Add the following:
Related compounds by HPLC—
[Note—On the basis of the synthetic route, perform either
Test 1 or
Test 2.
Test 2 is recommended if
N-methyl topiramate is a potential related compound.
]
TEST 1—
Mobile phase—
Proceed as directed in the
Assay.
NOTE—Prepare all solutions fresh before use.
Test solution—
Transfer about 1 g of Topiramate, accurately weighed, to a 25-mL volumetric flask, and dissolve in Mobile phase with the aid of sonication. Cool to room temperature, dilute with Mobile phase to volume, and mix.
Chromatographic system (see Chromatography 
621
)—
The liquid chromatograph is equipped with a refractive index detector and a 4.6-mm × 25-cm column that contains packing L1. The column and the detector temperatures are maintained at 55
. The flow rate is about 0.6 mL per minute. Chromatograph the
System suitability solution, and record the peak areas as directed for
Procedure: the relative retention times are about 0.45 for fructose, 0.9 for topiramate related compound A, and 1.0 for topiramate; the resolution,
R, between topiramate related compound A and topiramate is not less than 1.0; and the relative standard deviation for replicate injections is not more than 2.0% for the topiramate peak.
Procedure—
Separately inject equal volumes (about 50 µL) of the
Test solution and the
Mobile phase into the chromatograph, record the chromatograms, and measure all of the peak areas. Record the chromatogram for a period of time equivalent to not less than five times the retention time of the topiramate peak. Calculate the percentage of each of the impurities in the portion of Topiramate taken by the formula:
100(1/F)(rU / rs)
in which
F is the relative response factor and is equal to 1.2 for topiramate related compound A and 1.0 for all the other peaks;
rU is the area of any impurity peak; and
rs is the sum of the areas of all of the impurity peaks and the topiramate peak. Not more than 0.3% of fructose is found; not more than 0.3% of topiramate related compound A is found; not more than 0.1% of any other individual impurity is found; and not more than 0.5% of total impurities detected by
Test 1 is found.
TEST 2—
Mobile phase—
Prepare a mixture of water and methanol (68:32). Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Standard solution—
Dissolve an accurately weighed quantity of
USP Topiramate RS and
USP Topiramate Related Compound A RS in
Mobile phase, and dilute quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 10 mg of topiramate and 0.04 mg of topiramate related compound A per mL.
Test solution—
Dissolve an accurately weighed quantity of Topiramate in Mobile phase, and dilute quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 10 mg per mL.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a refractive index detector and a 4.6-mm × 15-cm column that contains 5-µm packing L15. The column temperature is maintained at 35
. The flow rate is about 1.5 mL per minute. Chromatograph the
Standard solution, and record the peak responses as directed for
Procedure: the resolution,
R, between topiramate and topiramate related compound A is not less than 1.0; and the relative standard deviation for six replicate injections is not more than 2.0% for topiramate.
Procedure—
Separately inject equal volumes (about 50 µL) of the
Standard solution and the
Test solution into the chromatograph, and measure the responses for all of the peaks. Calculate the percentage of each impurity in the portion of Topiramate taken by the formula:
100(1/F)(CS / CU)(ri / rS)
in which
F is the relative response factor, which has a value of 1.1 for topiramate related compound A and 1.0 for all other impurities;
CS and
CU are the concentrations of topiramate in the
Standard solution and the
Test solution, respectively;
ri is the peak response for each impurity in the
Test solution; and
rS is the peak response of topiramate in the
Standard solution: not more than 0.3% of topiramate related compound A is found; not more than 0.10% of any other individual impurity is found; and not more than 0.5% total impurities detected by
Test 2 is found.
1S (USP31)
Change to read:
Limit of sulfamate and sulfate—
[Note—Use
Purified Water (resistivity not less than 18 megohm-cm) for
Mobile phase and all solution preparations.
]1S (USP31)
Diluent—
Prepare a mixture of
Purified
1S (USP31) Water and acetonitrile (80:20).
Solution A—
Transfer about 4 g of sodium hydroxide to a 1000-mL volumetric flask. Dissolve in and dilute with water (see
Reagents in
Chemical Resistance under
Containers—Glass 660) to volume, filter, and degas.
Solution B—
Use filtered and degassed water.
Solution C—
Dilute 50 mL of
Solution A with water to 100 mL, filter, and degas.
1S (USP31)
Mobile phase—
Use variable mixtures of
Solution A, Solution B, and
Solution C as directed for
Chromatographic system. Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Sulfamic acid stock solution—
Transfer about 60 mg, accurately weighed, of sulfamic acid to a 100-mL volumetric flask. Dissolve in and dilute with Diluent to volume.
