- British Pharmacopoeia Volume III
- Formulated Preparations: Specific Monographs
Clobazam Tablets |
Benzodiazepine.
Clobazam Tablets contain Clobazam.
The tablets comply with the requirements stated under Tablets and with the following requirements.
95.0 to 105.0% of the stated amount.
A. Shake a quantity of the powdered tablets containing 20 mg of Clobazam with 10 mL of dichloromethane, filter and evaporate the filtrate to dryness. Dissolve the residue in the minimum amount of methanol, evaporate to dryness and dry the residue at 105° for 10 minutes. The infrared absorption spectrum of the residue, Appendix II A, is concordant with the reference spectrum of clobazam (RS 066).
B. In the Assay, the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the principal peak in the chromatogram obtained with solution (2).
Comply with the requirements in the dissolution test for tablets and capsules, Appendix XII B1.
(a) Use Apparatus 2, rotating the paddle at 75 revolutions per minute.
(b) Use 500 mL of 0.1m hydrochloric acid, at a temperature of 37°, as the medium.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) After 45 minutes withdraw a sample of the medium and filter. Use the filtered medium, diluted with acetonitrile if necessary, to produce a solution expected to contain 0.001% w/v of Clobazam.
(2) 0.001% w/v of clobazam BPCRS in a mixture of equal volumes of acetonitrile and water.
The chromatographic conditions described under Related substances may be used. Inject 50 µL of each solution.
Calculate the total content of clobazam, C16H13ClN2O2, in the medium using the declared content of C16H13ClN2O2 in clobazam BPCRS.
The amount of clobazam, C16H13ClN2O2 released is not less than 75% (Q) of the stated amount.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) To a quantity of the powdered tablets containing 25 mg of Clobazam add 25 mL of the mobile phase and mix with the aid of ultrasound. Add sufficient mobile phase to produce 50 mL, centrifuge and use the supernatant liquid.
(2) Dilute 1 volume of solution (1) to 50 volumes with the mobile phase. Further dilute 1 volume of this solution to 10 volumes with the mobile phase.
(3) Dilute 2.5 volumes of a 0.01% w/v solution of 7-chloro-1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione BPCRSin methanol to 100 volumes with the mobile phase.
(4) Dilute 1 volume of a 0.01% w/v solution of 7-chloro-1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione BPCRS in methanol to 2 volumes with a 0.1% w/v solution of clobazam BPCRS in mobile phase.
(5) Dilute 1 volume of solution (2) to 2 volumes with methanol.
(a) Use a stainless steel column (15 cm × 2.0 mm) packed with end-capped octadecylsilyl silica gel for chromatography (3 µm) (Nucleosil C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 0.25 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 230 nm.
(f) Inject 25 µL of each solution.
(g) Allow the chromatography to proceed for twice the retention time of clobazam.
30 volumes of acetonitrile and 70 volumes of water.
The test is not valid unless, in the chromatogram obtained with solution (4), the resolution factor between the peaks due to 7-chloro-1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione and clobazam is at least 3.0.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to 7-chloro-1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione is not greater than the area of the principal peak in the chromatogram obtained with solution (3) (0.5%);
the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);
the sum of the impurities is not greater than 1.0%.
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (5) (0.1%).
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) To a quantity of the powdered tablets containing 20 mg of Clobazam add 80 mL of methanol, mix with the aid of ultrasound, add sufficient methanol to produce 100 mL and centrifuge. Dilute 1 volume of the supernatant liquid to 10 volumes with methanol.
(2) 0.002% w/v of clobazam BPCRS in methanol.
(3) Dilute 1 volume of a 0.01% w/v solution of 7-chloro-1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione BPCRS in methanol to 2 volumes with a 0.1% w/v solution of clobazam BPCRS in mobile phase.
The chromatographic conditions described under Related substances may be used.
The Assay is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to 7-chloro-1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione and clobazam is at least 3.0.
Calculate the content of C16H13ClN2O2 in the tablets using the declared content of C16H13ClN2O2 in clobazam BPCRS.
The impurities limited by the requirements of this monograph include:
A. 7-Chloro-1,5-dihydro-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione; 7-chloro-5-phenyl-1,5-dihydro-3H-1,5-benzodiazepine-2,4-dione (desmethylclobazam; European Pharmacopoeia impurity A).