Phenytoin

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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C₁₅H₁₂N₂O₂            252.27

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

5,5-Diphenylhydantoin CAS RN®: 57-41-0; UNII: 6158TKW0C5.

1 DEFINITION

Phenytoin contains NLT 98.0% and NMT 102.0% of phenytoin (C₁₅H₁₂N₂O₂), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

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

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

Procedure

Solution A: Prepare a 0.05 M monobasic potassium phosphate solution and adjust with phosphoric acid to a pH of 2.5. Solution B: Methanol and acetonitrile (60:40)

Mobile phase: See Table 1.

Table 1

Diluent: Solution B and water (1:1)

Standard solution: 0.2 mg/mL of USP Phenytoin RS in Diluent. Dissolve with the aid of sonication if necessary.

Sample solution: 0.2 mg/mL of Phenytoin in Diluent. Dissolve with the aid of sonication if necessary.

3.1 Chromatographic system

3.2 (See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 0.73%

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of phenytoin (C₁₅H₁₂N₂O₂) in the portion of Phenytoin taken:

Result = (r_U /r_S ) × (C_S /C_U) × 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 the Sample solution (mg/mL)

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

4 IMPURITIES

Organic Impurities

Mobile phase, Diluent, and Chromatographic system: Proceed as directed in the Assay.

Standard solution: 1 µg/mL of USP Phenytoin RS, 5 µg/mL of USP Phenytoin Related Compound A RS, 9 µg/mL of USP Phenytoin Related Compound B RS, and 1 µg/mL of USP Benzophenone RS in Diluent

Sample solution: 1 mg/mL of Phenytoin in Diluent

4.1 System suitability

Sample: Standard solution

[Note—The relative retention times are given in Table 2.]

Suitability requirements

Signal-to-noise ratio: NLT 10

Relative standard deviation: NMT 5.0% for the phenytoin peak

4.2 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each specified impurity in the portion of Phenytoin taken:

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

r_U = peak area of specified impurity from the Sample solution

r_S = peak area of corresponding impurity from the Standard solution

C_S = concentration of corresponding impurity in the Standard solution (mg/mL)

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

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

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

r_U = peak area for each unspecified impurity

r_S = peak area of phenytoin from the Standard solution

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

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

Acceptance criteria: See Table 2. Disregard any impurity less than 0.05%.

Table 2

^a Excluding benzophenone.

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° for 4 h.

Acceptance criteria: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers.

USP Reference Standards 〈11〉

USP Benzophenone RS

Diphenylmethanone.

C₁₃H₁₀O          182.22

USP Phenytoin RS

USP Phenytoin Related Compound A RS

2,2-Diphenylglycine.

C₁₄H₁₃NO₂      227.26

USP Phenytoin Related Compound B RS

2,2-Diphenyl-2-ureidoacetic acid.

C₁₅H₁₄N₂O₃         270.28