Phenytoin Sodium

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

C₁₅H₁₁N₂NaO₂           274.25

2,4-Imidazolidinedione, 5,5-diphenyl-, monosodium salt;

5,5-Diphenylhydantoin sodium salt CAS RN®: 630-93-3; UNII: 4182431BJH.

1 DEFINITION

Phenytoin Sodium contains NLT 98.0% and NMT 102.0% of phenytoin sodium (C₁₅H₁₁N₂NaO₂), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

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

B. Identification Tests—General, Sodium 〈191〉

Solution A: Dissolve 2.7 g of methoxyphenylacetic acid in 6 mL of tetramethylammonium hydroxide TS, and add 20 mL of dehydrated alcohol. Solution B: 158 mg/mL of ammonium carbonate in water

Sample solution: Ignite 1 g, and cool. Add 2 mL of water to the residue, and neutralize the solution with hydrochloric acid. Filter, and dilute the filtrate with water to 4 mL.

Analysis: To 0.1 mL of the Sample solution add 1.5 mL of Solution A, and cool in ice water for 30 min. A voluminous, white, crystalline precipitate is formed. Place in water at 20°, and stir for 5 min.

Acceptance criteria: The precipitate does not disappear. Add 1 mL of ammonia TS. The precipitate dissolves completely. Add 1 mL of Solution B. No precipitate is formed.

C. 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

Procedure

Buffer: 0.05 M monobasic ammonium phosphate buffer, adjusted with phosphoric acid to a pH of 2.5

Mobile phase: Acetonitrile, methanol, and Buffer (35:20:45)

System suitability solution: 0.1 mg/mL of USP Phenytoin RS and 0.15 mg/mL of benzoin in Mobile phase

Standard solution: 0.05 mg/mL of USP Phenytoin RS in Mobile phase

Sample solution: 0.05 mg/mL of Phenytoin Sodium in Mobile phase

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 5-µm packing L1

Flow rate: 1.5 mL/min

Injection volume: 20 µL

3.2 System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for phenytoin and benzoin are 1.0 and 1.3, respectively.]

Suitability requirements

Resolution: NLT 1.5 between phenytoin and benzoin, 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 phenytoin sodium (C₁₅H₁₁N₂NaO₂) in the portion of Phenytoin Sodium taken:

Result = (r_U /r_S ) × (C_S /C_U ) × (M_r1 /M_r2 ) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Phenytoin RS in the Standard solution (mg/mL)

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

M_r1 = molecular weight of phenytoin sodium, 274.25

M_r2 = molecular weight of phenytoin, 252.27

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

4 IMPURITIES

Organic Impurities

Mobile phase, System suitability solution, and Chromatographic system: Proceed as directed in the Assay. Standard solution: 0.5 µg/mL of benzophenone, 1 µg/mL of USP Phenytoin RS, 9 µg/mL of USP Phenytoin Related Compound A RS, and 9 µg/mL of USP Phenytoin Related Compound B RS in Mobile phase

Sample solution: 1 mg/mL of Phenytoin Sodium in Mobile phase

4.1 System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for phenytoin and benzoin are 1.0 and 1.3, respectively.]

Suitability requirements

Resolution: NLT 1.5 between phenytoin and benzoin, System suitability solution

Relative standard deviation: NMT 5.0% for each compound, Standard solution

4.2 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of phenytoin related compound A, phenytoin related compound B, and benzophenone in the portion of Phenytoin Sodium taken:

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

r_U = peak response of phenytoin related compound A, phenytoin related compound B, or benzophenone from the Sample solution

r_S = peak response of phenytoin related compound A, phenytoin related compound B, or benzophenone from the Standard solution

C_S = concentration of the corresponding analyte in the Standard solution (µg/mL)

C_U = concentration of Phenytoin Sodium in the Sample solution (µg/mL)

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

Result = (r_U /r_S ) × (C_S /C_U ) × (M_r1 /M_r2 ) × 100

r_U = peak response of each impurity from the Sample solution

r = peak response of phenytoin from the Standard solution

C = concentration of USP Phenytoin RS in the Standard solution (µg/mL)

C_U = concentration of Phenytoin Sodium in the Sample solution (µg/mL)

M_r1 = molecular weight of phenytoin sodium, 274.25

M_r2 = molecular weight of phenytoin, 252.27

Acceptance criteria: See Table 1.

Table 1

^a Excluding benzophenone.

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° for 4 h.

Acceptance criteria: NMT 2.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers.

USP Reference Standards 〈11〉

USP Phenytoin RS

USP Phenytoin Related Compound A RS

Diphenylglycine.

C₁₄H₁₃NO₂             227.26

USP Phenytoin Related Compound B RS

Diphenylhydantoic acid.

C₁₅H₁₄N₂O₃         270.29

USP Phenytoin Sodium RS