Topiramate Extended-Release 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 Extended-Release Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of topiramate (C₁₂H₂₁NO₈S).

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197A or 197K

Sample for Infrared Spectroscopy 197K: Grind the contents of Capsules (NLT 20). Transfer an amount of powder equivalent to 250 mg of topiramate to a 250-mL separating funnel. Add 50 mL of 10% alcohol and shake for 5 min. Add 50 mL of chloroform and extract for 10 min, and allow the layers to separate. Filter the chloroform layer through anhydrous sodium sulfate. Evaporate the chloroform to dryness. Use the dry residue.

Acceptance criteria: The spectrum obtained from the Sample shows bands at approximately 3383 cm^-1, 3111 cm^-1, 2941 cm^-1, 2908 cm^-1, 1377 cm^-1, 1186 cm^-1, and 1072 cm^-1, similar to the spectrum from the Standard similarly obtained. Peak positions may vary slightly (within ±10 cm). [NOTE-Other peaks may be present in the spectra that do not appear in this list.]

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.

Mobile phase: Methanol and Buffer (40:60)

Diluent: Acetonitrile and water (30:70)

Standard solution: 2 mg/mL of USP Topiramate RS in Diluent. Sonicate to dissolve.

Sample solution: Nominally 2 mg/mL of topiramate in Diluent prepared as follows. Transfer a suitable quantity of topiramate from the contents of Capsules (NLT 20) to a suitable volumetric flask. Add 60% of the final volume of Diluent and sonicate with occasional shaking for NLT 10 min. Allow the solution to cool at room temperature and dilute with Diluent to volume. Pass a portion of this solution through a suitable filter of 0.45-µm or finer pore size, discarding NLT the first 1 mL of filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

Column: 4.6-mm x 10-cm; 5-µm packing L1

Temperatures

Column: 35°

Detector: 35°

Flow rate: 1 mL/min

Injection volume: 40 µl.

Run time: NLT 1.5 times the retention time of topiramate

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

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 of topiramate 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)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

DISSOLUTION (711)

Test 1

Medium: 0.05 M phosphate buffer, pH 7.5 (dissolve 6.8 g of monobasic potassium phosphate in 1 L of water adjust with 10% sodium hydroxide to a pH of 7.5); 750 mL

Apparatus 2: 50 rpm. Use a suitable sinker, if necessary.

Times: 2, 4, 8, and 12 h

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

Mobile phase: Methanol and Buffer (40:60)

Standard stock solution: 1.7 mg/mL of USP Topiramate RS prepared as follows. Transfer a suitable amount of USP Topiramate RS to a suitable volumetric flask. Add 10% of the flask volume of acetonitrile and sonicate to dissolve. Dilute with Medium to volume.

Standard solution: (L/750) mg/mL of USP Topiramate RS in Medium, from the Standard stock solution, where L is the label claim in mg/Capsule

Sample solution: At the times specified, withdraw a known volume of the solution under test and pass it through a suitable filter of 0.45-µm or finer pore size, discarding NLT the first 5 mL of filtrate. Replace the volume withdrawn with an equal volume of fresh Medium.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

Column: 4.6-mm x 10-cm; 5-µm packing L1

Temperatures

Column: 35°

Detector: 35°

Flow rate: 1 mL/min

Injection volume: 100 µL

Run time: NLT 1.5 times the retention time of topiramate

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 concentration (C_i) of topiramate (C₁₂H₂₁NO₈S) in the sample withdrawn from the vessel at each time point (i):

Result = (r_u /r_s ) × C_s

r_u = peak response of topiramate 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)

Calculate the percentage of the labeled amount of topiramate (C₁₂H₂₁NO₈S) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × V_s )] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁ ) × V_s ]} × (1/L) × 100

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁ ) × V_s ]} × (1/L) × 100

C_i = concentration of topiramate in the portion of sample withdrawn at time point i (mg/mL)

V = volume of Medium, 750 mL

L = label claim (mg/Capsule)

V_s = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of topiramate (C₁₂H₂₁NO₈S) dissolved at the times specied 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: Tris buffer, pH 7.2 (1.18 g/L of tris(hydroxymethyl)aminomethane and 6.35 g/L of tris(hydroxymethyl)aminomethane hydrochloride in water); 900 mL

Apparatus 1: 100 rpm

Times: 1, 2, and 6 h

Mobile phase: Methanol and water (45:55)

Standard solution: 0.22 mg/mL of USP Topiramate RS in Medium. Sonicate to dissolve, if necessary.

