Topiramate

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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C₁₂H₂₁NO₈S               339.36

β-d-Fructopyranose, 2,3:4,5-bis-O-(1-methylethylidene)-, sulfamate;

2,3:4,5-Di-O-isopropylidene-β-d-fructopyranose sulfamate CAS RN: 97240-79-4; UNII: 0H73WJJ391.

1 DEFINITION

Topiramate contains NLT 98.0% and NMT 102.0% of topiramate (C₁₂H₂₁NO₈S), calculated on the anhydrous basis.

[CAUTION-Great care must be exercised in handling topiramate because it is a suspected teratogen.]

2 IDENTIFICATION

Change to read:

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

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

Mobile phase: Acetonitrile and water (50:50)

Standard solution: 2 mg/mL of USP Topiramate RS in Mobile phase

Sample solution: 2 mg/mL of Topiramate in Mobile phase

System suitability solution: 0.02 mg/mL each of USP Fructose RS and USP Topiramate Related Compound A RS in the Sample solution

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: 50°

Detector: 55°

Flow rate: 0.6 mL/min

Injection volume: 20 µL

Run time: NLT 3 times the retention time of topiramate

System suitability

Samples: Standard solution and System suitability solution

[NOTE-See Table 1 for the relative retention times for fructose, topiramate related compound A, and topiramate.]

Suitability requirements

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

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of topiramate (C₁₂H₂₁NO₈S) in the portion of Topiramate 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 = concentration of Topiramate in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the anhydrous basis

4 IMPURITIES

RESIDUE ON IGNITION (281); NMT 0.2%

4.1 LIMIT OF SULFAMATE AND SULFATE

[NOTE-Use water with resistivity of 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: 0.0045 mg/mL of sodium sulfate and 0.0030 mg/mL of sulfamic acid in Mobile phase

Sample solution: 6.0 mg/mL of Topiramate in Mobile phase

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 volume: 70 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention time of sulfamate is 0.44 relative to sulfate.]

Suitability requirements

Relative standard deviation: NMT 15.0% for sulfamate and sulfate

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of sulfate ions in the portion of Topiramate taken:

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

r_u = peak response of the sulfate ion from the Sample solution

r_s = peak response of the 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 ions in the portion of Topiramate taken:

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

r_u = peak response of the sulfamate ion from the Sample solution

r_s = peak response of the 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 = molecular weight of sulfamate anion, 96.09

M = molecular weight of sulfamic acid, 97.09

Acceptance criteria: NMT 0.1% of sulfate; NMT 0.1% of sulfamate

[NOTE- If N-methyltopiramate is a potential impurity, Organic Impurities, Procedure 1 and Organic Impurities, Procedure 3 are recommended; on the basis of synthetic route, perform either Organic Impurities, Procedure 2 or Organic Impurities, Procedure 3.]

4.2 ORGANIC IMPURITIES, PROCEDURE 1

Identification solution: 0.2 mg/mL of USP Topiramate Related Compound A RS in methanol

Standard solution A: 40 mg/mL of USP Topiramate RS in methanol

Standard solution B: 0.08 mg/mL of Topiramate from Standard solution A and methanol

Standard solution C: 0.04 mg/mL of Topiramate from Standard solution A and methanol

Sample solution: 40 mg/mL of Topiramate in methanol

Chromatographic system

(See Chromatography (621), General Procedures, Thin-Layer Chromatography.)

Mode: TLC

Adsorbent: 0.20-mm layer of chromatographic silica gel mixture, prewashed with methanol and air-dried

Application volume: 20 µL

Developing solvent system: Acetonitrile, methanol, and 0.5 M sodium chlorideTS (35:15:50)

Spray reagent: 30-mg/mL solution of phenol in alcohol and concentrated sulfuric acid (95:5)

Analysis

Samples: Standard solution B, Standard solution C, and Sample solution

Proceed as directed in the chapter. After elution, air-dry the plate, spray the plate with the Spray reagent, and let the plate air-dry. Then dry the plate for 10 min in an oven at 125°. [NOTE-The approximate R, values for topiramate and topiramate related compound A are 0.65 and 0.70, respectively. Disregard any spots at the origins of the chromatograms. Disregard any spot corresponding to topiramate related compound A because this impurity should be quantified using Procedure 3.] Examine the plate using visible light, and estimate the percentage of all secondary spots in the chromatogram of the Sample solution by comparing each spot with the principal spot from the chromatograms of each Standard solution.

Acceptance criteria: Any single spot is not greater in size and intensity than the spot for Standard solution C, NMT 0.1% of any individual impurity and NMT 0.5% of total impurities is found by TLC.

4.3 ORGANIC IMPURITIES, PROCEDURE 2

Mobile phase: Prepare as directed in the Assay.

[NOTE-Prepare all solutions fresh before use.]

Sample solution: 40 mg/mL of Topiramate in Mobile phase. [NOTE-Sonication may be used to aid dissolution.]

System suitability solution: 0.3 mg/mL each of USP Fructose RS and USP Topiramate Related Compound A RS in the Sample solution

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

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

Temperatures

Column: 50°

Detector: 55°

Flow rate: 0.6 mL/min

Injection volume: 50 µL

Run time: NLT 5 times the retention time of topiramate

System suitability

Sample: System suitability solution

[Note— See Table 1 for the relative retention times for fructose, topiramate related compound A, and topiramate.]

Suitability requirements

Resolution: NLT 1.0 between topiramate related compound A and topiramate

Relative standard deviation: NMT 2.0% for topiramate

Analysis

Sample: Sample solution

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

Result = (r_u /r_T ) × (1/F) × 100

r_u = peak area of each impurity

r_T = sum of the peak areas of all the impurities and topiramate

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1.

Table 1

4.4 Organic Impurities, Procedure 3

Mobile phase: Methanol and water(32:68)

Standard solution: 10 mg/mL of USP Topiramate RS and 0.04 mg/mL of USP Topiramate Related Compound A RS in Mobile phase

Sample solution: 10 mg/mL of Topiramate in Mobile phase

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: Refractive index

Column: 4.6-mm × 15-cm; 5-µm packing L15

Column temperature: 35°

Flow rate: 1.5 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 1.0 between topiramate related compound A and topiramate

Relative standard deviation: NMT 2.0% for topiramate from six replicate injections

Analysis

Samples: Standard solution and Sample solution

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

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

r_u = peak area of each impurity from the Sample solution

r_s = peak area of topiramate from the Standard solution

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

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

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2.

Table 2

5 SPECIFIC TESTS

OPTICAL ROTATION (781S), Procedures. Specific Rotation

Sample solution: 4-10 mg/mL in methanol

Acceptance criteria: -28.6° to -35.0°, measured at 20°

WATER DETERMINATION (921), Method /: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers, and store at controlled room temperature.

LABELING: If an Organic Impurities procedure other than Procedure 2 is used, then the labeling states the test with which the article complies.

The label also states that it is a suspected teratogen.

USP REFERENCE STANDARDS (11)

USP Fructose RS

USP Topiramate RS

USP Topiramate Related Compound A RS

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

C₁₂H₂₀O₆            260.28