Topiramate 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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1 DEFINITION

Topiramate Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of topiramate (C₁₂H₂₁NO₈S).

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197F _{(CN 1-May-2020)}

Wavenumber range: 4000-650 cm^-1

Standard solution: 20 mg/mL of USP Topiramate RS in acetone

Sample solution: Grind an appropriate number of Tablets to prepare a 20-mg/mL topiramate solution in acetone. Shake the solution for 30 min, and centrifuge for 10 min. Then pass an aliquot of the clear supernatant through a suitable nylon filter of 0.45-µm pore size, and use the filtrate for analysis.

Analysis: Apply 50 µL of the Standard solution to a sodium chloride plate, allow the solution to dry, and then obtain the IR spectrum. Wash the window with acetone, and repeat the same procedure using the Sample solution.

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

Buffer: 1.54 g/L of ammonium acetate in water. Adjust with glacial acetic acid to a pH of 4.0.

Diluent: Methanol and water (1:4)

Mobile phase: Methanol and Buffer (1:4)

Standard solution: 6 mg/mL of USP Topiramate RS in Diluent

Sample solution: 6 mg/ml, of topiramate in Diluent from NLT 12 Tablets, based on the label claim. [NOTE-Shake vigorously for at least 30 min,

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

Temperature

Column: 35°

Detector: 35°

Flow rate: 1.5 mL/min

Injection size: 100 µL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of topiramate (C₁₂H₂₁NO₈S) 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 Topiramate RS in the Standard solution (mg/mL)

C_u = nominal concentration of topiramate in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Dissolution 〈711〉

Test 1

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Time: 20 min

Mobile phase: 0.1% triuoroacetic acid in water and methanol (1:1)

Standard solution: 0.1 mg/mL of USP Topiramate RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable lter of 1-µm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: Refractive index

Guard column: 4.0-mm × 1-cm

Column: 4.6-mm × 25-cm; 5-µm packing L11

Temperature

Column: 40°

Detector: 40°

Flow rate: 1.2 mL/min

Injection size: 100 µL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of topiramate (C₁₂H₂₁NO₈S) dissolved:

Result = (r_u /r_s ) × (C_s /L) × V × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

C_s = concentration of USP Topiramate RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

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

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

Medium: Water; 900 mL, deaerated

Apparatus 2: 50 rpm

Time: 40 min

Standard solution: (L/900) mg/mL of USP Topiramate RS in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable lter, discarding the rst few mL.

Mobile phase: Water and acetonitrile (1:1)

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: Refractive index

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

Temperature

Column: 30°

Detector: 50°

Flow rate: 1.0 mL/min

Injection size: 100 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Column eciency: NLT 5000 theoretical plates

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of topiramate (C₁₂H₂₁NO₈S) dissolved:

Result = (r_u /r_s ) × (C_s /L) × V × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

C_s = concentration of USP Topiramate RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

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

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

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Diluent: Acetonitrile and water (1:1)

Mobile phase: Water and acetonitrile (55:45)

Standard solution: 1.1 mg/mL of USP Topiramate RS in Diluent. Dilute with Medium to obtain a nal concentration of about (L/900) mg/mL, where L is the label claim in mg/Tablet.

Sample solution: Pass a portion of the solution under test through a suitable lter, discarding the rst few mL.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: Refractive index

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

Temperature

Column: 50°

Detector: 50°

Flow rate: 1.2 mL/min

Injection size: 100 µL

System suitability

Sample: Standard solution

Suitability requirements

Column eciency: NLT 2000 theoretical plates

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of topiramate (C₁₂H₂₁NO₈S) dissolved:

Result = (r_u /r_s ) × (C_s /L) × V × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

C_s = concentration of USP Topiramate RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

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

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

5.1 RELATED COMPOUNDS

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

Standard solution: 1.2 mg/mL of USP Topiramate RS and 0.6 mg/mL of USP Topiramate Related Compound A RS in Diluent

Peak identification solution: 0.6 mg/mL each of USP Topiramate RS and USP Topiramate Related Compound A RS in Diluent

System suitability

Samples: Standard solution and Peak identification solution

[NOTE-Identify the peaks due to topiramate related compound A and topiramate using the relative retention times given in Table 1.1

Suitability requirements

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Tablets taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (1/F) × 100

r_u = peak response for the individual impurity from the Sample solution

r_s = peak response of topiramate from the Standard solution

C_s = concentration of USP Topiramate RS in the Standard solution (mg/mL)

C_u = nominal concentration of topiramate in the Sample solution (mg/mL)

F = relative response factor (see Table 1)

Acceptance criteria See Table 1.

Table 1

6 SPECIFIC TESTS

6.1 LIMIT OF SULFAMATE AND SULFATE

[NOTE-Use water with resistivity NLT 18 megohm-cm for preparation of the Mobile phase, Standard solution, and Sample solution.]

Buffer: 0.8 g/L of p-hydroxybenzoic acid in water

Mobile phase: Methanol and Buffer (2.5:97.5). Adjust with sodium hydroxide solution to a pH of 9.4 ± 0.5.

Standard solution: 0.015 mg/mL each of sodium sulfate and sulfamic acid in Mobile phase from anhydrous sodium sulfate and sulfamic acid, respectively

Sample solution: Transfer a suitable amount of ground powder from NLT 20 Tablets to a suitable volumetric flask to obtain a nominal concentration of 6 mg/mL of topiramate. Add 80% of the flask volume of Mobile phase, and shake for 30 min. Sonicate for 10 min, and dilute with Mobile phase to volume. Centrifuge, and pass through a polyethersulfone membrane 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: Conductivity

Column: 4.6-mm x 15-cm; 5-µm packing L47

Detector temperature: 30°

Flow rate: 1.5 mL/min

[NOTE-A suitable background suppression unit may be used.]

Injection size: 70 µL

System suitability

Sample: Standard solution

[NOTE-The approximate relative retention time of the sulfamate ion peak is 0.44 relative to the sulfate ion peak.]

Suitability requirements

Relative standard deviation: NMT 15.0% for the sulfamate and sulfate peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of sulfate ion in the portion of Tablets taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (M_r1 /M_r2 ) × 100

r_u = peak response of sulfate ion from the Sample solution

r_s = peak response of sulfate ion from the Standard solution

C_s = concentration of sodium sulfate in the Standard solution (mg/mL)

C_u = concentration of topiramate in the Sample solution (mg/mL)

M_r1 = molecular weight of the sulfate anion, 96.04

M_r2 = molecular weight of anhydrous sodium sulfate, 142.04

Calculate the percentage of sulfamate ion in the portion of Tablets taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (M_r1 /M_r2 ) × 100

r_u = peak response of sulfamate ion from the Sample solution

r_s = peak response of sulfamate ion from the Standard solution

C_s = concentration of sulfamic acid in the Standard solution (mg/mL)

C_u = concentration of topiramate in the Sample solution (mg/mL)

M_r1 = molecular weight of the sulfamate anion, 96.09

M_r2 = molecular weight of sulfamic acid, 97.09

Acceptance criteria: NMT 0.25% of sulfate ion; NMT 0.25% of sulfamate ion

7 ADDITIONAL REQUIREMENTS

Packaging and Storage: Store in tightly closed containers at controlled room temperature, protected from moisture.

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 Topiramate RS

2,3:4,5-Di-O-isopropylidene-β-d-fructopyranose sulfamate.

C₁₂H₂₁NO₈S        339.36

USP Topiramate Related Compound A RS

2,3:4,5-Bis-O-(1-methylethylidene)-β-d-fructopyranose.

C₁₂H₂₀O₆              260.28