Sulfate stock solution—
Transfer about 90.7 mg, accurately weighed, of potassium sulfate to a 100-mL volumetric flask. Dissolve in and dilute with Diluent to volume.
Standard solution—
Transfer 3.0 mL each of Sulfamic acid stock solution and Sulfate stock solution to a 50-mL volumetric flask, dilute with Diluent to volume, and mix.
Test solution—
Transfer about 100 mg, accurately weighed, of Topiramate to a 10-mL volumetric flask. Dissolve in and dilute with
Diluent1S (USP31) to volume.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a conductivity detector, a 4.0-mm × 5-cm guard column that contains packing L46 and a 4.0-mm × 25-cm column that contains packing L46. The flow rate is about 2.0 mL per minute. The chromatograph is programmed as follows.
Time
(minutes) |
Solution
A (%) |
Solution
B (%) |
Solution
C (%) |
 Elution |
| 0 |
0 |
95 |
5 |
equilibration |
| 0–7.0 |
0 |
95 |
5 |
isocratic |
| 7.0–15.0 |
0®20 |
95®0 |
5®80 |
linear gradient |
| 15.0–20.0 |
20 |
0 |
80 |
isocratic |
| 20.0–20.1 |
20®0 |
0®95 |
80®5 |
linear gradient |
| 20.1–25.0 |
0 |
95 |
5 |
re-equilibration |
Chromatograph the
Standard solution, and record the peak areas as directed for
Procedure: the relative retention time is 1.0 for the sulfate peak and about 0.27 for the sulfamate peak; and the relative standard deviation for replicate injections is not more than 2.0% for both the sulfate and sulfamate peaks.
Procedure—
Separately inject equal volumes (about 20 µL) of the
Standard solution and the
Test solution into the chromatograph, record the chromatograms, and measure the peak areas for the sulfate and sulfamate peaks. Calculate the percentage of sulfate in the portion of Topiramate taken by the formula:
1000(96.06/174.25)(C/W)(ri / rS)
in which 96.06 and 174.25 are the molecular weights of the sulfate ion and potassium sulfate, respectively;
C is the concentration, in mg per mL, of potassium sulfate in the
Standard solution; W is the weight, in mg, of Topiramate taken; and
ri and
rS are the peak areas of the sulfate ion obtained from the
Test solution and the
Standard solution, respectively: not more than 0.10% of sulfate ion is found. Calculate the percentage of sulfamate in the portion of Topiramate taken by the formula:
1000(96.08/97.09)(C/W)(ri / rS)
in which 96.08 and 97.09 are the molecular weights of sulfamate ion and sulfamic acid respectively;
C is the concentration, in mg per mL, of sulfamic acid in the
Standard solution; W is the weight, in mg, of Topiramate taken; and
ri and
rS are the peak areas of the sulfamate ion obtained from the
Test solution and the
Standard solution, respectively: not more than 0.10% of sulfamate ion is found.
1S (USP31)
Change to read:
Assay—
Mobile phase—
Prepare a filtered and degassed mixture of acetonitrile and water (1:1). Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Standard preparation—
Dissolve an accurately weighed quantity of
USP Topiramate RS in
Mobile phase, and dilute quantitatively, and stepwise if necessary, with
Mobile phase to obtain a solution having a known concentration of about 2.0 mg per mL.
Assay preparation—
Transfer about 50 mg of Topiramate, accurately weighed, to a 25-mL volumetric flask, and dissolve in and dilute with Mobile phase to volume.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a refractive index detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The flow rate is about 0.6 mL per minute. The detector and column temperatures are maintained at 50
. Chromatograph the
Standard preparation, and record the peak responses as directed for
Procedure: the column efficiency is not less than 1500 theoretical plates; the tailing factor is not more than 2.0; and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 20 µL) of the
Standard preparation and the
Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in
percentage,
1S (USP31) of C
12H
21NO
8S in the portion of Topiramate taken by the formula:
100(
CS /
CU)(
rU /
rS)
in which
CS is the concentration, in mg per mL, of
USP Topiramate RS in the
Standard preparation; CU is the concentration, in mg per mL, of Topiramate in the
Assay preparation;1S (USP31) and
rU and
rS are the peak
areas for topiramate
1S (USP31) obtained from the
Assay preparation and the
Standard preparation, respectively.
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-d-Fructopyranose, 2,3:4,5-bis-O-(1-methylethylidene)-, sulfamate.
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28.6