Risperidone Oral Solution

1 DEFINITION 

Risperidone Oral Solution contains NLT 90.0% and NMT 110.0% of the labeled amount of risperidone (C₂₃H₂₇FN₄O₂). It may contain a suitable preservative. 

2 IDENTIFICATION 

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. Add the following:

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 

3 ASSAY 

Change to read: Procedure 

Buffer: 5.0 g/L of ammonium acetate in water 

Mobile phase: Acetonitrile and Buffer (22:78)  

System suitability solution: 250 µg/mL of USP Risperidone Related Compounds Mixture RS prepared as follows. Weigh USP Risperidone Related Compounds Mixture RS into a suitable volumetric flask. Dissolve first in 20% of the flask volume of methanol. Add 20% of the flask volume of water followed by 50% of the flask volume of Buffer, and allow to cool to room temperature. Dilute with methanol to volume. 

Standard stock solution: 1000 µg/mL of USP Risperidone RS in methanol 

Standard solution: 200 µg/mL of USP Risperidone RS prepared from the Standard stock solution as follows. Transfer 5.0 mL of the Standard stock solution to a 25-mL volumetric flask. Add 5.0 mL of water followed by 12.5 mL of Buffer, and allow to cool to room temperature. Dilute with methanol to volume. 

Sample solution: Nominally 200 µg/mL of risperidone from Oral Solution as follows. Transfer an amount of Oral Solution, equivalent to 5 mg of risperidone to a 25-mL volumetric flask, add 12.5 mL of Buffer, ll with methanol almost to volume, and mix well. Allow to cool to room temperature, and dilute with methanol to volume. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 275 nm. 

For identification B, use a diode array detector in the range of 190–400 nm. Column: 4.6-mm × 10-cm; 3-µm packing L1 

Flow rate: 1.5 mL/min 

Injection volume: 10 µL 

Run time: NLT 2 times the retention time of risperidone 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—See Table 1 for the relative retention times.] 

Suitability requirements 

Resolution: NLT 1.5 between bicyclorisperidone and risperidone Z-oxime, System suitability solution Relative standard deviation: NMT 1.0%,

Standard solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of risperidone (C₂₃H₂₇FN₄O₂) in the portion of Oral Solution taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of risedronate  from the Sample solution 

r_S = peak response of risedronate  from the Standard solution 

C_S = concentration of USP Risedronate RS in the Standard solution (mg/mL)  

C_U = nominal concentration of Risedronate in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0% 

4 PERFORMANCE TESTS 

Deliverable Volume 〈698〉: Meets the requirements 

5 IMPURITIES 

Change to read: 

Organic Impurities 

Buffer, Mobile phase, System suitability solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay. Standard stock solution: 5 µg/mL of USP Risperidone RS in methanol 

Standard solution: 1 µg/mL of USP Risperidone RS from the Standard stock solution prepared as follows. Transfer 5.0 mL of the Standard stock solution to a 25-mL volumetric flask. Add 5.0 mL of water followed by 12.5 mL of Buffer, and allow to cool to room temperature. Dilute with methanol to volume. 

Sensitivity solution: 0.2 µg/mL of USP Risperidone RS from the Standard stock solution prepared as follows. Transfer 1.0 mL of the Standard stock solution to a 25-mL volumetric flask. Add 5.0 mL of water followed by 12.5 mL of Buffer, and allow to cool to room temperature. Dilute with methanol to volume. 

System suitability 

Samples: System suitability solution, Standard solution, and Sensitivity solution

[Note—See Table 1 for the relative retention times.] 

Suitability requirements 

Resolution: NLT 1.5 between bicyclorisperidone and risperidone Z-oxime, System suitability solution Relative standard deviation: NMT 5%,  Standard solution 

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of each degradation product in the portion of Oral Solution taken: 

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100 

r_U = peak response of each degradation product  from the Sample solution 

r_S = peak response of risperidone from the Standard solution 

C_S = concentration of USP Risperidone RS in the Standard solution (µg/mL) 

C_U = nominal concentration of risperidone in the Sample solution (µg/mL) 

F = relative response factor (see Table 1) 

Acceptance criteria: See Table 1. The reporting threshold is 0.10%.

Table 1 

a acis-3-{2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one N-oxide. 

b 3-(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. 

c 3-(2-{4-[(Z)-(2,4-Diuorophenyl)(hydroxyimino)methyl]piperidin-1-yl}ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one. 

d Process impurity included in the table for identification only. Process impurities are controlled in the drug substance, and are not to be reported or included in the total impurities for the drug product. 

6 SPECIFIC TESTS 

pH 〈791〉: 2.0–4.0 

Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉: The total aerobic microbial count does not exceed 102 cfu/mL. The total yeasts and molds count does not exceed 101 cfu/mL. It meets the requirements of the test for absence of Escherichia coli. 

7 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in light-resistant containers. Store at controlled room temperature. Do not freeze. Change to read: 

USP Reference Standards 〈11〉 

USP Risperidone RS 

USP Risperidone Related Compounds Mixture RS 

Contains a mixture of the following four compounds: 

Risperidone. 

Risperidone cis-N-oxide: cis-3-{2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin 4-one N-oxide. 

C₂₃H₂₇FN₄O₃ 426.48 

Bicyclorisperidone: 3-(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. 

C₂₃H₂₈FIN₄O₂ 538.41 

Risperidone  Z-oxime: 3-(2-{4-[(Z)-(2,4-Diuorophenyl)(hydroxyimino)methyl]piperidin-1-yl}ethyl)-2-methyl-6,7,8,9-tetrahydro 4H-pyrido[1,2-a]pyrimidin-4-one. 

C₂₃H₂₈F₂N₄O₂ 430.50