Rufinamide Tablets

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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To view the Notice from the Expert Committee that posted in conjunction with this accelerated revision, please click https://www.uspnf.com/rb-rufinamide-tabs-20220930.

1 DEFINITION

Rufinamide Tablets contain an amount of Rufinamide equivalent to NLT 95.0% and NMT 105.0% of the labeled amount of rufinamide (C₁₀H₈F₂N₄O).

2 IDENTIFICATION

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. The UV spectrum 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: 2.7 g/L of potassium dihydrogen phosphate in water

Diluent: Acetonitrile, methanol, and water (40:50:10)

Mobile phase: Methanol, tetrahydrofuran, and Buffer (15:5:80)

System suitability stock solution: 0.8 mg/mL of USP Rufinamide RS, and 0.02 mg/mL each of USP Rufinamide Related Compound A RS and USP Rufinamide Related Compound B RS in Diluent.

[Note—USP Rufinamide Related Compound B RS is used for identification purposes only.]

System suitability solution: 0.08 mg/mL of USP Rufinamide RS, and 2 µg/mL each of USP Rufinamide Related Compound A RS and USP Rufinamide Related Compound B RS, in Buffer from the System suitability stock solution

Standard stock solution: 0.8 mg/mL of USP Rufinamide RS in Diluent

Standard solution: 0.08 mg/mL of USP Rufinamide RS in Buffer from the Standard stock solution

Sample stock solution: Nominally 0.8 mg/mL of rufinamide in Diluent from a portion of NLT 20 finely powdered Tablets. Sonicate for 10 min, and shake for 15 min. Centrifuge a portion of the suspension.

Sample solution: Nominally 0.08 mg/mL of rufinamide in Buffer, from a portion of suspension obtained from the Sample stock solution

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm. For Identification B, use a diode array detector in the range of 190–400 nm.

Column: 4.6-mm × 12.5-cm; 5-µm packing L1

Flow rate: 1 mL/min

Injection volume: 25 µL

Run time: NLT 2.3 times the retention time of rufinamide

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 9 for relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between rufinamide and rufinamide related compound A, System suitability solution

Tailing factor: NMT 1.5, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of rufinamide (C₁₀H₈F₂N₄O) in the portion of Tablets 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 Rufinamide RS in the Standard solution (mg/mL)

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

Acceptance criteria: 95.0%–105.0%

4 PERFORMANCE TESTS

Change to read:

4.1 Dissolution 〈711〉

Test 1

Medium 1: 0.1 N hydrochloric acid

Medium 2: pH 6.8 phosphate buffer

Apparatus 4: With 22.6-mm cell, glass beads in the cone, with Tablet laying on the beads. Insert 320–350 mg of glass wool in the filter insert and then a glass microfiber filter of 2.7-µm pore size and a glass microfiber filter of 0.7-µm pore size.

Times:

5 and 12 h for the 200-mg Tablets

6 and 16 h for the 400-mg Tablets

Flow rate: 16 mL/min, pulsating

Test intervals, media, and sample solutions for the 200-mg Tablets: See Table 1.

Table 1

Test intervals (I): See Table 2.

Table 2

Sample solutions (Vᵢ): See Table 3.

Table 3

Test intervals, media, and sample solutions for the 400-mg Tablets: See Table 4.

Table 4

Test intervals (I): See Table 5.

Table 5

Sample solutions (Vᵢ): See Table 6.

Table 6

Mobile phase: Water, methanol, tetrahydrofuran, and acetic acid (100:50:13:0.12), with the addition of 206 mg of sodium pentanesulfonate, monohydrate

Standard stock solution: 600 µg/mL of USP Rufinamide RS in methanol

Standard solution 1: 60 µg/mL of rufinamide in Medium 1 from the Standard stock solution

Standard solution 2: 60 µg/mL of rufinamide in Medium 2 from the Standard stock solution

Standard solution 3: 12 µg/mL of rufinamide prepared as follows. Transfer 10 mL of the Standard stock solution to a 500-mL volumetric flask, add 40 mL of methanol, and dilute with Medium 2 to volume.

Standard solution 4: 6 µg/mL of rufinamide in Medium 2 from Standard solution 3

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 10-µm packing L1

Flow rate: 1.2 mL/min

Injection volume: 20 µL

Run time: NLT 1.4 times the retention time of rufinamide

System suitability

Sample: Standard solution 1

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Sample solutions and Standard solutions

Calculate the percentage of the labeled amount of rufinamide (C₁₀H₈F₂N₄O) [f(Sᵢ)] dissolved in the Sample solution (Sᵢ) by the following steps:

Calculate the regression line for the Standard solutions:

y = ax + b

y = peak area of rufinamide from the Standard solution

a = slope

x = concentration of rufinamide in the Standard solution (µg/mL)

b = y-intercept

f(Sᵢ) = [(y − b)/a] × [(Vᵢ)/(1000 × L)] × 100

y = peak area of rufinamide from the Sample solution

b = y-intercept

a = slope

Vᵢ = volume of Sample solution (mL)

L = label claim (mg/Tablet)

Cumulative percentage of the Tablet label claim dissolved:

i,j = indices of test interval

Tolerances

For Tablets labeled to contain 200 mg: See Table 7.