Sample solution: At the times specified, pass a portion of the solution under test through a suitable filter of 10-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

Columns

Guard: 3.0 - mm x 4 - 1 mm; packing 187

Analytical: 4.6-mm x 15-cm; 4-µm packing L8Z

Temperatures

Column: 35°

Detector: 35°

Flow rate: 1.5 mL/min

Injection volume: 75 µL

Run time: NLT 2 times the retention time of topiramate

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 concentration (C_i ) of topiramate (C₁₂H₂₁NO₈S) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_u /r_s ) × C_s

r_u = peak response of topiramate 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)

Calculate the percentage of the labeled amount of topiramate (C₁₂H₂₁NO₈S) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_s )] + (C₁ × V_s )} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × V_s )]} + [(C₂ + C₁ ) × V_s ]) × (1/L) × 100

C_i = concentration of topiramate in the portion of sample withdrawn at time point i (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

V_s = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of topiramate (C₁₂H₂₁NO₈S) dissolved at the times specified conform to Dissolution (711),

Acceptance Table 2.

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

Medium: 0.05 M phosphate buffer, pH 7.5 (dissolve 6.8 g of potassium phosphate, monobasic in 1 L water, and add to this solution 7.6 mL of 5 N sodium hydroxide solution; adjust with 1 N hydrochloric acid or 1 N sodium hydroxide solution to a pH of 7.5); 750 mL, deaerated

Apparatus 2: 50 rpm

Times: 1, 6, and 20 h

Buffer: Dissolve 1.54 g of ammonium acetate in 1 L water. Adjust with acetic acid. glacial to a pH of 4.0

Mobile phase: Acetonitrile and Buffer (46:54)

Standard stock solution: 2.222 mg/mL of USP Topiramate RS prepared as follows. Transfer an appropriate quantity of USP Topiramate RS to a suitable volumetric flask, add 40% of the flask volume of acetonitrile and dissolve. Dilute with water to volume.

Standard solution

For Capsules labeled to contain 25 and 50 mg: 0.067 mg/mL of USP Topiramate RS from Standard stock solution in Medium

For Capsules labeled to contain 100 and 200 mg: 0.267 mg/mL of USP Topiramate RS from Standard stock solution in Medium

Sample solution: At the times specified, withdraw a portion of the solution under test without replacing the withdrawn volume. Pass the solution through a suitable filter of 10-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

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

Temperatures

Column: 40°

Detector: 40°

Flow rate: 1 mL/min

Injection volume: 100 µL

Run time: NLT 1.5 times the retention time of topiramate

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 5%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i ) of topiramate (C₁₂H₂₁NO₈S) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_u /r_s ) × C_s

r_u = peak response of topiramate 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)

Calculate the percentage of the labeled amount of topiramate (C₁₂H₂₁NO₈S) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_s )] + (C₁ × V_s )} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × V_s )]} + [(C₂ + C₁ ) × V_s ]) × (1/L) × 100

C_i = concentration of topiramate in the portion of sample withdrawn at time point i (mg/mL)

V = volume of Medium, 750 mL

L = label claim (mg/Capsule)

V_s = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of topiramate (C₁₂H₂₁NO₈S) dissolved at the times specified conform to Dissolution (711). Acceptance Table 2.

Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4

Medium: Tris buffer, pH 7.2 (dissolve 6 g of tris(hydroxymethyl)aminomethane in 1 L of water; adjust with 1 M hydrochloric acid to a pH of 7.2); 900 mL, deaerated

Apparatus 1: 100 rpm

Times: 1, 2, and 6 h

Buffer: Dissolve 1.54 g of ammonium acetate in 1 L water. Adjust with acetic acid, glacial to a pH of 4.0

Mobile phase: Methanol and Buffer (40:60)

Standard stock solution: 1.12 mg/mL of USP Topiramate RS prepared as follows. Transfer an appropriate quantity of USP Topiramate RS to a suitable volumetric flask, add 10% of the flask volume of acetonitrile. Sonicate to dissolve, if necessary. Dilute with Medium to volume.

