Clonazepam Orally Disintegrating Tablets
» Clonazepam Orally Disintegrating Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of clonazepam C15H10ClN3O3.
Packaging and storage—
Preserve in well-closed, light-resistant containers, and store at controlled room temperature.
USP Reference standards 
11
—
11—
USP Clonazepam RS 
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USP Clonazepam Related Compound A RS
3-Amino-4-(2-chlorophenyl)-6-nitrocarbostyril.
C15H10ClN3O3 315.72
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3-Amino-4-(2-chlorophenyl)-6-nitrocarbostyril.
C15H10ClN3O3 315.72
USP Clonazepam Related Compound B RS
2-Amino-2¢-chloro-5-nitrobenzophenone.
C13H9ClN2O3 276.68
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2-Amino-2¢-chloro-5-nitrobenzophenone.
C13H9ClN2O3 276.68
Identification—
A:
The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
Disintegration 701:
not more than 60 seconds.
701:
not more than 60 seconds.
Dissolution 711—
711—
Medium:
water; 900 mL, degassed.
Apparatus 2:
50 rpm.
Time:
60 minutes.
Mobile phase, Standard preparation, and Chromatographic system—
Prepare as directed in the Assay.
Standard solution—
Quantitatively dilute with Medium the Standard preparation as directed in the Assay according to the Tablet strength. The final concentration of the Standard solution corresponding to each Tablet strength is given in Table 1.
Table 1
| Tablet Strength mg per Tablet |
Final Standard solution µg/mL of Clonazepam |
|---|---|
| 0.125 | 0.125 |
| 0.25 | 0.25 |
| 0.5 | 0.50 |
| 1.0 | 1.0 |
| 2.0 | 2.0 |
Test solution—
Pass a portion of the solution under test through a 0.45-µm nylon membrane filter, discarding the first few mL.
Procedure—
Separately inject equal volumes (about 100 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the responses for the clonazepam peak. Calculate the percentage of clonazepam dissolved by the formula:
in which rU and rS are the peak responses obtained from the Test solution and the Standard solution, respectively; CS is the concentration of USP Clonazepam RS, in mg per mL, in the Standard solution; 900 is the volume of the Medium; and L is the Tablet label claim, in mg.
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Tolerances—
Not less than 75% (Q) of the labeled amount of clonazepam is dissolved in 60 minutes.
Uniformity of dosage units 905:
meet the requirements.
905:
meet the requirements.
Related compounds—
Mobile phase and Standard preparation—
Prepare as directed in the Assay.
System suitability solution—
Dissolve weighed quantities of USP Clonazepam Related Compound A RS and USP Clonazepam Related Compound B RS in Mobile phase to obtain a solution having a known concentration of about 0.2 µg per mL each of USP Clonazepam Related Compound A RS and USP Clonazepam Related Compound B RS.
Standard solution—
Quantitatively dilute with Mobile phase the Standard preparation to obtain a solution having a known concentration of about 0.2 µg per mL of clonazepam.
Test solution—
Weigh and finely powder not fewer than 20 Tablets. Grind the Tablets into a fine powder and transfer an accurately weighed portion of the powder, equivalent to about 2 mg of clonazepam, to a 50-mL volumetric flask, pipet 20.0 mL of Mobile phase into the flask, and sonicate for about 2 minutes with intermittent shaking. DO NOT dilute to volume. Shake the flask for 30 minutes on a mechanical shaker. Pass a portion of this solution through a nylon membrane filter having a 0.45-µm or finer porosity, and use the filtrate after discarding the first 4 mL of the filtrate.
Chromatographic system (see Chromatography 621)—
Prepare as directed in the Assay. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure. Identify the peaks due to clonazepam related compound A and clonazepam related compound B using the relative retention times given in Table 2; the resolution, R, between clonazepam related compound A and clonazepam related compound B is not less than 2.0. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the tailing factor is not more than 2.0, and the relative standard deviation for six replicate injections is not more than 6.0%.
