Topiramate Tablets
DEFINITION
Topiramate Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of topiramate (C12H21NO8S).
IDENTIFICATION
•  A. Infrared Absorption 197F
Wavenumber range:  4000–650 cm1
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.
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, and pass a portion through a chemical-resistant filter (PTFE) of 0.45-µm pore size. ]
Chromatographic system 
Mode:  LC
Detector:  Refractive index
Column:  4.6-mm × 25-cm; 5-µm packing L1
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 = (rU/rS) × (CS/CU) × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of USP Topiramate RS in the Standard solution (mg/mL)
CU== nominal concentration of topiramate in the Sample solution (mg/mL)
Acceptance criteria:  90.0%–110.0%
PERFORMANCE TESTS
•  Dissolution 711
Test 1 
Medium:  Water; 900 mL
Apparatus 2:  50 rpm
Time:  20 min
Mobile phase:  0.1% trifluoroacetic 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 filter of 1-µm pore size.
Chromatographic system 
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 = (rU/rS) × (CS/L) × V × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== 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 filter, discarding the first few mL.
Mobile phase:  Water and acetonitrile (1:1)
Chromatographic system 
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 efficiency:  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 = (rU/rS) × (CS/L) × V × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== 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 final 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 filter, discarding the first few mL.
Chromatographic system 
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 efficiency:  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 = (rU/rS) × (CS/L) × V × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== 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
IMPURITIES
•  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. ]
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 = (rU/rS) × (CS/CU) × (1/F) × 100
rU== peak response for the individual impurity from the Sample solution
rS== peak response of topiramate from the Standard solution
CS== concentration of USP Topiramate RS in the Standard solution (mg/mL)
CU== nominal concentration of topiramate in the Sample solution (mg/mL)
F== relative response factor (see Table 1)
Acceptance criteria  See Table 1.
Table 1
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
Topiramate related compound A 0.66 1.1 0.5
Topiramate 1.0
Individual unspecified degradation product 0.2
Total impurities 0.7
SPECIFIC TESTS
•  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  
Mode:  LC
Detector:  Conductivity
Column:  4.6-mm × 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 = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
rU== peak response of sulfate ion from the Sample solution
rS== peak response of sulfate ion from the Standard solution
CS== concentration of sodium sulfate in the Standard solution (mg/mL)
CU== concentration of topiramate in the Sample solution (mg/mL)
Mr1== molecular weight of the sulfate anion, 96.04
Mr2== molecular weight of anhydrous sodium sulfate, 142.04
Calculate the percentage of sulfamate ion in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
rU== peak response of sulfamate ion from the Sample solution
rS== peak response of sulfamate ion from the Standard solution
CS== concentration of sulfamic acid in the Standard solution (mg/mL)
CU== concentration of topiramate in the Sample solution (mg/mL)
Mr1== molecular weight of the sulfamate anion, 96.09
Mr2== molecular weight of sulfamic acid, 97.09
Acceptance criteria:  NMT 0.25% of sulfate ion; NMT 0.25% of sulfamate ion
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 Click to View Structure
2,3:4,5-Di-O-isopropylidene--d-fructopyranose sulfamate.
    C12H21NO8S        339.36
USP Topiramate Related Compound A RS Click to View Structure
2,3:4,5-Bis-O-(1-methylethylidene)--d-fructopyranose.
    C12H20O6        260.28
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Hariram Ramanathan, M.S.
Associate Scientific Liaison
1-301-816-8313
(SM42010) Monographs - Small Molecules 4
711 Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison
1-301-816-8106
(GCDF2010) General Chapters - Dosage Forms
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
USP35–NF30 Page 4900
Pharmacopeial Forum: Volume No. 34(5) Page 1197