Fenofibric Acid Delayed-Release Capsules

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

Fenofibric Acid Delayed-Release Capsules contain an amount of Choline Fenofibrate equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄).

2 IDENTIFICATION

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

Sample: Grind the contents of one Capsule, excluding the gelatin shell, to a fine powder. Use an appropriate amount of sample.

Acceptance criteria: The IR absorption spectrum of the Sample exhibits maxima at about 1700-1200 and 950-650 cm^-1 wavenumbers, typical for choline fenofibrate.

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

Protect all solutions containing fenofibric acid from light.

Solution A: Water adjusted with phosphoric acid to a pH of 2.5

Mobile phase: Acetonitrile and Solution A (55:45)

Diluent: Methanol and water (50:50)

Standard solution: Equivalent to 0.25 mg/mL of fenofibric acid from USP Choline Fenofibrate RS in Diluent

Sample stock solution: Nominally equivalent to 1 mg/mL of fenofibric acid from Capsules prepared as follows. Empty, weigh, and mix the contents of Capsules (NLT 20) and transfer a suitable amount of the mixture to a suitable volumetric flask. Add 50% of the flask volume of methanol and sonicate for about 15 min. Add an additional 40% of the flask volume of water and stir for about 30 min. Cool to room temperature and dilute with water to volume. Centrifuge a portion and use the clear supernatant.

Sample solution: Nominally equivalent to 0.25 mg/mL of fenofibric acid in Diluent from the Sample stock solution

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 286 nm

Column: 4.6-mm × 25-cm; 5-µm L1 packing

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 1.3 times the retention time of the fenofibric acid

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.7

Relative standard deviation: NMT 1.0%

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄) in the portion of Capsules taken:

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

r_U = peak response of fenofibric acid from the Sample solution

r_S = peak response of fenofibric acid from the Standard solution

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

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

M_r1 = molecular weight of fenofibric acid, 318.75

M_r2 = molecular weight of choline fenofibrate, 421.91

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

4.1.1 Test 1

Protect all solutions containing fenofibric acid from light.

Acid stage medium: 0.05 M monobasic sodium phosphate, pH 3.5 prepared as follows. Dissolve 6.9 g of monobasic sodium phosphate in 1 L of water. Adjust with 0.05 M phosphoric acid to a pH of 3.5; 510 mL.

Buffer concentrate: 0.05 M sodium phosphate, pH 11.5 prepared as follows. Dissolve 6.9 g of monobasic sodium phosphate and 2.4 g of sodium hydroxide in 1 L of water.

Buffer stage medium: 0.05 M sodium phosphate buffer, pH 6.8 (add 400 mL of Buffer concentrate over a period of time not exceeding 5 min, to the vessel containing the Acid stage medium); 900 mL

Apparatus 2: 50 rpm

Times

Acid stage: 2 h

Buffer stage: 2.5, 3.5, and 6 h

Acidified water: 0.3% perchloric acid in water

Mobile phase: Acetonitrile and Acidified water (65:35)

Standard stock solution: 0.9 mg/mL of USP Fenofibric Acid RS prepared as follows. Weigh a known amount of USP Fenofibric Acid RS into a suitable volumetric flask. Dissolve in 10% of the total volume of acetonitrile, mix, and sonicate for about 30 min. Dilute with Buffer stage medium to volume.

Standard solutions: Prepare Standard solutions in Buffer stage medium as described in Table 1, from the Standard stock solution.

Table 1

Sample solution: Pass a portion of the solution under test through a suitable filter.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 286 nm

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

Column temperature: 35°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

Run time: NLT 1.5 times the retention time of fenofibric acid

System suitability

Samples: Standard solution I, Standard solution II, Standard solution III, Standard solution IV, and Standard solution V

Suitability requirements

Correlation coefficient: NLT 0.9990 for fenofibric acid of the standard curve from the linear regression in the Analysis

Tailing factor: NMT 2.0, Standard solution V

Relative standard deviation: NMT 2.0%, Standard solution III

Analysis

Samples: Standard solution I, Standard solution II, Standard solution III, Standard solution IV, Standard solution V, and Sample solution

Acid stage: At the 2-h time point, remove a 10-mL aliquot from each vessel. Dilute the aliquot with Buffer concentrate at a 5:4 ratio.