621)—
Prepare as directed in the Assay. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure. Identify the peaks due to clonazepam related compound A and clonazepam related compound B using the relative retention times given in Table 2; the resolution, R, between clonazepam related compound A and clonazepam related compound B is not less than 2.0. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the tailing factor is not more than 2.0, and the relative standard deviation for six replicate injections is not more than 6.0%.
Procedure—
Separately inject equal volumes (about 100 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms for at least four times the retention time of clonazepam, and measure the responses for all the peaks. [note—Disregard any peaks with a retention time less than 3.5 minutes. ] Calculate the percentage of each impurity in the portion of Tablets taken by the formula:
(CS / CT)(rT / rS)(1 / F)100
in which CS is the concentration, in µg per mL, of USP Clonazepam RS in the Standard solution; CT is the nominal concentration, in µg per mL, of clonazepam in the Test solution; rT is the peak response of each impurity obtained from the Test solution; rS is the peak response for clonazepam obtained from the Standard solution; and F is the relative response factor for the impurity given in Table 2. The limits of each impurity along with relative retention times and relative response factors are given in Table 2.
Table 2
| Peak ID | Relative Retention Time | Relative Response Factor |
Limit % ( w/w) |
|---|---|---|---|
| Clonazepam | 1.0 | 1.0 | — |
| Clonazepam related compound A1 |
1.71 | 0.67 | 0.4 |
| Clonazepam related compound B2 |
2.25 | 0.79 | 1.0 |
| Any other unspecified degradation product |
— | 1.0 | 0.2 |
| Total impurities | — | — | 2.0 |
|
1
3-Amino-4-(2-chlorophenyl)-6-nitrocarbostyril.
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2
2-Amino-2'-chloro-5-nitrobenzophenone.
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Assay—
Mobile phase—
Prepare a filtered and degassed mixture of water, acetonitrile, and methanol (2:1:1). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Standard preparation—
Dissolve an accurately weighed quantity of USP Clonazepam RS in Mobile phase, and dilute, if necessary, to obtain a solution having a known concentration of about 0.01 mg per mL of USP Clonazepam RS.
Assay preparation—
Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 2 mg of clonazepam, to a 200-mL volumetric flask, add 120 mL of Mobile phase, and sonicate for about 15 minutes with intermittent shaking. Shake the flask on a mechanical shaker for about 30 minutes. Dilute with Mobile phase to volume, and mix. Pass a portion of this solution through a nylon membrane filter having a 0.45-µm or finer porosity, and use the filtrate after discarding the first 4 mL of the filtrate. [note—The solution is stable for 48 hours at room temperature. ]
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm × 15-cm column that contains 5-µm packing L7. The flow rate is about 1.2 mL per minute. The column temperature is maintained at 30
. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the column efficiency is not fewer than 2000 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%.
621)—
The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm × 15-cm column that contains 5-µm packing L7. The flow rate is about 1.2 mL per minute. The column temperature is maintained at 30. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the column efficiency is not fewer than 2000 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 60 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the clonazepam peak. Calculate the quantity, in percentage, of label claim of clonazepam (C15H10ClN3O3) in the portion of Tablets taken by the formula:
(CS / CU)(rU / rS)100
in which CS is the concentration, in mg per mL, of USP Clonazepam RS in the Standard solution; CU is the nominal concentration based on label claim, in mg per mL, of clonazepam in the Assay preparation; rU is the peak response for clonazepam obtained from the Assay preparation; and rS is the peak response for clonazepam obtained from the Standard preparation.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Ravi Ravichandran, Ph.D.
Principal Scientific Liaison 1-301-816-8330 |
(SM42010) Monographs - Small Molecules 4 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
|
| 701 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
USP35–NF30 Page 2726
Pharmacopeial Forum: Volume No. 34(2) Page 254