Dimethyl Fumarate 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

Dimethyl Fumarate Delayed-Release Capsules contain an amount of Dimethyl Fumarate equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of dimethyl fumarate (C₆H₈O₄).

2 IDENTIFICATION

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

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

Change to read:

3.1 Procedure

Dilute phosphoric acid: Dilute 11.5 mL of phosphoric acid with 88.5 mL of water.

Dilute sodium hydroxide solution: 10% sodium hydroxide in water (w/v)

Buffer A: 1.38 g/L of sodium phosphate, monobasic in water; adjusted with either Dilute sodium hydroxide solution or Dilute phosphoric acid to a pH of 2.5

Buffer B: 6.9 g/L of sodium phosphate, monobasic in water; adjusted with either Dilute sodium hydroxide solution or Dilute phosphoric acid to a pH of 3.15

Solution A: Buffer A

Solution B: Methanol

Mobile phase: See Table 1.

Table 1

Diluent: Methanol and Buffer B (40:60)

System suitability stock solution: 0.48 mg/mL each of USP Dimethyl Fumarate RS, USP Dimethyl Fumarate Related Compound A RS, and USP Fumaric Acid RS in Diluent prepared as follows. Transfer appropriate quantities of USP Dimethyl Fumarate RS, USP Dimethyl Fumarate Related Compound A RS, and USP Fumaric Acid RS into a suitable volumetric flask and add 80% of the flask volume of Diluent. Sonicate to completely dissolve and dilute with Diluent to volume.

System suitability solution: 4.8 µg/mL each of USP Dimethyl Fumarate RS, USP Dimethyl Fumarate Related Compound A RS, and USP Fumaric Acid RS from the System suitability stock solution in Diluent

Standard solution: 0.96 mg/mL of USP Dimethyl Fumarate RS prepared as follows. Transfer an appropriate quantity of USP Dimethyl Fumarate RS into a suitable volumetric flask, add 60% of the flask volume of methanol, and sonicate to completely dissolve. Add about 30% of the flask volume of Buffer B and allow the solution to cool to room temperature. Dilute with Buffer B to volume.

Sample solution: Nominally 0.96 mg/mL of dimethyl fumarate prepared as follows. Transfer an appropriate quantity, equivalent to 5 Capsules, of micro-tablets from the content of 10 Capsules into a suitable volumetric flask and add about 60% of the flask volume of methanol. Sonicate with occasional swirling to disintegrate the micro-tablets. An additional two cycles of the sonication step may be added to ensure all micro-tablets are disintegrated. [Note-A sonication time of about 15 min for each cycle may be suitable.] Add about 30% of the flask volume of Buffer B and allow the solution to cool to room temperature. Dilute with Buffer B to volume. Pass the solution through a suitable filter of 0.7-µm pore size, discarding the first few milliliters. Further dilute with Diluent to the final concentration.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 223 nm. For Identification A, use a diode array detector in the range of 200–300 nm.
• Column: 4.6-mm × 10-cm; 5-µm packing L1
• Temperatures
• Autosampler: 5°
• Column: 30°
• Flow rate: 1.5 mL/min
• Injection volume: 5 µL

System suitability

• Samples: System suitability solution and Standard solution
• [Note-See Table 2 for the relative retention times.]
• Suitability requirements
• Resolution: NLT 6.0 between fumaric acid and dimethyl fumarate related compound A, System suitability solution
• Tailing factor: 0.8–1.5, Standard solution
• Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of dimethyl fumarate (C₆H₈O₄) in the portion of Capsules taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of dimethyl fumarate from the Sample solution

rₛ = peak response of dimethyl fumarate from the Standard solution

Cₛ = concentration of USP Dimethyl Fumarate RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of dimethyl fumarate in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉

Acid stage

• Acid stage medium: 0.1 N hydrochloric acid in water; 500 mL
• Apparatus 2: 100 rpm
• Time: 120 min
• At the end of 120 min, pour the Acid stage medium through a suitable strainer into a suitable container and carefully transfer the micro-tablets in the strainer to a dissolution vessel containing the Buffer stage medium.

Buffer stage

• Buffer stage medium: pH 6.8 buffer (4.8 g/L of citric acid and 21.9 g/L of sodium phosphate dibasic anhydrous prepared as follows. Transfer suitable quantities of citric acid and sodium phosphate dibasic anhydrous to an appropriate container and dissolve with 98% of the final volume of water. Adjust with Dilute sodium hydroxide solution or Dilute phosphoric acid (prepare as directed in the Assay) to a pH of 6.8, and dilute with water to the final volume); 500 mL.
• Apparatus 2: 100 rpm
• Time: 30 min

Buffer A and Buffer B: Prepare as directed in the Assay.

Mobile phase: Methanol and Buffer A (40:60)

Acid stage diluent: Methanol and Buffer B (50:50)

Buffer stage diluent: Acid stage diluent and Dilute phosphoric acid (90:10)

Acid stage standard stock solution 1: 600 µg/mL of USP Dimethyl Fumarate RS prepared as follows. Transfer an appropriate quantity of USP Dimethyl Fumarate RS into a suitable volumetric flask. Add 10% of the flask volume of methanol and sonicate for approximately 10 min to dissolve, dilute with Acid stage medium to volume.

Acid stage standard stock solution 2: 60 µg/mL of USP Dimethyl Fumarate RS from Acid stage standard stock solution 1 in Acid stage medium

Acid stage standard solution: 3.0 µg/mL of USP Dimethyl Fumarate RS prepared as follows. Transfer 5 mL of Acid stage standard stock solution 2 to a 100-mL volumetric flask and add 50 mL of Acid stage diluent, then dilute with Acid stage medium to volume.

