Risperidone
C23H27FN4O2 Mol. Wt. 410.5
Risperidone is 3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H -pyrido[1,2-a]pyrimidin-4-one.
Risperidone contains not less than 98.0 per cent and not more than 102.0 per cent of C23H27FN4O2, calculated on dried basis.
Category. Dopamine D2 receptor antagonist; serotonin 5HT2 receptor antagonist; neuroleptic.
Dose. Day 1:2 mg; day 2:4 mg. The usual dose ranges between 4 and 6 mg daily with a maximum of 16 g. In the elderly and those with hepatic or renal impairment: 500 µg twice daily increased in 500 µg steps to 1 to 2 mg daily.
Description. A white or almost white powder.
Identification
- Determine by infrared absorption spectrophotometry (2.4.6). Compare the spectrum with that obtained withrisperidone RSor with the reference spectrum of risperidone.
- In the Assay, the principal peak in the chromatogram obtained with the test solution (b) corresponds to the peak in the chromatogram obtained with the reference solution (b).
Tests
Related substances. Determine by liquid chromatography (2.4.14).
Test solution. Dissolve 100 mg of the substance under examination in methanol and dilute to 10.0 ml with the same solvent.
Reference solution (a). A solution containing 0.002 per cent w/v of risperidone related compound G RS [3-[2-[4-(4-Fluoro-2-hydroxybenzoyl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-α]pyrimidin-4-one hydrochloride RS] and 1.0 per cent w/v of risperidone RS in methanol.
Reference solution (b). A 0.002 per cent w/v solution of risperidone RS in methanol.
Chromatographic system
– a stainless steel column 25 cm x 4.6 mm packed with octylsilane bonded to porous silica (5 µm),
– column temperature 50º,
– mobile phase: A. a 0.5 per cent w/v solution of ammonium acetate, adjusted to pH 6.0 with glacial acetic acid and filter,
- a mixture of 40 volumes ofacetonitrile and 60 volumes of methanol,
– a gradient programme using the conditions given below,
– flow rate: 2 ml per minute,
– spectrophotometer set at 260 nm,
– injection volume: 10 µl.
Time Mobile phase A Mobile phase B
(in min.) (per cent v/v) (per cent v/v)
0 70 30
12 65 35
18 65 35
25 35 65
35 30 70
40 30 70
42 70 30
50 70 30
Name Relative Correction
retention time factor
Risperidone 1.0 1.0
E-Oxime 1 0.52 1.0
Z-Oxime 2 0.64 1.0
9-Hydroxyrisperidone 3 0.71 1.0
Desfluoro risperidone 4, 5 0.79 1.0
Risperidone difluoroketone 6 0.90 0.71
5-Fluororisperidone 7 0.94 1.0
Risperidone related compound G 5 1.08 0.4
6-Methylrisperidone8 1.44 1.0
Individual unidentified impurities --- 1.0
Total impurities --- ---
13-(2-[4-[(E)-(2,4-Difluorophenyl)(hydroxyimino)methyl]piperidin-1-yl]ethyl)-2-methyl-6,7,8,9-tetrahydro-4H -pyrido[1,2-a]pyrimidin-4-one,
23-[2-[4-[(Z)-(2,4-Difluorophenyl)(hydroxyimino)methyl]piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H -pyrido[1,2-a]pyrimidin-4-one,
3(9RS )-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H -pyrido[1,2-a]pyrimidin-4-one,
43-{2-[4-(Benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H -pyrido[1,2-a]pyrimidin-4-one,
5This impurity may not be relevant to all manufacturing processes,
63-[2-[4-(2,4-Difluorobenzoyl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H -pyrido[1,2-a]pyrimidin-4-one,
73-[2-[4-(5-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H -pyrido[1,2-a]pyrimidin-4-one (also known as 5-fluororisperidone),
8 (6RS )-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2,6-dimethyl-6,7,8,9-tetrahydro-4H -pyrido[1,2-a]pyrimidin-4-one,
Inject reference solutions (a) and (b). The test is not valid unless the resolution between the peaks due to risperidone and risperidone related compound G is not less than 1.5 in the chromatogram obtained with reference solution (a), the tailing factor is not more than 2.0 and the relative standard deviation for replicate injections is not more than 5.0 per cent in the chromatogram obtained with reference solution (b).
Inject reference solution (b) and the test solution. In the chromatogram obtained with the test solution, the area of any peak corresponding to E-oxime, Z-oxime, 9-hydroxyrisperidone, 5-fluororisperidone and 6-methylrisperidone is not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent), desfluoro risperidone, risperidone difluoroketone and risperidone related compound G is not more than 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent), the area of any other secondary peak is not more than 0.5 times the area of the principal peak in the chromatogram obtained with the reference solution (b) (0.1 per cent) and the sum of areas of all the secondary peaks is not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.3 per cent). Disregard any peak with an area less than 0.25 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).
Heavy metals (2.3.13). 2.0 g complies with the limit test for heavy metals, Method B (10 ppm).
Sulphated ash (2.3.18). Not more than 0.1 per cent, determined on 2 g.
Loss on drying (2.4.19). Not more than 0.5 per cent, determined on 1.0 g, dry under vacuum at 80º for 4 hours.
Assay. Determine by liquid chromatography (2.4.14).
Solution A. A 0.5 per cent w/v solution of ammonium acetate, adjusted to pH 6.0 with glacial acetic acid and filter.
Solution B. A mixture of 80 volumes of acetonitrile and 20 volumes of tetrahydrofuran,
Test solution (a). Dissolve a suitable quantity of the substance under examination in methanol containing 20 per cent of the final volume and dilute with the mobile phase to obtain a 0.1 per cent w/v solution.
Test solution (b). Dilute test solution (a) with the mobile phase to obtain a 0.02 per cent w/v solution of risperidone.
Reference solution (a). Dissolve a suitable quantity of risperidone RS in methanol containing 20 per cent of the final volume and dilute with the mobile phase to obtain a 0.1 per cent w/v solution of risperidone.
Reference solution (b). Dilute reference solution (a) with the mobile phase to obtain a 0.02 per cent w/v solution of risperidone.
Reference solution (c). A 0.002 per cent w/v solution of risperidone related compound G RS in reference solution (b).
Chromatographic system
– a stainless steel column 15 cm x 4.6 mm packed with octadecylsilane bonded to porous silica (5 µm),
– column temperature 50º,
– mobile phase: a mixture of 80 volumes of solution A and 20 volumes of solution B,
– flow rate: 1.5 ml per minute,
– spectrophotometer set at 275 nm,
– injection volume: 10 µl.
Run the chromatogram twice the retention time of the principal peak.
The relative retention time with reference to risperidone for risperidone related compound G is about 1.1.
Inject reference solution (b) and (c). The test is not valid unless the resolution between the peaks due to risperidone and risperidone related compound G is not less than 1.5 in the chromatogram obtained with reference solution (c), the tailing factor is not more than 2.0 and the relative standard deviation for replicate injections is not more than 1.0 per cent in the chromatogram obtained with reference solution (b) for risperidone peak.
Inject reference solution (b) and test solution (b).
Calculate the content of C23H27FN4O2.
Storage. Store in well-closed containers at room temperature