Valproic 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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C₈H₁₆O₂  144.21

Pentanoic acid, 2-propyl-;

Propylvaleric acid CAS RN®: 99-66-1; UNII: 614OI1Z5WI.

1 DEFINITION

Valproic Acid contains NLT 98.0% and NMT 102.0% of valproic acid (C₈H₁₆O₂), calculated on the anhydrous basis.

2 IDENTIFICATION

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

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

Buffer: 3.5 g/L of monobasic sodium phosphate in water. Adjust with phosphoric acid to a pH of 3.5.

Mobile phase: Acetonitrile and Buffer (45:55)

Diluent: Acetonitrile and water (45:55)

System suitability solution: 0.05 mg/mL of USP Valproic Acid Related Compound B RS and 0.5 mg/mL of USP Valproic Acid RS in Diluent

Standard solution: 0.5 mg/mL of USP Valproic Acid RS in Diluent

Sample solution: 0.5 mg/mL of Valproic Acid in Diluent

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 215 nm
• Column: 4.6-mm × 15-cm; 5-µm packing L7
• Flow rate: 1 mL/min
• Injection volume: 20 µL

System suitability

• Samples: System suitability solution and Standard solution
• Suitability requirements
• Resolution: NLT 2.0 between valproic acid related compound B and valproic acid, System suitability solution
• Tailing factor: NMT 1.5, Standard solution
• Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of valproic acid (C₈H₁₆O₂) in the portion of Valproic Acid taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of valproic acid from the Sample solution

rₛ = peak response of valproic acid from the Standard solution

Cₛ = concentration of USP Valproic Acid RS in the Standard solution (mg/mL)

Cᵤ = concentration of Valproic Acid in the Sample solution (mg/mL)

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

4 IMPURITIES

4.1 Residue on Ignition 〈281〉: NMT 0.1%

Change to read:

4.2 Organic Impurities

System suitability solution: 0.5 mg/mL of USP Valproic Acid RS, 0.05 mg/mL of USP Valproic Acid Related Compound B RS, and 0.05 mg/mL of USP Valproic Acid Related Compound K RS in n-heptane

Standard solution: 0.005 mg/mL of USP Valproic Acid RS in n-heptane

Sensitivity solution: 0.0025 mg/mL of USP Valproic Acid RS from Standard solution in n-heptane

Sample solution: 5 mg/mL of Valproic Acid in n-heptane

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: GC
• Detector: Flame ionization
• Column: 0.32-mm × 60-m capillary; coated with a 0.5-µm film of phase G35
• Temperatures
• Injection port: 220°
• Detector: 220°
• Column: See Table 1.

Table 1

• Carrier gas: Helium
• Flow rate: 2.0 mL/min
• Injection volume: 2.0 µL
• Injection type: Split, split ratio 5:1. [Note-Use of a split liner, deactivated with glass wool, is recommended.]

System suitability

• Samples: System suitability solution, Standard solution, and Sensitivity solution
• [Note-The relative retention times for valproic acid related compound B, valproic acid, and valproic acid related compound A (also known as 2-allylpent-4-enoic acid) are about 0.97, 1.0, and 1.13, respectively. For other relative retention times, see Table 2.]
• Suitability requirements
• Resolution: NLT 1.5 between valproic acid related compound B and valproic acid related compound K, System suitability solution
• Tailing factor: NMT 1.5 for valproic acid, Standard solution
• Signal-to-noise ratio: NLT 10 for valproic acid, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Valproic Acid taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (1/F) × 100

rᵤ = peak response of each impurity from the Sample solution

rₛ = peak response of valproic acid from the Standard solution

Cₛ = concentration of USP Valproic Acid RS in the Standard solution (mg/mL)

Cᵤ = concentration of valproic acid in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

Table 2

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight glass, stainless steel, or polyethylene (HDPE) containers.

Change to read:

USP Reference Standards 〈11〉

USP Valproic Acid RS

USP Valproic Acid Related Compound B RS

2-Isopropylpentanoic acid;

Also known as (2RS)-2-(1-Methylethyl)pentanoic acid.

C₈H₁₆O₂  144.21

USP Valproic Acid Related Compound K RS

Ethylmethylvaleric acid;

Also known as 2-Ethyl-2-methylpentanoic acid.

C₈H₁₆O₂  144.21