Acid stage sample solution

• For Capsules labeled to contain 120 mg: Transfer 5 mL of a filtered portion of the solution under test to a 10-mL volumetric flask, and dilute with Acid stage diluent to volume.
• For Capsules labeled to contain 240 mg: Transfer 2.5 mL of a filtered portion of the solution under test to a 10-mL volumetric flask, add 2.5 mL of Acid stage medium, and dilute with Acid stage diluent to volume.

Buffer stage standard stock solution 1: 1.32 mg/mL of USP Dimethyl Fumarate RS prepared as follows. Transfer an appropriate quantity of USP Dimethyl Fumarate RS into a suitable volumetric flask. Add 10% of the flask volume of methanol, sonicate for about 10 min, and dilute with Buffer stage medium to volume.

Buffer stage standard stock solution 2: 0.26 mg/mL of USP Dimethyl Fumarate RS from Buffer stage standard stock solution 1 in Buffer stage medium

Buffer stage standard solution: 0.11 mg/mL of USP Dimethyl Fumarate RS prepared as follows. Transfer 4 mL of Buffer stage standard stock solution 2 into a 10-mL volumetric flask, add 1 mL of Buffer stage medium, and dilute with Buffer stage diluent to volume.

Buffer stage sample solution

• For Capsules labeled to contain 120 mg: Transfer 5 mL of a filtered portion of the solution under test to a 10-mL volumetric flask, and dilute with Buffer stage diluent to volume.
• For Capsules labeled to contain 240 mg: Transfer 2.5 mL of a filtered portion of the solution under test to a 10-mL volumetric flask, add 2.5 mL of Buffer stage medium, and dilute with Buffer stage diluent to volume.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 223 nm
• Column: 4.6-mm × 10-cm; 5-µm packing L1
• Temperatures
• Autosampler: 5°
• Column: 30°
• Flow rate: 1.2 mL/min
• Injection volume: 5 µL
• Run time: NLT 2.2 times the retention time of dimethyl fumarate

System suitability

• Samples: Acid stage standard solution and Buffer stage standard solution
• Suitability requirements
• Tailing factor: 0.8–1.5, Acid stage standard solution and Buffer stage standard solution
• Relative standard deviation: NMT 1.5%, Buffer stage standard solution

Analysis

Samples: Acid stage standard solution, Acid stage sample solution, Buffer stage standard solution, and Buffer stage sample solution

Calculate the percentage of the labeled amount of dimethyl fumarate (C₆H₈O₄) dissolved in the Acid stage medium:

Result = (rᵤ/rₛ) × Cₛ × V × D × (1/L) × 100

rᵤ = peak response of dimethyl fumarate from the Acid stage sample solution

rₛ = peak response of dimethyl fumarate from the Acid stage standard solution

Cₛ = concentration of USP Dimethyl Fumarate RS in the Acid stage standard solution (mg/mL)

V = volume of Acid stage medium, 500 mL

D = dilution factor, if needed

L = label claim (mg/Capsule)

Calculate the percentage of the labeled amount of dimethyl fumarate (C₆H₈O₄) dissolved in the Buffer stage medium:

Result = (rᵤ/rₛ) × Cₛ × V × D × (1/L) × 100 + Q_A

rᵤ = peak response of dimethyl fumarate from the Buffer stage sample solution

rₛ = peak response of dimethyl fumarate from the Buffer stage standard solution

C = concentration of USP Dimethyl Fumarate RS in the Buffer stage standard solution (mg/mL)

V = volume of Buffer stage medium, 500 mL

D = dilution factor, if needed

L = label claim (mg/Capsule)

Q_A = percentage of dimethyl fumarate dissolved in the Acid stage

Tolerances

• Acid stage: NMT 10% of the labeled amount of dimethyl fumarate (C₆H₈O₄) is dissolved.
• Buffer stage: NLT 80% (Q) of the labeled amount of dimethyl fumarate (C₆H₈O₄) is dissolved.
• The percentages of the labeled amount of dimethyl fumarate (C₆H₈O₄) dissolved at the times specified conform to Dissolution 〈711〉, Delayed-Release Dosage Forms.

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements.

5 IMPURITIES

Change to read:

5.1 Organic Impurities

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

Sensitivity solution: 0.96 µg/mL of USP Dimethyl Fumarate RS from the Standard solution in Diluent

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[Note-The relative retention times in Table 2 are provided as information that could aid in peak assignment.]

Table 2

Suitability requirements

• Resolution: NLT 6.0 between fumaric acid and dimethyl fumarate related compound A, System suitability solution
• Tailing factor: 0.8–1.5, Standard solution
• Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Sample: Sample solution

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

Result = (rᵤ/rₛ) × 100

rᵤ = peak response of any degradation product

rₛ = sum of all peak responses

Acceptance criteria: See Table 3. Use an appropriate reporting threshold.

[Note-A reporting threshold of 0.1% may be suitable when the maximum daily dose is ≤1 g.]

Table 3

6 ADDITIONAL REQUIREMENTS

6.1 Packaging and Storage

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

6.2 USP Reference Standards 〈11〉

USP Dimethyl Fumarate RS

USP Dimethyl Fumarate Related Compound A RS

(E)-4-Methoxy-4-oxobut-2-enoic acid.

C₅H₆O₄    130.10

USP Fumaric Acid RS

Fumaric acid.

C₄H₄O₄   116.07