Fosphenytoin Sodium Injection

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

Fosphenytoin Sodium Injection is a sterile solution of Fosphenytoin Sodium in Water for Injection. Fosphenytoin Sodium is a prodrug. Injectionn containing 1 mg/mL of Fosphenytoin Sodium is equivalent to 0.667 mg/mL of Phenytoin Sodium after injection. It contains NLT 90.0% and NMT 110.0% of the labeled amount of fosphenytoin sodium (C₁₆H₁₃N₂Na₂O₆P).

2 IDENTIFICATION

Change to read:

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

Sample: Transfer a 5-mL aliquot of Injection to a 100-mL beaker. Add 30 mL of acetone to form a white precipitate, and stir for 20 min using a magnetic stirrer. Filter under vacuum, and collect the precipitate using suitable filter paper. Allow to dry under vacuum for 15 min.

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

3.1 Procedure

Buffer: 8.2 g/L of monobasic potassium phosphate in water. Adjust with 6 N potassium hydroxide solution to a pH of 6.5 ± 0.05.

Mobile phase: Methanol, acetonitrile, and Buffer (25:2:73)

Standard stock solution A: 0.75 mg/mL of USP Fosphenytoin Sodium RS prepared as follows. Transfer a suitable amount of the standard in a suitable volumetric flask. Dissolve in a minimum amount of methanol. Dilute with Buffer to volume.

Standard stock solution B: 7.5 μg/mL of USP Phenytoin RS, 7.5 μg/mL of USP Phenytoin Related Compound A RS, and 15 μg/mL of USP Phenytoin Related Compound B RS in methanol

Standard solution: 150 μg/mL of USP Fosphenytoin Sodium RS from Standard stock solution A, 0.75 μg/mL each of USP Phenytoin RS and USP Phenytoin Related Compound A RS, and 1.5 μg/mL of USP Phenytoin Related Compound B RS from Standard stock solution B in Buffer

Sample stock solution: Nominally 1.5 mg/mL of fosphenytoin sodium from a volume of Injection prepared in methanol

Sample solution: Nominally 150 μg/mL of fosphenytoin sodium from Sample stock solution in Buffer

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 214 nm

Column: 4.6-mm × 15-cm; packing L11

Flow rate: 1.25 mL/min

Injection volume: 40 μL

3.3 System suitability

Sample: Standard solution

[Note - See Table 1 for the approximate relative retention times.]

3.4 Suitability requirements

Resolution: NLT 4.0 between phenytoin related compound B and phenytoin related compound A

Column efficiency: NLT 2250 theoretical plates for fosphenytoin

Tailing factor: NMT 1.8 for fosphenytoin

Relative standard deviation: NMT 1.0% for fosphenytoin and NMT 5.0% for phenytoin, phenytoin related compound A, and phenytoin related compound B

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of fosphenytoin sodium (C₁₆H₁₃N₂Na₂O₆P) in the portion of Injection taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of fosphenytoin sodium from the Sample solution

r_S = peak response of fosphenytoin sodium from the Standard solution

C_S = concentration of USP Fosphenytoin Sodium RS in the Standard solution (μg/mL)

C_U = nominal concentration of fosphenytoin sodium in the Sample solution (μg/mL)

Acceptance criteria: 90.0%–110.0%

4 IMPURITIES

Organic Impurities

Buffer, Mobile phase, Standard solution, Sample solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentages of phenytoin, phenytoin related compound A, and phenytoin related compound B in the portion of Injection taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

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

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

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

C_U = nominal concentration of fosphenytoin sodium in the Sample solution (μg/mL)

Calculate the percentages of unspecified degradation products in the portion of Injection taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of each unspecified degradation product from the Sample solution

r_S = peak response of phenytoin from the Standard solution

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

C_U = nominal concentration of fosphenytoin sodium in the Sample solution (μg/mL)

Acceptance criteria: See Table 1.

Table 1

5 SPECIFIC TESTS

Bacterial Endotoxins Test 〈85〉: NMT 14 USP Endotoxin Units/mL

pH 〈791〉: 8.3–9.3

Other Requirements: It meets the requirements in Injections and Implanted Drug Products 〈1〉.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in single-dose or multiple-dose containers, preferably of Type I glass. Store between 2° and 8°. Do not store at room temperature for more than 48 h.

Labeling: Both the actual content of fosphenytoin sodium and the content of phenytoin sodium, expressed in terms of phenytoin sodium equivalents, are stated on the label.

USP Reference Standards 〈11〉

USP Fosphenytoin Sodium RS

USP Phenytoin RS

USP Phenytoin Related Compound A RS

Diphenylglycine.

C₁₄H₁₃NO₂ 227.26

USP Phenytoin Related Compound B RS

Diphenylhydantoic acid.

C₁₅H₁₄N_{​​​​​​​2}O_{​​​​​​​3} 270.29