Topiramate Capsules

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 Capsules 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 to 650 cm

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

Sample solution: Open an appropriate number of Capsules 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 0.2-um pore size, and use the filtrate for analysis.

Analysis

Samples: Standard solution and Sample solution

Apply 50 µL to an NaCl plate, allow the solution to dry, then obtain the IR spectrum.

Acceptance criteria: Meet 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

Buffer: 1.5 g/L of ammonium acetate in water. Adjust with glacial acetic acid to a pH of 4.0.

Diluent: Acetonitrile and water (20:80)

Mobile phase: Methanol and Buffer (20:80)

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

Sample solution: Nominally 6 mg/mL of topiramate in Diluent from NLT 20 Capsules. [NOTE-Shake vigorously for at least 60 min, and pass a portion through a PTFE chemical-resistant filter of 0.45-µm pore size.]

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

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

Flow rate: 1.5 mL/min

Injection volume: 100 µL

Temperatures

Column: 35°

Detector: 35°

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of topiramate (C₁₂H₂₁NO₈S) in the portion of Capsules 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)

4.1 Test 1

Medium: Water; 900 mL

Apparatus 2: 50 rpm. Use an appropriate sinker as necessary.

Time: 45 min

Standard stock solution: 0.56 mg/mL of USP Topiramate RS in Medium prepared as follows. Transfer a suitable amount to a suitable volumetric flask. Add 2% of the flask volume of acetone to dissolve the solid. Dilute with Medium to volume.

Standard solution: (L/900) mg/mL of USP Topiramate RS in Medium, where L is the label claim, in mg of topiramate per Capsule from the Standard stock solution

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

Mobile phase: Methanol and water (32:68)

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

Column: 4.6-mm x 15-cm; 5-µm packing L.7

Flow rate: 2 mL/min

Injection volume: 200 µL

Temperatures

Column: 35°

Detector: 35"

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0% for Capsules labeled to contain more than 15 mg of topiramate; NMT 3.0% for Capsules labeled to contain less than or equal to 15 mg of topiramate

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of topiramate (C₁₂H₂₁NO₈S) dissolved:

Result = (r_u /r_s ) × C_s × V × (1/L) × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

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

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

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

4.2 Test 2

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

Medium: Water; 900 mL

Apparatus 2: 50 rpm. Use an appropriate sinker as necessary.

Time: 60 min

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

Sample solution: Pass a portion of the solution under test through a suitable lter.

Mobile phase: Methanol and water (40:60)

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: Refractive index

Column: 4.6-mm × 25-cm; 5-µm packing L7

Flow rate: 1.5 mL/min

Injection volume: 100 µL

Temperatures

Column: 35°

Detector: 35°

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 topiramate (C₁₂H₂₁NO₈S) dissolved:

Result = (r_u /r_s ) × C_s × V × (1/L) × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

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

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

Tolerances: NLT 75% (Q) of the labeled amount of topiramate (C₁₂H₂₁NO₈S) is dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

LIMIT OF SULFAMATE AND SULFATE: Use water with a resistivity of NLT 18 megohm-cm for the 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: Grind the contents of NLT 20 Capsules. Transfer an amount of powder equivalent to 300 mg of topiramate to a 50-mL

volumetric flask. Add about 40 mL of Mobile phase, and stir 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

Flow rate: 1.5 mL/min. [NOTE-A suitable background suppression unit may be used.]

Detector temperature: 30°

Injection volume: 70 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention time of the sulfamate peak is 0.44 relative to the sulfate 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 in the portion of Capsules taken:

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

r_u = peak response of sulfate from the Sample solution

r_s = peak response of sulfate from the Standard solution

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

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

M_r1 = molecular weight of sulfate anion, 96.04

M_r2 = molecular weight of anhydrous sodium sulfate, 142.04

Calculate the percentage of sulfamate in the portion of Capsules taken:

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

r_u = peak response of sulfamate from the Sample solution

r_s = peak response of sulfamate from the Standard solution

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

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

M_r1 = molecular weight of sulfamate anion, 96.09

M_r2 = molecular weight of sulfamic acid, 97.09

Acceptance criteria: NMT 0.25% (w/w) of sulfate and NMT 0.25% (w/w) of sulfamate

5.1 Organic Impurities

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

System suitability

Sample: Standard solution

[Note—Identify the peaks due to topiramate related compound A and topiramate using the relative retention times given in Table 1.]

Suitability requirements

Relative standard deviation: NMT 5.0%

Analysis

Samples: Sample solution and Standard solution

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

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

r_u = peak response of 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 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Store in tightly closed containers at controlled room temperature, protected from moisture.

LABELING: Topiramate Capsules may be swallowed whole or may be administered by carefully opening the Capsule and sprinkling the entire contents on a teaspoon of soft food. This drug-food mixture should be swallowed immediately and not chewed. It should not be stored for future us use. 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

USP Topiramate Related Compound A RS

2,3:4,5-Bis-0-(1-methylethylidene)-β-D-fructopyranose.

C₁₂H₂₀O₆              260.28