Dimethyl Fumarate

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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C₆H₈O₄ 144.13

2-Butenedioic acid, (2E)-, dimethyl ester;

Dimethyl (2E)-but-2-enedioate;

Dimethyl fumarate    CAS RN®: 624-49-7; UNII: FO2303MNI2

1 DEFINITION

Dimethyl Fumarate contains NLT 98.0% and NMT 102.0% of dimethyl fumarate (C₆H₈O₄).

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197K

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

Solution A: 0.1% phosphoric acid in water, prepared by diluting 1.2 mL of phosphoric acid with water to 1000 mL

Mobile phase: Acetonitrile and Solution A (30:70)

Buffer: 2.72 g/L of potassium phosphate, monobasic in water prepared as follows. Dissolve 2.72 g of potassium phosphate, monobasic in 800 mL of water in a 1-L volumetric flask. Adjust with 25% phosphoric acid to a pH of 3.0 and dilute with water to volume.

Diluent: Acetonitrile and Buffer (30:70)

Impurity standard stock solution 1: 0.5 mg/mL of USP Fumaric Acid RS in Diluent. Sonicate to completely dissolve.

Impurity standard stock solution 2: 0.5 mg/mL of USP Dimethyl Fumarate Related Compound A RS in Diluent. Sonicate to completely dissolve.

Standard solution: 300 µg/mL of USP Dimethyl Fumarate RS, 1.5 µg/mL of USP Fumaric Acid RS, and 0.9 µg/mL of USP Dimethyl Fumarate Related Compound A RS in Diluent prepared as follows. Transfer an appropriate quantity of USP Dimethyl Fumarate RS to a suitable volumetric flask and dissolve in 80% of the flask volume of Diluent. Sonicate to completely dissolve. Transfer appropriate volumes of Impurity standard stock solution 1 and Impurity standard stock solution 2 to the flask and dilute with Diluent to volume.

Sample solution: 300 µg/mL of Dimethyl Fumarate in Diluent. Sonicate to completely dissolve.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 210 nm
• Column: 4.0-mm × 25-cm; 4-µm packing L1
• Temperatures
• Autosampler: 5°
• Column: 35°
• Flow rate: 1 mL/min
• Injection volume: 5 µL
• Run time: NLT 3.7 times the retention time of dimethyl fumarate

System suitability

• Sample: Standard solution
• [Note-See Table 1 for the relative retention times.]
• Suitability requirements
• Resolution: NLT 6.0 between fumaric acid and dimethyl fumarate related compound A
• Tailing factor: 0.8–1.5 for dimethyl fumarate
• Relative standard deviation: NMT 0.73% for dimethyl fumarate

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of dimethyl fumarate (C₆H₈O₄) in the portion of Dimethyl Fumarate 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 (µg/mL)

Cᵤ = concentration of Dimethyl Fumarate in the Sample solution (µg/mL)

Acceptance criteria: 98.0%–102.0%

4 IMPURITIES

4.1 Residue on Ignition 〈281〉: NMT 0.1%

4.2 Organic Impurities

Solution A, Mobile phase, Buffer, Diluent, Impurity standard stock solution 1, Impurity standard stock solution 2, Standard solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Sensitivity solution: 0.15 µg/mL of USP Dimethyl Fumarate RS from the Standard solution in Diluent

System suitability

• Samples: Standard solution and Sensitivity solution
• [Note-See Table 1 for the relative retention times.]
• Suitability requirements
• Resolution: NLT 6.0 between fumaric acid and dimethyl fumarate related compound A, Standard solution
• Tailing factor: 0.8–1.5 for fumaric acid, dimethyl fumarate related compound A, and dimethyl fumarate, Standard solution
• Signal-to-noise ratio: NLT 10 for dimethyl fumarate, Sensitivity solution

Analysis

Sample: Sample solution

Calculate the percentage of any individual impurity in the portion of Dimethyl Fumarate taken:

Result = (rᵤ/rₛ) × 100

rᵤ = peak response of any individual impurity

rₛ = sum of all peak responses

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

Table 1

5 SPECIFIC TESTS

Chloride and Sulfate 〈221〉, Sulfate: NMT 0.03%

6 ADDITIONAL REQUIREMENTS

6.1 Packaging and Storage

Preserve in tight containers.

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