Risperidone Tablets                

Risperidone Tablets contain not less than 90.0 per cent and not more than 110.0 per cent of the stated amount of risperidone, C23H27FN4O2.

Usual strengths. 1 mg; 2 mg; 3 mg; 4 mg.

Identification

A. Powder an appropriate number of tablets to prepare about 0.055 per cent w/v solution of risperidone in ethyl acetate, shake for 30 minutes and centrifuge for 20 minutes. Evaporate 5 ml of the supernatant liquid with the aid of a stream of nitrogen to dryness; the residue complies with the following test.

Determine by infrared absorption spectrophotometry (2.4.6). Compare the spectrum with that obtained with risperidone RS or with the reference spectrum of risperidone.

B. In the Assay, the chromatogram obtained with the test solution corresponds to the chromatogram obtained with the reference solution.

Tests

Dissolution (2.5.2).

Apparatus No.1,

Medium. 500 ml of 0.1 M hydrochloric acid,

Speed and time. 50 rpm and 45 minutes.

Withdraw a suitable volume of the medium and filter.

Determine by liquid chromatography (2.4.14).

Test solution. Dilute the filtrate, if necessary, with the dissolution medium.

Reference solution. Dissolve a quantity of risperidone RS in the dissolution medium and dilute with the same solvent to obtain a solution having a known concentration similar to the test solution.

Chromatographic system

     –   a stainless steel column 15 cm ´ 4.6 mm, packed with octadecylsilane bonded to porous silica (5 µm),

     –   mobile phase: a mixture of 65 volumes of water, 35 volumes of acetonitrile and 0.1 volume of trifluoroacetic acid, adjust the pH to 3.0 with ammonium hydroxide,

     –   flow rate: 1.5 ml per minute,

     –   spectrophotometer set at 237 nm,

     –   injection volume: 50 µl.

Inject the reference solution. The test is not valid unless the relative standard deviation for replicate injections is not more than 2.0 per cent.

Inject the reference solution and the test solution.

Calculate the content of C23H27FN4O2 in the dissolution medium.

D. Not less than 75 per cent of the stated amount of C23H27FN4O2.

Related substances. Determine by liquid chromatography (2.4.14), as described under Assay with the following modifications.

Dilute sodium hydroxide solution. To 1000 ml of water in a beaker, add 0.1 M sodium hydroxide dropwise to obtain a pH of about 8.5. 

Dilute hydrogen peroxide solution. Dilute 1 ml of hydrogen peroxide with water to 500 ml.

Reference solution. Dissolve 10 mg of risperidone RS in 10 ml of dilute sodium hydroxide solution in a 100.0 ml volumetric flask. Store the flask at 90° for 24 hours. Cool the solution to room temperature. Add 10 ml of dilute hydrogen peroxide solution to the flask, and store at 90° for an additional two hours. Cool the mixture to room temperature, and dilute with methanol to volume.

Name                                                              Relative                  Correction

                                                                     retention time                  factor

Bicyclorisperidone 1                                       0.68                             1.23

Risperidone                                                    1.0                 1.0

Risperidone trans-N-oxide2                            1.65                            ---

Risperidone cis-N-oxide3                                1.81                            1.05

Individual unidentified impurities                   ---                             1.0

Total impurities                                                ---                                 --- 

13-(4-fluoro-2-hydroxyphenyl)-1-[2-(6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyrido-[1,2-a]pyrimidin-3-yl)ethyl]-2-aza-1-azoniabicyclo[2.2.2]oct-2-ene iodide,

2trans-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, N-oxide monohydrate,

3cis-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, N-oxide monohydrate, 

Inject reference solution. The test is not valid unless the resolution between the peaks due to risperidone trans-N-oxide and risperidone cis-N-oxide is not less than 1.2.

Inject the test solution. The area of any peak corresponding to bicyclorisperidone, and risperidone cis-N-oxide is not more than 0.5 per cent, any other secondary peak is not more than 0.3 per cent and the sum of areas of all the secondary peaks is not more than 1.0 per cent, calculated by area normalisation.

Uniformity of content. Complies with the test stated under Tablets.

Determine by liquid chromatography (2.4.14), using the chromatographic system as described under Dissolution, except using injection volume: 20 µl.

Test solution. Transfer 1 tablet to a 100-ml volumetric flask. Add 50 ml of 0.1 M hydrochloric acid and shake mechanically for 30 minutes, dilute to the volume with 0.1 M hydrochloric acid, filter.

Reference solution. Weigh accurately and dissolve the risperidone RS in 0.1 M hydrochloric acid to obtain a solution having a known concentration similar to the test solution.

Inject the reference solution and the test solution.

Calculate the content of C23H27FN4O2 in the tablet.

Other tests. Comply with the tests stated under Tablets.

Assay. Determine by liquid chromatography (2.4.14).

Solvent mixture. A mixture of 80 volumes of methanol and 20 volumes of water.

Test solution. Transfer not less than 10 tablets to a suitable volumetric flask to obtain a 0.01 per cent w/v solution of Risperidone. Add an appropriate amount of waterequivalent to 20 per cent of the total volume of the volumetric flask, and shake mechanically for about 30 minutes. Add a volume of methanol equivalent to 60 per cent of the total volume of the volumetric flask, and shake mechanically for about 30 minutes, dilute with methanol to volume and filter.

Reference solution. A 0.01 per cent w/v solution of risperidone RS in the solvent mixture.

Chromatographic system

     –   a stainless steel column 15 cm ´ 4.6 mm, packed with octadecylsilane bonded to porous silica (5 µm),

     –   mobile phase:            A. a mixture of 80 volumes of water, 19.5 volumes of acetonitrile and 0.1 volume of trifluoroacetic acid, adjust the pH to 3.0 with ammonium hydroxide,

                                    B. a mixture of 61 volumes of water, 39 volumes of methanol and 0.1 volume of trifluoroacetic acid, adjust the pH to 3.0 with ammonium hydroxide,

     –   a gradient programme using the conditions given below,

     –   flow rate: 2.5 ml per minute,

     –   spectrophotometer set at 275 nm,

     –   injection volume: 20 µl. 

              Time           Mobile phase A          Mobile phase B

           (in min.)          (per cent v/v)               (per cent v/v)

                  0                         100                                  0       

                  8                         100                                  0

                16                          0                                  100

                20                          0                                  100

                21                        100                                 0

               30                      100                               0

Inject the reference solution. The test is not valid unless the tailing factor is not more than 2.5 and the relative standard deviation for replicate injections is not more than 2.0 per cent.

Inject the reference solution and the test solution.

Calculate the content of C23H27FN4O2 in the tablets.

Storage. Store protected from light and moisture, at a temperature not exceeding 25°.