0.15%

Change to read:

4.5 ORGANIC IMPURITIES

Buffer, Mobile phase, System suitability solution, Standard solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay, and use 40 µL injection volume for the Sensitivity solution. (ERR 1-Dec-2022)

Sensitivity solution: 0.15 µg/mL of USP Felodipine RS in Mobile phase from the Standard solution. [NOTE-Prepare fresh before analysis.]

System suitability

Samples: System suitability solution and Sensitivity solution

[NOTE-See Table 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 2.5 between the felodipine related compound A and felodipine, System suitability solution

Relative standard deviation: NMT 10.0%, Sensitivity solution

Analysis

Sample: Sample solution

Calculate the percentage of each impurity in the portion of Felodipine taken:

Result = (r_U/r_T) x (1/F) x 100

r_U = peak response for each impurity

r_T = sum of all the peak responses

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1. The reporting threshold is 0.05%.

Table 1

^a Methyl 2-(2,3-dichlorobenzylidene)-3-oxobutanoate.

^b Dimethyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

^c Diethyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

^d Total impurities include the sum of the results from the tests for Organic Impurities and Limit of Ethyl 3-Aminocrotonate.

5 SPECIFIC TESTS

5.1 LOSS ON DRYING (731)

Analysis: Dry at 105° for 3 h.

Acceptance criteria: NMT 0.5%

5.2 COLOR OF SOLUTION

Sample solution: 20 mg/mL of Felodipine in methanol

Instrumental conditions

Mode: Vis

Analytical wavelength: 440 nm

Cell: 5 cm

Blank: Methanol

Acceptance criteria: NMT 0.2 absorbance

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in tight, light-resistant containers, and store at controlled room temperature.

6.2 USP REFERENCE STANDARDS (11)

USP Ethyl 3-Aminocrotonate RS

Ethyl (Z)-3-aminobut-2-enoate.

C₆H₁₁NO₂ 129.16

USP Felodipine RS

USP Felodipine Related Compound A RS

3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylate.

C₁₈H₁₇CI₂NO₄ 382.24