Fumaric Acid

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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C₄H₄O₄            116.07

2-Butenedioic acid, E-;

Fumaric acid CAS RN^®: 110-17-8.

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1 DEFINITION

Fumaric Acid contains ^▲NLT 98.0% and NMT 102.0% of fumaric acid _{▲(NF 1-Dec-2022)} of (C₄H₄O₄), calculated on the anhydrous basis.

2 IDENTIFICATION

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

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B. Chromatographic Identity: The retention time of the fumaric acid peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. _{▲(NF 1-Dec-2022)}

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3 ASSAY

3.1 PROCEDURE

Solution A: 10 mM potassium phosphate buffer; adjusted with phosphoric acid to a pH of 2.3

Solution B: Acetonitrile and Solution A (55:45)

Mobile phase: See Table 1.

Table 1

Return to starting conditions and re-equilibrate the system.

Diluent: Acetonitrile and Solution A (2:98)

System suitability solution: 50 µg/mL of USP Fumaric Acid RS and 200 µg/mL each of USP Glacial Acetic Acid RS, USP Lactic Acid RS, and USP Succinic Acid RS in Diluent

Standard solution: 50 µg/mL of USP Fumaric Acid RS in Diluent. Sonicate, if necessary.

Sample solution: 50 µg/mL of Fumaric Acid in Diluent. Sonicate, if necessary.

3.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 15-cm; 3-µm packing 11

Flow rate: 0.8 mL/min

Injection volume: 10 µL

3.1.2 System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for lactic acid, acetic acid, succinic acid, and fumaric acid are about 0.51, 0.54, 0.91, and 1.0, respectively.]

3.1.3 Suitability requirements

Resolution: NLT 2.0 between the lactic acid and acetic acid peaks; NLT 3.0 between the succinic acid and fumaric acid peaks, System suitability solution

Tailing factor: NMT 1.5, Standard solution

3.1.4 Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of fumaric acid (C₄H₄O₄) in the portion of Fumaric Acid taken:

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

r_U = peak area of fumaric acid from the Sample solution

r_S = peak area of fumaric acid from the Standard solution S s

C_S = concentration of USP Fumaric Acid RS in the Standard solution (µg/mL)

C_U = concentration of Fumaric Acid in the Sample solution (µg/mL)

Acceptance criteria: 98.0%-102.0% on the anhydrous basis _{▲(NF 1-Dec-2022)}

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281): NMT 0.1%

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4.2 LIMIT OF MALEIC ACID AND MALIC ACID

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

System suitability solution: 25 µg/mL of USP Fumaric Acid RS and 100 µg/mL each of USP Glacial Acetic Acid RS, USP Lactic Acid RS, and USP Succinic Acid RS in Diluent prepared by diluting the System suitability solution described in the Assay with Diluent in half.

Standard solution: 2.5 µg/mL of USP Maleic Acid RS and 37.5 µg/mL of USP Malic Acid RS

Sample solution: 2.5 mg/mL of Fumaric Acid in Diluent, prepared as follows. To a volumetric flask containing an accurately weighed amount of Fumaric Acid, add Diluent up to about 80% of the flask volume, sonicate the content at 35° for 30 min, cool to room temperature, and dilute with Diluent to volume. Vortex, if necessary.

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

Injection volume: 20 µL

4.2.1 System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for lactic acid, acetic acid, succinic acid, and fumaric acid are about 0.51, 0.54, 0.91, and 1.0, respectively.]

4.2.2 Suitability requirements

Resolution: NLT 2.0 between the lactic acid and acetic acid peaks; NLT 3.0 between the succinic acid and fumaric acid peaks, System suitability solution

Tailing factor: NMT 1.5 for maleic acid and malic acid, Standard solution

Relative standard deviation: NMT 3.0% for the maleic acid and malic acid peaks, Standard solution

4.2.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of maleic acid or malic acid in the portion of Fumaric Acid taken:

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

r_U = peak area of maleic acid or malic acid from the Sample solution

r_S = peak area of maleic acid or malic acid from the Standard solution 

C_S = concentration of USP Maleic Acid RS or USP Malic Acid RS in the Standard solution (µg/mL) S

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

F = conversion factor, 0.001 mg/µg

4.2.4 Acceptance criteria

Maleic acid: NMT 0.1%

Malic acid: NMT 1.5% (NF 1-Dec-2022)

5 SPECIFIC TESTS

WATER DETERMINATION (921), Method 1: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers.

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USP REFERENCE STANDARDS (11)

USP Fumaric Acid RS

USP Glacial Acetic Acid RS

USP Lactic Acid RSA _{▲(NF 1-Dec-2022)}

USP Maleic Acid RS

USP Malic Acid RS

USP Succinic Acid RSA _{▲(NF 1-Dec-2022)}