Felodipine Extended-Release 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

Felodipine Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of felodipine (C₁₈H₁₉CI₂NO₄).

2 IDENTIFICATION

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

B. The UV spectrum 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 solution: 6.9 mg/mL of monobasic sodium phosphate in water. Adjust with 1 M phosphoric acid to a pH of 3.0 ± 0.05.

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

Standard stock solution: 2 mg/mL of USP Felodipine RS in methanol. Sonication may be necessary for complete dissolution.

Standard solution: 0.02 mg/mL of USP Felodipine RS from the Standard stock solution in Mobile phase

Sample stock solution: Nominally 0.1 mg/mL of felodipine prepared as follows. Dissolve a quantity equivalent to 10 mg of felodipine from powdered Tablets (NLT 10) in 40 mL of acetonitrile and 20 mL of methanol in a 100-mL volumetric flask, and sonicate for 5 min. Add about 30 mL of Buffer solution, and shake by mechanical means for 30 min. Allow the solution to cool to room temperature, and dilute with Buffer solution to volume. Centrifuge a portion of the solution at high speed for 15 min.

Sample solution: Nominally 0.02 mg/mL of felodipine prepared as follows. Transfer 10 mL of the supernatant from the Sample stock solution to a 50-mL volumetric flask, and dilute with Mobile phase to volume. Pass a portion of this solution through a filter of 0.5-µm or finer pore size, discarding the first 4 mL of the filtrate.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 362 nm. For Identification B, use a diode array detector in the range of 210-400 nm.

Column: 4.6-mm x 15-cm; 4-um packing L1

Flow rate: 1 mL/min

Injection volume: 40 µL

Run time: NLT 2 times the retention time of felodipine

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of felodipine (C₁₈H₁₉CI₂NO₄) in the portion of Tablets 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 = nominal concentration of felodipine in the Sample solution (mg/mL)

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

4.1 DISSOLUTION (711)

4.1.1 Test 1

Medium: pH 6.5 phosphate buffer with 1% sodium lauryl sulfate (Transfer 206 mL of 1 Mmonobasic sodium phosphate (USP 1-Aug-2022) 196 mL of 0.5 M dibasic sodium phosphate anhydrous, and 50.0 g of sodium lauryl sulfate to a 5000-mL volumetric flask. Add about 4000 mL of water, and mix well. If necessary, adjust with 1 N sodium hydroxide to a pH of 6.5. Dilute with water to volume); 500 mL

Apparatus 2: 50 rpm, with stationary basket. See (711), Figures 2b and 20. (USP 1-Aug-2022)

Times: 2, 6, and 10 h

Buffer solution: Prepare as directed for Assay (USP 1-Aug-2022)

Mobile phase: Acetonitrile, methanol, and Buffer solution (25:10:20)

Standard stock solution: 0.25 mg/mL of USP Felodipine RS in alcohol

Standard solution: (0.6 L/500) mg/mL of USP Felodipine RS from the Standard stock solution in Medium, where L is the label claim in mg/Tablet

Sample solution: (USP 1-Aug-2022) Pass a 10-mL portion of the solution under test, obtained at each time interval, through a suitable filter. (USP 1-Aug-2022)

Chromatographic system: Proceed as directed in the Assay, except for the Injection volume.

Injection volume: 100 µL

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of felodipine (C₁₈H₁₉CI₂NO₄) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) x C_S

r_U = peak response of felodipine from the Sample solution at each time point, i

r_S = peak response of felodipine from the Standard solution

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

Calculate the percentage of the labeled amount of felodipine (C₁₈H₁₉CI₂NO₄) dissolved at each time point (i):

Result₁ = C₁ x V x (1/L) x 100

Result₂ = {[C₂ x (V - V_S)] + (C₁ x V_S)} x (1/L) x 100

Result₃ = ({C x [V - (2 x V_S)]} + [(C₂ + C₁) × V_S]) × (1/L) x 100

C_i = concentration of felodipine in the Sample solution at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point, i (mL)

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of felodipine (C₁₈H₁₉CI₂NO₄) dissolved at the times specified conform to Dissolution (711) Acceptance Table 2.

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

Medium: 1% (w/v) Polysorbate 80 in water (USP 1-Aug-2022); 500 mL

Apparatus 1: 100 rpm

Times: 1, 4, and 8 h

Buffer solution: Dissolve 6.9 g of monobasic sodium phosphate in 400 mL of water, add 8.0 mL of 1 M phosphoric acid, and dilute with water to 1000 mL.

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

Standard stock solution: 0.2 mg/mL of USP Felodipine RS in methanol. Sonicate for 2 min, cool, and dilute with methanol to final concentration.

Standard solution: (L/500) mg/mL of USP Felodipine RS in Medium, from the Standard stock solution, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Replace the withdrawn amount with Medium.