Buffer stage: At the specified sampling times for the Buffer stage, remove a 10-mL aliquot from each vessel and filter.

Using linear regression analysis, generate a standard curve for the fenofibric acid peak responses versus concentrations of Standard solution I, Standard solution II, Standard solution III, Standard solution IV, and Standard solution V. Determine the concentration (C), in mg/mL, of the fenofibric acid in the Sample solution using the standard curve.

Calculate the percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄) dissolved in the acid stage:

Result₁ = C₁ x V x D x (1/L) x 100

C₁ = concentration of fenofibric acid in the Acid stage (mg/mL)

V = volume of Acid stage medium, 510 mL

D = dilution factor

L = label claim (mg/Capsule)

Calculate the percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄) dissolved in the buffer stage at each time point (i):

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

Result = {C₄ x [V - (3 x V_S)]} + [(C₃ + C₂ + C₁) x V_S] x (1/L) x 100

C_i = concentration of fenofibric acid in the Sample solution (from the Standard curve) at the specified time point (i) (mg/mL)

V = volume of Buffer stage medium, 900 mL

V_S = volume of the Sample solution withdrawn at each time point in the Buffer stage (mL)

L = label claim (mg/Capsule)

Tolerances: See Table 2.

Table 2

The percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄), dissolved at the times specified in Table 2, conform to Dissolution (711), Acceptance Table 2.

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

Acid stage medium: 0.05 M sodium phosphate prepared as follows. Dissolve 7.8 g of sodium phosphate monobasic dihydrate and 11.68 g of sodium chloride in 1 L of water. Adjust with diluted phosphoric acid to a pH of 3.5; 500 mL.

Buffer concentrate: Dissolve 19.0 g of tribasic sodium phosphate in 1 L of water. Adjust with phosphoric acid to a pH of 11.5.

Buffer stage medium: 0.05 M sodium phosphate buffer, pH 6.8 prepared as follows. Add 400 mL of Buffer concentrate to the vessel containing 500 mL of the Acid stage medium. The pH of the final solution is about 6.8 (if necessary adjust with phosphoric acid or 0.1 N sodium hydroxide VS solution to the required pH); 900 mL.

Apparatus 2: 50 rpm, with suitable sinkers

Times

Acid stage: 2 h

Buffer stage: 2.5, 3.5, and 8 h

Buffer: Dissolve 1.4 g of potassium phosphate monobasic in 1 L of water.

Mobile phase: Acetonitrile and Buffer (50:50). Adjust with phosphoric acid to a pH of 3.0.

Diluent: 0.05 M sodium phosphate prepared as follows. Dissolve 7.8 g of sodium phosphate monobasic dihydrate and 11.68 g of sodium chloride in 1 L of water. Adjust with diluted phosphoric acid to a pH of 3.0.

Standard solution

For capsule strength of 45 mg: Equivalent to 0.1 x (L/900) mg/mL of fenofibric acid from USP Choline Fenofibrate RS prepared as follows. Transfer a suitable amount of USP Choline Fenofibrate RS into a suitable volumetric flask. Add 5% of the flask volume of methanol and sonicate to dissolve and then dilute with Buffer stage medium. Further dilute a suitable amount of this solution in a suitable volumetric flask with Diluent to volume.

For capsule strength of 135 mg: Equivalent to 0.1 x (L/900) mg/mL of fenofibric acid from USP Choline Fenofibrate RS prepared as follows. Transfer a suitable amount of USP Choline Fenofibrate RS into a suitable volumetric flask. Add 5% of the flask volume of methanol and sonicate to dissolve and then dilute with Buffer stage medium. Transfer a suitable amount of this solution to a suitable volumetric flask, add 5% of the flask volume of Buffer stage medium, and dilute with Diluent to volume.

Sample solution

Acid stage: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Dilute 3 mL of the filtrate with Diluent to 50 mL.