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

Sample solution: At the times specified, withdraw a portion of the solution and replace with equal volumes of fresh portions of Medium maintained at 37". Pass the solution through a suitable filter of 0.45-µm pore size, discarding an appropriate volume of filtrate so that a consistent result can be obtained.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

Column: 4.6-mm x 10-cm; 5-µm packing L1

Temperatures

Column: 35°

Detector: 35°

Flow rate: 1 mL/min

Injection volume: 100 µL

Run time: NLT 1.6 times the retention time of topiramate

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 concentration (C_i ) of topiramate (C₁₂H₂₁NO₈S) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_u /r_s ) × C_s

r_u = peak response of topiramate 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)

Calculate the percentage of the labeled amount of topiramate (C₁₂H₂₁NO₈S) dissolved at each time point (i):

Result₁ = C₁ × V_s × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × V_s )] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁ ) × V_s ]} × (1/L) × 100

C_i = concentration of topiramate in the portion of sample withdrawn at time point i (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

V_s = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See Table 4.

Table 4

The percentages of the labeled amount of topiramate (C₁₂H₂₁NO₈S) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. _{(RB 1-Feb-2025)}

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

5.1 LIMIT OF SULFAMATE AND SULFATE

Solution A: 8 mL of 50% sodium hydroxide solution in 1000 mL of water

Solution B: Water

Solution C: Solution A and Solution B (50:50)

Diluent: Acetonitrile and water (20:80)

Mobile phase: See Table 5 _{(RB 1-Feb-2025)}

[NOTE-It is recommended to use suitable anion trapping techniques to ensure the Mobile phase is free of all anionic impurities.]

Table 5 _{(RB 1-Feb-2025)}

Standard solution: 0.037 mg/mL of sodium sulfate and 0.025 mg/mL of sulfamic acid in Diluent

Sample solution: Nominally 10 mg/mL of topiramate in Diluent prepared as follows. Crush the contents of Capsules (NLT 20) and mix.

Transfer a suitable quantity of mixed contents to a suitable volumetric flask. Add 60% of the final volume of Diluent, sonicate with occasional shaking for NLT 60 min, and dilute with Diluent to volume. Pass a portion of this solution through a suitable filter, discarding NLT the first 1 mL of filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Conductivity with suppression

Columns

Guard: 4-mm x 5-cm; 13-µm packing L81

Analytical: 4-mm x 25-cm; 9-µm packing L81

Detector temperature: 35°

Flow rate: 2 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

[Note—Identify the components using the Standard solution. The elution order is the sulfamate peak, followed by the sulfate peak.]

Suitability requirements

Relative standard deviation: NMT 10.0% for sulfamate and sulfate

Analysis

Samples: Standard solution and Sample solution

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

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

Acceptance criteria: NMT 0.25% of sulfamate and NMT 0.25% of sulfate

Change to read:

5.2 ORGANIC IMPURITIES

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

Mobile phase: Methanol and Buffer (30:70)

Diluent: Acetonitrile and water (30:70)

System suitability solution: 20 mg/mL of USP Topiramate RS and 0.1 mg/mL of USP Topiramate Related Compound A RS in Diluent. Sonicate to dissolve.

Standard solution: 0.1 mg/mL of USP Topiramate RS in Diluent. Sonicate to dissolve.

Sensitivity solution: 0.01 mg/mL of USP Topiramate RS from Standard solution in Diluent

Sample solution: Nominally 20 mg/mL of topiramate in Diluent prepared as follows. Grind the contents of Capsules (NLT 20) and mix. Transfer a suitable quantity of mixed contents to a suitable volumetric flask. Add 60% of the final volume of Diluent and sonicate with intermittent shaking for NLT 60 min. Allow the solution to cool at room temperature and dilute with Diluent to volume. Pass a portion of this solution through a suitable filter, discarding NLT the first 1 mL of filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index.

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

Temperatures

Column: 35°

Detector: 35°

Flow rate: 1 mL/min

Injection volume: 100 µL

System suitability

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

[Note—See Table 6 (RB 1-Feb-2025) for the relative retention times.]

Suitability requirements

Resolution: NLT 1.2 between topiramate related compound A and topiramate, System suitability solution

Relative standard deviation: NMT 10.0%, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any degradation product in the portion of Capsules taken:

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

r_u = peak response of any degradation product 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 6 _{(RB 1-Feb-2025) )}

Acceptance criteria: See Table 6. _{(RB 1-Feb-2025)} The reporting threshold is 0.1%.

Table 6

6 ADDITIONAL REQUIREMENTS

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

Labeling: 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-O-(1-Methylethylidene)-β-d-fructopyranose.

C₁₂H₂₀O₆            260.29