Sodium Phenylbutyrate

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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C₁₀H₁₁NaO₂ 186.18

Benzenebutanoic acid, sodium salt;

Sodium 4-phenylbutyrate;

Sodium 4-phenylbutanoate. CAS RN®: 1716-12-7; UNII: NT6K61736T.

1 DEFINITION

Sodium Phenylbutyrate contains NLT 99.0% and NMT 101.0% of sodium phenylbutyrate (C₁₀H₁₁NaO₂), calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020)

B. Identification Tests—General 〈191〉, Sodium

Sample solution: Dissolve 150 mg in 2 mL of water.

Acceptance criteria: Meets the requirements of test A

3 ASSAY

Procedure

Sample: 150 mg

Analysis: Disperse the Sample in 50 mL of anhydrous acetic acid. [Note—The opalescence of the solution disappears during the titration.]

Titrate with 0.1 N perchloric acid VS, determining the endpoint potentiometrically. Each mL of 0.1 N perchloric acid is equivalent to 18.62 mg of sodium phenylbutyrate (C₁₀H₁₁NaO₂).

Acceptance criteria: 99.0%–101.0% on the anhydrous basis

4 IMPURITIES

Limit of Phenylbutyrate Related Compound C

Silylation solution: To 2 mL of bis(trimethylsilyl)trifluoroacetamide add 0.04 mL of chlorotrimethylsilane, and mix.

Sample solution: Dissolve 50.0 mg of Sodium Phenylbutyrate in 3 mL of water, and add 0.5 mL of hydrochloric acid. Extract with 2 quantities, each of 5 mL, of methylene chloride. Evaporate the combined methylene chloride extracts to dryness in a vial with a screw cap, and add 0.5 mL of the Silylation solution. Seal the vial, and heat at 70 ± 5° for 20 min.

Standard stock solution: 0.5 mg/mL of USP Phenylbutyrate Related Compound C RS in methylene chloride

Diluted standard stock solution: 0.05 mg/mL of USP Phenylbutyrate Related Compound C RS in methylene chloride from Standard stock solution

Standard solution: Place an amount of the Diluted standard stock solution, equivalent to 0.05 mg, in a vial with a screw cap, evaporate to dryness, and add 0.5 mL of the Silylation solution. Seal the vial, and heat at 70 ± 5° for 20 min.

System suitability solution: Prepare a solution containing 0.4 mg/mL of USP Sodium Phenylbutyrate RS in water. To 3 mL of this solution add 0.1 mL of hydrochloric acid. Extract with 2 quantities, each of 5 mL, of methylene chloride. Combine the methylene chloride extracts in a vial with a screw cap, and add 2 mL of Standard stock solution. Evaporate to dryness, and add 0.5 mL of the Silylation solution. Seal the vial, and heat at 70 ± 5° for 20 min.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 25-m × 0.25-mm fused silica capillary; coated with a 1.0-μm

lm of phase G27

Temperatures

Injector: 270°

Detector: 270°

Column: See Table 1.

Table 1

Carrier gas: Helium

Flow rate: 0.9 mL/min

Injection volume: 1 μL

Split ratio: 1:100

System suitability

Sample: System suitability solution

[Note—The relative retention times for phenylbutyrate related compound C and phenylbutyrate are about 0.98 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 3.0 between the phenylbutyrate related compound C and phenylbutyrate peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of phenylbutyrate related compound C in the portion of Sodium Phenylbutyrate taken:

Result = (r_U/r_S) × (W_S/W_U ) × 100

r_U = peak response of phenylbutyrate related compound C from the Sample solution

r_S = peak response of phenylbutyrate related compound C from the Standard solution

W_S = amount of USP Phenylbutyrate Related Compound C RS taken to prepare the Standard solution (mg)

W_U = amount of Sodium Phenylbutyrate taken to prepare the Sample solution (mg)

Acceptance criteria: NMT 0.1%

Organic Impurities

Mobile phase: Methanol, glacial acetic acid, and water (49:1:50)

Impurity stock solution A: 0.1 mg/mL of USP Phenylbutyrate Related Compound A RS in methanol

Impurity standard solution A: Dilute 1.0 mL of Impurity stock solution A with water to 50.0 mL. This solution contains 2 μg/mL of USP Phenylbutyrate Related Compound A RS.

Impurity stock solution B: 0.02 mg/mL of USP Phenylbutyrate Related Compound B RS in methanol

Impurity standard solution B: Dilute 1.0 mL of Impurity stock solution B with water to 50.0 mL. This solution contains 0.4 μg/mL of USP

Phenylbutyrate Related Compound B RS.

System suitability solution: Prepare a solution containing 20 mg/mL of USP Sodium Phenylbutyrate RS in methanol. Transfer 10 mL of this solution to a 50-mL volumetric flask, add 1.0 mL of Impurity stock solution B, and dilute with water to volume.

Sensitivity solution: Dilute 6.0 mL of Impurity standard solution A with water to 10.0 mL. This solution contains 1.2 μg/mL of USP

Phenylbutyrate Related Compound A RS.

Sample solution: 4.0 mg/mL of Sodium Phenylbutyrate, prepared as follows. Dissolve it first in methanol, using 20% of the final volume, and dilute with water to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 245 nm

Column: 4.6-mm × 25-cm; 5-μm base-deactivated end-capped packing L1

Flow rate: 1.3 mL/min

Injection volume: 20 μL

System suitability

Samples: System suitability solution and Sensitivity solution

Suitability requirements

Resolution: NLT 6 between phenylbutyrate and phenylbutyrate related compound B, System suitability solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Impurity standard solution A, Impurity standard solution B, and Sample solution

Calculate the percentage of phenylbutyrate related compound A or phenylbutyrate related compound B in the portion of Sodium

Phenylbutyrate taken:

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

r_U = peak response of respective impurity in the Sample solution

r_S = peak response of phenylbutyrate related compound A or phenylbutyrate related compound B in the respective Impurity standard solution

C_S = concentration of USP Phenylbutyrate Related Compound A RS or USP Phenylbutyrate Related Compound B RS in the respective Impurity standard solution (mg/mL)

C_U = concentration of Sodium Phenylbutyrate in the Sample solution (mg/mL)

Calculate the percentage of any individual unspecified impurity in the portion of Sodium Phenylbutyrate taken:

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

r_U = peak response of each unspecified impurity in the Sample solution

r_S = peak response of phenylbutyrate related compound A in Impurity standard solution A

C_S = concentration of USP Phenylbutyrate Related Compound A RS in Impurity standard solution A (mg/mL)

C_U = concentration of Sodium Phenylbutyrate in the Sample solution (mg/mL)

Acceptance criteria: See Table 2. Disregard any peak below 0.03%.

Table 2

5 SPECIFIC TESTS

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

pH 〈791〉

Sample solution: 20 mg/mL in carbon dioxide-free water

Acceptance criteria: 6.5–7.5

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve under argon in tight containers. Store at room temperature.

USP Reference Standards 〈11〉

USP Sodium Phenylbutyrate RS

USP Phenylbutyrate Related Compound A RS

3-Benzoylpropionic acid;

4-Oxo-4-phenylbutanoic acid.

C₁₀H₁₀O₃ 178.18

USP Phenylbutyrate Related Compound B RS

α-Tetralone;

3,4-Dihydronaphthalen-1(2H)-one.

C₁₀H₁₀O 146.19

USP Phenylbutyrate Related Compound C RS

4-Cyclohexylbutanoic acid.

C₁₀H₁₈O₂ 170.25