Buffer stage: At the end of the acid stage, add 400 mL of Buffer concentrate to the vessel. Withdraw 10 mL samples at the specified times and pass through a suitable filter of 0.45-µm pore size and discard the first few milliliters. Dilute 2 mL of the filtrate with Diluent to 20 mL.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 299 nm

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

Temperatures

Autosampler: 10°

Column: 30°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

Run time: NLT 2 times the retention time of fenofibric acid

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of fenofibric acid (C₁₇H₁₅CIO₄) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) x C_S x (M_r1/M_r2)

r_U = peak response of fenofibric acid from the Sample solution

r_S = peak response of fenofibric acid from the Standard solution

C_S = concentration of USP Choline Fenofibrate RS from the Standard solution (mg/mL)

M_r1 = molecular weight of fenofibric acid, 318.75

M_r2 = molecular weight of choline fenofibrate, 421.91

Calculate the percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄) dissolved in the acid stage:

Result₁ = C₁ x V x D x (1/L) x (M_r1/M_r2) × 100

C₁ = concentration of fenofibric acid in the Acid stage (mg/mL)

V = volume of Acid stage medium, 500 mL

D = dilution factor

L = label claim (mg/Capsule)

M_r1 = molecular weight of fenofibric acid, 318.75

M_r2 = molecular weight of choline fenofibrate, 421.91 12

Calculate the percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄) dissolved in the buffer stage at each time point (i):

Result₂ = {[C₂ x (V - V_S)] + (C₁ x V_S)} x (1/L) x (M_r1/M_r2) x 100

Result₃ = {C₃ x [V - (2 x V_S)]} + [(C₂ + C₁) x V_S] x (1/L) x (M_r1/M_r2) x 100

Result₄ = {C₄ x [V - (3 x V_S)]} + [(C₃ + C₂ + C₁) x V_S] x (1/L) x (M_r1/M_r2) x 100

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

V = volume of Buffer stage medium, 900 mL

V_S = volume of the Sample solution withdrawn at each time point in the buffer stage (mL) S

L = label claim (mg/Capsule)

M_r1 = molecular weight of fenofibric acid, 318.75

M_r2 = molecular weight of choline fenofibrate, 421.91

Tolerances: See Table 3.

Table 3

15 The percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄), dissolved at the times specified in Table 3, 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

Acid stage medium: 0.05 M sodium phosphate, monobasic, pH 3.5 prepared as follows. Dissolve 6.9 g of sodium phosphate, monobasic in 1 L of water. Adjust with 0.1% hydrochloric acid to a pH of 3.5; 500 mL.

Buffer concentrate: 0.05 M sodium phosphate, pH 11.2 prepared as follows. Dissolve 6.9 g of sodium phosphate, monobasic in 1 L of water. Adjust with a solution of 0.2 g/mL of sodium hydroxide to a pH of 11.2.

Buffer stage medium: 0.05 M sodium phosphate buffer, pH 6.8 prepared as follows. Add 400 mL of Buffer concentrate to the vessel containing 500 mL of the Acid stage medium. The pH of the final solution is about 6.8; 900 mL.

Apparatus 2: 50 rpm

Times

Acid stage: 2 h

Buffer stage: 2.5, 3.5, and 6 h

Acidified water: 0.1% v/v phosphoric acid in water

Mobile phase: Acetonitrile and Acidified water (55:45)

Standard stock solution: Equivalent to 0.5 mg/mL of fenofibric acid from USP Choline Fenofibrate RS prepared as follows. Weigh a known amount of USP Choline Fenofibrate RS into a suitable volumetric flask. Add 20% of the total volume of methanol and sonicate to dissolve. Dilute with Buffer stage medium to volume.

Standard solution

Acid stage: Equivalent to 0.18 x (L/1000) mg/mL of fenofibric acid in Acid stage medium from the Standard stock solution

Buffer stage: Equivalent to 1.12 x (L/1000) mg/mL of fenofibric acid in Buffer stage medium from the Standard stock solution

Sample solution: Pass a portion of the solution under test through a suitable filter. Replace with an amount equivalent to the sample withdrawn with the Acid stage medium at the end of acid stage or the Buffer concentrate at the specified sampling times in the buffer stage.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 286 nm

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

Flow rate: 2 mL/min

Injection volume: 10 µL

Run time: NLT 1.6 times the retention time of fenofibric acid

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solutions and Sample solution

Acid stage: Add one Capsule to each vessel containing Acid stage medium. At the 2-h time point, remove a 5-mL aliquot from each vessel and replace with 5 mL of fresh Acid stage medium.

