Action and use
Dopamine D2 receptor antagonist; serotonin 5HT2 receptor antagonist; neuroleptic.
DEFINITION
Risperidone Tablets contain Risperidone.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of risperidone, C23H27FN4O2
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions in methanol.
(1) Disperse a quantity of powdered tablets containing 2 mg of Risperidone in 15 mL, mix with the aid of ultrasound and dilute to 20 mL and filter.
(2) 0.01% w/v of risperidone BPCRS.
(3) 0.01% w/v each of risperidone BPCRS and trazodone hydrochloride BPCRS.
CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel F254.
(b) Use the mobile phase as described below.
(c) Apply 20 μL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry it in a current of air and examine under ultraviolet light (254 nm).
MOBILE PHASE
3 volumes of glacial acetic acid, 5 volumes of water and 12 volumes of butan-1-ol.
SYSTEM SUITABILITY
The test is not valid unless the chromatogram obtained with solution (3) shows two clearly separated spots.
CONFIRMATION
The principal spot in the chromatogram obtained with solution (1) corresponds in position and colour to that in the chromatogram obtained with solution (2).
B. In the Assay, the principal peak in the chromatogram obtained with solution (1) has the same retention time as the principal peak in the chromatogram obtained with solution (2).
TESTS
Dissolution
Comply with the requirements in the dissolution test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 50 revolutions per minute.
(b) Use 500 mL of 0.1M hydrochloric acid, at a temperature of 37°, as the medium.
PROCEDURE
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, suitably diluted with 0.1M hydrochloric acid if necessary, expected to contain 0.00005% w/v of Risperidone.
(2) 0.00005% w/v risperidone BPCRS in 0.1M hydrochloric acid.
(3) 0.005% w/v of risperidone impurity standard BPCRS in 0.1M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with base-deactivated octadecylsilyl silica gel for chromatography (5 μm) (Zorbax SB-C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 2.5 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 237 nm.
(f) Inject 50 μL of each solution.
MOBILE PHASE
0.1 volumes of trifluoroacetic acid, 20 volumes of acetonitrile and 80 volumes of water, adjusting the pH of the mixture to 3.0 with 13.5M ammonia.
When the chromatograms are recorded under the prescribed conditions the retention times relative to risperidone (retention time about 10 minutes) are impurity 2, about 0.65, impurity B, about 0.7 and impurity 1, about 1.6.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between impurity 2 and impurity B is at least 1.5.
DETERMINATION OF CONTENT
Calculate the total content of risperidone, C23H27FN4O2, in the medium from the chromatograms obtained and using the declared content of C23H27FN4O2 in risperidone BPCRS.
LIMITS
The amount of risperidone released is not less than 75% (Q) of the stated amount.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared immediately before use.
(1) To a quantity of the powdered tablets containing 5 mg of Risperidone add 10 mL of water and mix with the aid of ultrasound for 30 minutes. Add 40 mL of methanol to the mixture and mix with the aid of ultrasound for a further 15 minutes. Cool and filter through a suitable 0.45-μm filter.
(2) Dilute 1 volume of solution (1) to 200 volumes with 0.1M hydrochloric acid.
(3) Dilute 1 volume of solution (2) to 5 volumes with 0.1M hydrochloric acid.
(4) 0.01% w/v of risperidone impurity standard BPCRS with 0.1M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with base-deactivated octadecylsilyl silica gel for chromatography (5 μm) (Zorbax SB-C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 2.5 mL per minute. Equilibrate the column for at least 30 minutes with methanol at the end of each run.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 275 nm.
(f) Inject 50 μL of each solution.
MOBILE PHASE
Mobile phase A: 0.1 volumes of trifluoroacetic acid, 20 volumes of acetonitrile and 80 volumes of water, adjusting the pH of the mixture to 3.0 with 13.5M ammonia.
Mobile phase B: 0.1 volumes of trifluoroacetic acid, 39 volumes of methanol and 61 volumes of water adjusting the pH to 3.0 with 13.5M ammonia.
When the chromatograms are recorded under the prescribed conditions the retention times relative to risperidone (retention time about 11 minutes) are impurity B, about 0.6; impurity 2, about 0.7 and impurity 1, about 1.8.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (4), the resolution between impurity 2 and impurity B is at least 1.5.
LIMITS
In the chromatogram obtained with solution (1):
the area of any secondary peak corresponding to impurity 1 is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);
the area of any secondary peak corresponding to impurity 2 is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);
the area of any other secondary peak is not greater than twice the area of the principal peak in the chromatogram obtained with solution (3) (0.2%);
the sum of the areas of any secondary peaks is not greater than 2.4 times the area of the principal peak in the chromatogram obtained with solution (2) (1.2%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (3) (0.1%).
Uniformity of content
Tablets containing less than 2 mg and/or less than 2% w/w of Risperidone comply with the requirements stated under Tablets using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the
following solutions.
(1) Place 1 tablet in a 50 mL volumetric flask, add 25 mL of 0.1M hydrochloric acid, mix with the aid of ultrasound for 30 minutes or until completely dispersed, dilute to volume with 0.1M hydrochloric acid and filter through a suitable 0.45-μm filter. Dilute a quantity of the filtrate, if necessary, with sufficient 0.1M hydrochloric acid to produce a solution expected to contain 0.0005% w/v of Risperidone.
(2) 0.0005% w/v of risperidone BPCRS in 0.1M hydrochloric acid.
(3) 0.005% w/v of risperidone impurity standard BPCRS in 0.1M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
The chromatographic procedure described under Dissolution may be used.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between impurity 2 and impurity B is at least 1.5.
DETERMINATION OF CONTENT
Calculate the content of C23H27FN4O2 in each tablet from the chromatograms obtained and from the declared content of C23H27FN4O2 in risperidone BPCRS.
ASSAY
For tablets containing the equivalent of less than 2 mg and/or less than 2% w/w of Risperidone
Use the average of the individual results determined in the test for Uniformity of content.
For tablets containing the equivalent of 2 mg or more and 2% w/w or more of Risperidone
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) To a quantity of the powdered tablets containing 10 mg of Risperidone add 50 mL of 0.1M hydrochloric acid and mix with the aid of ultrasound for 30 minutes. Dilute the mixture to 100 mL with 0.1M hydrochloric acid and filter. Dilute 1 volume of the resulting solution to 10 volumes with 0.1M hydrochloric acid.
(2) 0.001% w/v of risperidone BPCRS in 0.1M hydrochloric acid.
(3) 0.005% w/v of risperidone impurity standard BPCRS in 0.1M hydrochloric acid.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between impurity 2 and impurity B is at least 1.5.
CHROMATOGRAPHIC CONDITIONS
The chromatographic procedure described under Dissolution may be used.
DETERMINATION OF CONTENT
Calculate the total content of Risperidone, C23H27FN4O2, in the tablets from the chromatograms obtained and using the declared content of C23H27FN4O2 in risperidone BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include impurity B, listed under Risperidone and the following:
1. cis-4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl]piperidine N-oxide hydrate
2. 3-(4-fluoro-2-hydroxyphenyl)-1-[2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl]-1,2-diazabicyclo[2.2.2]oct-2-en-1-ium iodide