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

Run time: NLT 2.5 times the retention time of felodipine (USP 1-Aug-2022)

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of felodipine (C₁₈H₁₉CI₂NO₄) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) x C_S

r_U = peak response of felodipine from the Sample solution at each time point, i

r_S = peak response of felodipine from the Standard solution

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

Calculate the percentage of the labeled amount of felodipine (C₁₈H₁₉CI₂NO₄) dissolved at each time point (i):

Result₁ = C₁ x V x (1/L) x 100

Result₂ = [(C₂ x V) + (C₁ x V_S)] x (1/L) x 100

Result₃ = {(C₃ x V) + [(C₂ + C₁) x V_S]} x (1/L) x 100

C_i = concentration of felodipine in the Sample solution at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point, i (mL)

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of felodipine (C₁₈H₁₉CI₂NO₄) dissolved at the times specified conform to Dissolution (711) Acceptance Table 2.

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

Medium: pH 6.5 phosphate buffer with 1% sodium lauryl sulfate prepared as follows. 5.7 g/L of monobasic sodium phosphate (USP 1-Aug-2022) 2.8 g/L of dibasic sodium phosphate, and 10 g/L of sodium lauryl sulfate in water, adjusted, if necessary, with diluted sodium hydroxide to a pH of 6.5 ± 0.05; 500 mL

Apparatus 2: 50 rpm, with stationary basket. See (711), Eigures 2b and 20 (USP 1-Aug-2022)

Times: 2, 6, and 10 h

Buffer solution: 6.9 g/L of monobasic sodium phosphate (USP 1-Aug-2022) in water. Adjust with phosphoric acid to a pH of 3.0 ± 0.05.

Mobile phase: Acetonitrile, methanol, and Buffer solution (45:25:30)

Standard stock solution: 0.5 mg/mL of USP Felodipine RS in methanol. Sonication may be necessary for complete dissolution.

Standard solution: 0.01 mg/mL of USP Felodipine RS from the Standard stock solution in Medium. (USP 1-Aug-2022)

Sample solution: (USP 1-Aug-2022) Pass a portion of the solution under test, obtained at each time interval, through a suitable filter, discarding the first few milliliters.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 362 nm

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

Flow rate: 2.0 mL/min

Injection volume: 40 µL

Run time: NLT 1.7 times the retention time of felodipine (USP 1-Aug-2022)

System suitability

Sample: Standard solution

Suitability requirements

Column efficiency: NLT 1500 theoretical plates

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of felodipine (C₁₈H₁₉CI₂NO₄) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) x C_S

r_U = peak response of felodipine from the Sample solution at each time point, i

r_S = peak response of felodipine from the Standard solution

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

Calculate the percentage of the labeled amount of felodipine (C₁₈H₁₉CI₂NO₄) dissolved at each time point (i):

Result₁ = C₁ x V x (1/L) x 100

Result₂ = {[C₂ x (V - V_S)] + (C₁ x V_S)} x (1/L) x 100

Result₃ = ({C₃ x [V - (2 x V_S)]} + [(C₂ + C₁) x V_S]) x (1/L) x 100

C_i = concentration of felodipine in the Sample solution at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point, i (mL)

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of felodipine (C₁₈H₁₉CI₂NO₄) dissolved at the times specified conform to Dissolution (711) Acceptance Table 2.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

Change to read:

ORGANIC IMPURITIES

Buffer solution and Mobile phase: Prepare as directed in the Assay.

Standard stock solution: 150 µg/mL each of USP Felodipine RS and USP Felodipine Related Compound A RS in methanol. Sonication may be necessary for complete dissolution.

Standard solution: 1.5 µg/mL each of USP Felodipine RS and USP Felodipine Related Compound A RS from the Standard stock solution in Mobile phase

Sensitivity solution: 0.075 µg/mL each of USP Felodipine RS and USP Felodipine Related Compound A RS from the Standard solution in Mobile phase

Sample solution: Nominally 150 µg/mL of felodipine prepared as follows. Dissolve a quantity equivalent to 30 mg of felodipine from powdered Tablets (NLT 20) in a 200-mL volumetric flask. Add 80 mL of acetonitrile and 40 mL of methanol, and sonicate for 15 min. Add about 60 mL of Buffer solution, and stir for 30 min. Allow the solution to cool to room temperature, and dilute with Buffer solution to volume. Centrifuge a portion of the solution at high speed for 15 min, and pass a portion of the supernatant through a filter of 0.5-µm or finer pore size, discarding the first 4 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

Flow rate: 1 mL/min

Injection volume: 80 µL

Run time: NLT 7 times the retention time of felodipine

System suitability

Samples: Standard solution and Sensitivity solution

[NOTE-See Table 4 for relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between felodipine related compound A and felodipine, Standard solution

Relative standard deviation: NMT 5.0% for both felodipine and felodipine related compound A peaks, Standard solution

Signal-to-noise ratio: NLT 10 for the felodipine peak, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

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

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

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

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

Calculate the percentage of any unspecified impurity in the portion of Tablets taken:

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

r_U = peak response of each unspecified impurity 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 (µg/mL)

C_U = nominal concentration of felodipine in the Sample solution (µg/mL)

Acceptance criteria: See Table 4. The reporting threshold is 0.05%.

Name

Table 4

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

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

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in tight containers. Store at controlled room temperature. Protect from light.

6.2 LABELING

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

6.3 USP REFERENCE STANDARDS (11)

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