Maleic 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

(Z)-Butenedioic acid;

cis-Butenedioic acid CAS RN®: 110-16-7.

1 DEFINITION

Maleic Acid contains NLT 98.0% and NMT 102.0% of maleic acid (C₄H₄O₄), calculated on the anhydrous basis.

2 IDENTIFICATION

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

B. The retention time of the maleic acid peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

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 original 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 Lactic Acid RS, USP Glacial Acetic Acid RS, and USP Succinic Acid RS in Diluent

Standard solution: 50 µg/mL of USP Maleic Acid RS in Diluent

Sample solution: 50 µg/mL of Maleic Acid in Diluent

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 15-cm; 3-µm packing L1

Flow rate: 0.8 mL/min

Injection volume: 10 µL

3.2 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 0.5, 0.6, 0.9, and 1.0, respectively.]

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

Relative standard deviation: NMT 1.0%, Standard solution

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of maleic acid in the portion of Maleic Acid taken:

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

r_U = peak area of maleic acid from the Sample solution

r_S = peak area of maleic acid from the Standard solution

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

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

Acceptance criteria: 98.0%–102.0% on the anhydrous basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%, determined on a 1.0-g portion

Change to read:

4.1 Limit of Iron

Solution A: Dissolve 9.7 g of potassium thiocyanate in 100 mL of water.

Diluted standard iron solution: Immediately before use, dilute 1 volume of Standard Iron Solution, prepared as directed in ▲Iron 〈241〉, Procedures, Procedure 1▲ (CN 1-Jun-2023) , with 9 volumes of water. [Note—This solution contains the equivalent of 1 µg/mL of iron.] Standard solution: Add 6 mL of water to 5 mL of Diluted standard iron solution. Add 1 mL of diluted hydrochloric acid and 0.05 mL of bromine TS. After 5 min, remove the excess of bromine with the aid of a current of air, add 3 mL of Solution A, and shake well. Sample solution: Dissolve 1 g of Maleic Acid in 10 mL of water. Add 2 mL of diluted hydrochloric acid and 0.05 mL of bromine TS. After 5 min, remove the excess of bromine with the aid of a current of air, add 3 mL of Solution A, and shake well.

Analysis: Allow the Standard solution and Sample solution to stand for 5 min.

Acceptance criteria: Any red color in the Sample solution is not more intense than that in the Standard solution (NMT 5 ppm). • Limit of Fumaric Acid and Malic Acid

Solution A, Solution B, Mobile phase, Diluent, System suitability solution, and Chromatographic system: Proceed as directed in the Assay. Standard solution: 50 µg/mL of USP Fumaric Acid RS and 25 µg/mL of USP Malic Acid RS

Sample solution: 5 mg/mL of Maleic Acid in Diluent

4.1.1 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 0.5, 0.6, 0.9, and 1.0, respectively.] 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 malic acid and fumaric acid, Standard solution

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

4.1.2 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of fumaric acid or malic acid in the portion of Maleic Acid taken:

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

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

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

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

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

F = conversion factor, 0.001 mg/µg

4.1.3 Acceptance criteria

Fumaric acid: NMT 1.0%

Malic acid: NMT 0.5%

5 SPECIFIC TESTS

Water Determination, Method I 〈921〉: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight glass containers, protected from light. Store at room temperature.

Labeling: Where Maleic Acid is intended for use in the manufacture of injectable dosage forms, it is so labeled. Where Maleic Acid must be subjected to further processing during the preparation of injectable dosage forms to ensure acceptable levels of bacterial endotoxins, it is so labeled.

USP Reference Standards 〈11〉

USP Fumaric Acid RS

USP Glacial Acetic Acid RS

USP Lactic Acid RS

USP Maleic Acid RS

USP Malic Acid RS

USP Succinic Acid RS