Phenytoin Oral Suspension

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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1 DEFINITION

Phenytoin Oral Suspension is Phenytoin suspended in a suitable medium. It contains NLT 95.0% and NMT 105.0% of the labeled amount of phenytoin (C₁₅H₁₂N₂O₂).

2 IDENTIFICATION

Change to read:

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

Sample: Shake a volume of Oral Suspension equivalent to 100 mg of phenytoin with 50 mL of a mixture of ether and chloroform (1 in 2) in a separator, evaporate the extract to dryness, and dry under vacuum at 105° for 4 h. Weigh 2–4 mg of the residue and 200 mg of potassium bromide in a mortar. Pestle, mix, and grind well, and prepare the potassium bromide pellet.

Acceptance criteria: Meets the requirements

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: Nominally 0.2 mg/mL of phenytoin prepared as follows. Weigh and transfer a suitable volume of Oral Suspension containing the equivalent of 20 mg of phenytoin to a 100-mL volumetric flask. Add 20 mL of methanol, and dissolve. Dilute with Diluent to volume. Dissolve with the aid of sonication, if necessary.

Chromatographic system

(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%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of phenytoin (C₁₅H₁₂N₂O₂) in the portion of Oral Suspension 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 = nominal concentration of phenytoin in the Sample solution (mg/mL)

Acceptance criteria: 95.0%–105.0%

4 PERFORMANCE TESTS

Dissolution 〈711〉

Buffer 1: Dissolve 36.3 g of tris(hydroxymethyl)aminomethane and 60 g of sodium lauryl sulfate in 6 L of water, adjust with hydrochloric acid to a pH of 7.5, and degas.

Medium: Buffer 1; 900 mL

Apparatus 2: 35 rpm

Time: 60 min

Buffer 2: 2.76 g/L of monobasic sodium phosphate in water

Mobile phase: Methanol, acetonitrile, and Buffer 2 (27:23:50). Adjust with phosphoric acid to a pH of 3.0.

Standard solution: 0.14 mg/mL of USP Phenytoin RS prepared as follows. Transfer a suitable amount of USP Phenytoin RS to a suitable volumetric flask. Dissolve in 3% of the flask volume of methanol. Dilute with Medium to volume.

Sample solution: Shake the sample suspension well (100 shakes). Determine the density, d (g/mL), of Oral Suspension using appropriate means. Using a 5-mL syringe, collect approximately 5 mL of Oral Suspension, and record the weight. With the paddles lowered, gently empty the contents of each syringe into the bottom of each vessel containing Medium. Start rotating the paddles. Reweigh each syringe, and determine the weight (g) of Oral Suspension delivered into each vessel. At the end of 60 min, remove 4 mL from each vessel, and pass through a nylon filter of 0.45-μm pore size, presaturated with Medium. [Note - Dilute with Medium if necessary to a concentration that is similar to the Standard solution.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm × 15-cm; packing L1

Flow rate: 1 mL/min

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0% for phenytoin

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of phenytoin (C₁₅H₁₂N₂O₂) dissolved:

Result = (r_U/r_S) × C_S × V × D × (d/W) × (1/L) × 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)

V = volume of Medium, 900 mL

D = dilution factor (necessary only if the Sample solution requires dilution)

d = density of Oral Suspension (g/mL)

W = weight of Oral Suspension delivered (g)

L = label claim of Oral Suspension (mg/mL)

Tolerances: NLT 80% (Q) of the labeled amount of phenytoin (C₁₅H₁₂N₂O₂) is dissolved.

Uniformity of Dosage Units 〈905〉

For single-unit containers

Acceptance criteria: Meets the requirements

Deliverable Volume 〈698〉

For multiple-unit containers

Acceptance criteria: Meets the requirements

5 IMPURITIES

Organic Impurities

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

Standard solution: 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 Diluent

Sample solution: Nominally 1 mg/mL of phenytoin prepared as follows. Weigh and transfer a suitable volume of Oral Suspension to an appropriate volumetric flask. Add methanol to about 20% of the final flask volume and dissolve. Dilute with Diluent to volume. Dissolve with the aid of sonication, if necessary.

System suitability

Sample: Standard solution

Suitability requirements

Signal-to-noise ratio: NLT 10

Relative standard deviation: NMT 5.0% for the phenytoin peak

Analysis

Samples: Standard solution and Sample solution

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

Calculate the percentage of phenytoin related compound A and phenytoin related compound B in the portion of Oral Suspension taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak area of each specified impurity from the Sample solution

r_S = peak area of each specified impurity from the Standard solution

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

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

Calculate the percentage of any individual unspeci

ed impurity in the portion of Oral Suspension 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 = nominal concentration of phenytoin in the Sample solution (mg/mL)

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

Table 2

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature. Protect from freezing and light.

Labeling: The label bears a statement that the patient must use an accurately calibrated measuring device with multiple-dose containers.

USP Reference Standards 〈11〉

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