Buffer stage: After 2 h into the acid stage, add 400 mL of the Buffer concentrate. At the specified sampling times for the buffer stage, remove a 10-mL aliquot from each vessel and replace with 10 mL of fresh Buffer concentrate and filter.

Calculate the concentration of the fenofibric acid (C₁₇H₁₅CIO₄) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) x C_S x (M_r1/M_r2)

r_U = peak response of fenofibric acid from the Sample solution

r_S = peak response of fenofibric acid from the Standard solution

C_S = concentration of USP Choline Fenofibrate RS from the Standard solution (mg/mL)

M_r1 = molecular weight of fenofibric acid, 318.75

M_r2 = molecular weight of choline fenofibrate, 421.91

Calculate the percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄) dissolved in the acid stage:

Result₁ = C₁ x V x D x (1/L) x (M_r1/M_r2) × 100

C₁ = concentration of fenofibric acid in the acid stage (mg/mL)

V = volume of Acid stage medium, 500 mL

D = dilution factor

L = label claim (mg/Capsule)

M_r1 = molecular weight of fenofibric acid, 318.75

M_r2 = molecular weight of choline fenofibrate, 421.91

Calculate the percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄) dissolved in the buffer stage at each time point (i):

Result₂ = [(C₂ x V) + (C₁ x V_S)] x (1/L) x (M_r1/M_r2) x 100

Result₃ = (C₃ x V) + [(C₂ + C₁) x V_S] x (1/L) x (M_r1/M_r2) x 100

Result₄ = (C₄ x V) + [(C₃ + C₂ + C₁) x V_S] x (1/L) x (M_r1/M_r2) x 100

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

V = volume of Buffer stage medium, 900 mL

V_S = volume of the Sample solution withdrawn at each time point in the buffer stage (mL)

L = label claim (mg/Capsule)

M_r1 = molecular weight of fenofibric acid, 318.75

M_r2 = molecular weight of choline fenofibrate, 421.91

Tolerances: See Table 4.

Table 4

The percentage of the labeled amount of fenofibric acid (C₁₇H₁₅CIO₄), dissolved at the times specified in Table 4, conform to Dissolution (711), Acceptance Table 2.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

Solution A, Mobile phase, and Diluent: Prepare as directed in the Assay.

Standard stock solution: Equivalent to 0.25 mg/mL of fenofibric acid from USP Choline Fenofibrate RS in Diluent

Standard solution: Equivalent to 0.01 mg/mL of fenofibric acid from the Standard stock solution in Diluent

Sensitivity solution: Equivalent to 0.001 mg/mL of fenofibric acid from the Standard solution in Diluent

Sample solution: Nominally 1 mg/mL of fenofibric acid from Capsules prepared as follows. Empty, weigh, and mix the contents of Capsules (NLT 20) and transfer a suitable amount of the mixture to a suitable volumetric flask. Add 50% of the flask volume of methanol and sonicate for about 15 min. Add an additional 40% of the flask volume of water and stir for about 30 min. Dilute with water to volume. Centrifuge a portion of the solution and use the clear supernatant.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 286 nm

Column: 4.6-mm × 25-cm; 5-µm packing L1

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 1.3 times the retention time of fenofibric acid

System suitability

Samples: Standard solution and Sensitivity solution

Suitability requirements

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any degradation product in the portion of Capsules taken:

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

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

r_S = peak response of fenofibric acid from the Standard solution

C_S = concentration of fenofibric acid in the Standard solution (mg/mL)

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

Acceptance criteria: See Table 5. The reporting threshold is 0.1%.

Table 5

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in well-closed containers. Store at controlled room temperature. Protect from moisture.

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.

6.3 USP REFERENCE STANDARDS (11)

USP Choline Fenofibrate RS

USP Fenofibric Acid RS

2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic acid.

C₁₇H₁₅CIO₄ 318.75 (USP 1-Dec-2024)