Table 7

For Tablets labeled to contain 400 mg: See Table 8.

Table 8

The percentages of the labeled amount of rufinamide dissolved in the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: pH 6.8 sodium phosphate buffer containing 2% sodium dodecyl sulfate (7.8 g/L of monobasic sodium phosphate dihydrate and 0.89 g/L of sodium hydroxide in water, adjusted with phosphoric acid or 1 N sodium hydroxide VS to a pH of 6.8; to each liter of this solution add 20.0 g of sodium dodecyl sulfate and sonicate to dissolve); 2000 mL

Apparatus 2: 50 rpm

Time: 1 h for 100-mg and 200-mg Tablets; 4 h for 400-mg Tablets

Buffer: 6.8 g/L of monobasic potassium phosphate in water

Mobile phase: Acetonitrile and Buffer (30:70)

Standard stock solution: 1 mg/mL of USP Rufinamide RS in methanol

Standard solution: 0.05 mg/mL of USP Rufinamide RS from the Standard stock solution diluted with Medium

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discard the first few milliliters, and dilute with Medium if necessary.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 5 µL

Run time: NLT 2 times the retention time of the rufinamide peak

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of rufinamide (C₁₀H₈F₂N₄O) dissolved:

Result = (r_U/r_S) × C_S × V × D × (1/L) × 100

r_U = peak response of rufinamide from the Sample solution

r_S = peak response of rufinamide from the Standard solution

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

V = volume of Medium, 2000 mL

D = dilution factor of the Standard solution

L = label claim of rufinamide (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of rufinamide (C₁₀H₈F₂N₄O) is dissolved. (RB 16-Sep-2022)

Test 3

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: pH 6.8 phosphate buffer containing 2.5% of sodium lauryl sulfate (Dissolve 6.9 g of sodium phosphate monobasic, 0.95 g of sodium hydroxide, and 25 g of sodium lauryl sulfate in 1 L of water. Adjust with phosphoric acid or 5 N sodium hydroxide to a pH of 6.8.); 2000 mL

Apparatus 2: 75 rpm

Time: 30 min

Buffer: 1.74 g/L of potassium phosphate dibasic in water. Adjust with phosphoric acid to a pH of 3.5.

Mobile phase: Acetonitrile and Buffer (30:70)

Diluent: Acetonitrile and methanol (50:50)

Standard solution: (L/2000) mg/mL of USP Rufinamide RS, where L is the label claim in mg/Tablet, prepared as follows. Transfer a suitable amount of USP Rufinamide RS to an appropriate volumetric flask. Dissolve in NMT 25% of the flask volume of Diluent using sonication. Dilute with Medium to volume.

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding the first 3 mL of the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 260 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Temperature: 35°

Flow rate: 1 mL/min

Injection volume: 25 µL

Run time: NLT 2.0 times the retention time of rufinamide

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of rufinamide (C₁₀H₈F₂N₄O) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L) × 100

r_U = peak response of rufinamide from the Sample solution

r_S = peak response of rufinamide from the Standard solution

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

V = volume of Medium, 2000 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of rufinamide (C₁₀H₈F₂N₄O) is dissolved.

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

5.1 Organic Impurities

Buffer, Diluent, Mobile phase, Sample stock solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

System suitability stock solution: 0.8 mg/mL of USP Rufinamide RS, and 0.02 mg/mL each of USP Rufinamide Related Compound A RS and USP Rufinamide Related Compound B RS in Diluent.

[Note—USP Rufinamide Related Compound B RS is used for identification purposes.]

System suitability solution: 0.08 mg/mL of USP Rufinamide RS, and 2 µg/mL each of USP Rufinamide Related Compound A RS and USP Rufinamide Related Compound B RS, in Buffer from the System suitability stock solution

Standard stock solution: 0.8 mg/mL of USP Rufinamide RS in Diluent

Standard solution: 0.4 µg/mL of USP Rufinamide RS from the Standard stock solution prepared as follows. Transfer a suitable volume of Standard stock solution to an appropriate volumetric flask. Add 10% of the flask volume of Diluent, and dilute with Buffer to volume.

Sensitivity solution: 0.04 µg/mL of USP Rufinamide RS from the Standard solution prepared as follows. Transfer a suitable volume of Standard solution to an appropriate volumetric flask. Add 10% of the flask volume of Diluent, and dilute with Buffer to volume.

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[Note—See Table 9 for relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between rufinamide and rufinamide related compound A, System suitability solution

Tailing factor: NMT 1.5 for rufinamide, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

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

Analysis

Samples: Sample solution and Standard solution

Calculate the percentage of any individual unspecified degradation product in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

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

r_S = peak response of rufinamide from the Standard solution

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

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

Acceptance criteria: See Table 9. The reporting threshold is 0.05%.

Table 9

6 ADDITIONAL REQUIREMENTS

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

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

USP Reference Standards 〈11〉

USP Rufinamide RS

USP Rufinamide Related Compound A RS

1-(2-Fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide.

C₁₀H₉FN₄O 220.20

USP Rufinamide Related Compound B RS

Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate.

C₁₁H₉F₂N₃O₂ 253.20