Review on Risperidone and its related Impurities

Risperidone is an antipsychotic second-generation medication to treat mental health disorders which includes treating schizophrenia, bipolar disorder, psychosis, and irritability related to autism. 

Is Risperidone brand or generic?

Risperidone is sold under the brand name Risperdal and it is available as a generic medication.  Paliperidone is another used second-generation antipsychotic which is the primary active metabolite of Risperidone. Risperidone is available in the form of tablets, oral solutions, oral dissolving tablets, etc.

Risperidone an overview:

The Risperidone study began in late 1980 and in 1993 it was approved for sale in the United States. Risperidone comes under the essential list of medicines of the World Health Organization.          

Risperidone is approved for and in which year?

US Food and Drug Administration FDA approved Risperidone in the year 1993 for the treatment of Schizophrenia, and further FDA in 2003 approved Risperidone for bipolar disorder (associated with the short-term treatment of mixed and manic states). Risperidone is marketed through the regulated and nonregulated markets and the impurities are determined as per the different pharmacopeia.

The structure of Risperidone is represented as:

Risperidone Impurity and Compound

Molecular Formula: C23H27FN4O2

Molecular Weight: 410.48

IUPAC Name: 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

CAS NO: 106266-06-2

As per the European Medicines and Agency (EMA) mentions that Risperidone is a benzisoxazole derivative and has a nonchiral structure. Risperidone shows polymorphism and based on the literature and X-ray diffraction pattern exists in three polymorphic forms A, B & E. The active substance and its impurities are characterized and are in accordance with the guidelines.

In the manufacturing process of the active substance, the impurity profile is considered the critical part as overall it depends on the manufacturing process and its parameters. There are different analytical techniques that are used to control the impurities at different stages and can be analyzed by column chromatography to get the final product purity as per the required pharmacopeia. The specification and the critical intermediates have limits for the specified and unspecified impurities and also the impurity profile as specified for the final active pharmaceutical ingredient (API).

To have control over impurities, process parameters, and methods of manufacturing recent strategy QbD can be used for development and manufacturing i.e. quality by design QbD. This method helps to ensure that the final drug substance is as per the purity, quality, and other parameters.

What are the Impurities reported for Risperidone?

Several impurities of Risperidone have been isolated and purified by synthetic chemical methods and analytical techniques and are reported in pharmacopeia and also available at Veeprho as Pharmacopeial and nonpharmacopeial impurities.

LIST OF RISPERIDONE IMPURITIES:

Risperidone EP Impurity A / Risperidone BP Impurity A / Risperidone E-Oxime
CAS No:  691007-09-7
Molecular Weight: 430.49
IUPAC Name: 3-[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  
Risperidone EP Impurity B / Risperidone BP Impurity B / Risperidone Z-Oxime
CAS No:  132961-05-8
Molecular Weight: 430.49
IUPAC Name: 3-[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  
Risperidone EP Impurity C / 9-Hydroxy Risperidone
CAS No:  144598-75-4
Molecular Weight: 426.48
IUPAC Name: (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  
Risperidone EP Impurity D / Risperidone BP Impurity D / Risperidone 5-Fluoro Isomer
CAS No:  1199589-74-6
Molecular Weight: 410.48
IUPAC Name: 3-[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  
Risperidone EP Impurity E / 6-Methyl Risperidone
CAS No: 1346602-28-5
Molecular Weight: 424.51
IUPAC Name: (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
Risperidone EP Impurity H / Risperidone Difluoro Ketone
CAS No:  158697-67-7
Molecular Weight: 415.48
IUPAC Name: 3-[2-[4-(2, 4-Difluorobenzoyl)piperidin-1-yl]ethyl]-2-methyl- 6, 7, 8, 9-tetrahydro-4H-pyrido[1, 2-a]pyrimidin-4-one  
Risperidone EP Impurity K / Risperidone Desfluoro
CAS No:  106266-09-5
Molecular Weight: 392.49
IUPAC Name: 3-[2-[4-(1, 2-Benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6, 7, 8, 9-tetrahydro-4Hpyrido[1, 2-a]pyrimidin-4-one
Risperidone EP Impurity L / Risperidone Chloroethyl Impurity
CAS No:  63234-80-0
Molecular Weight: 226.7
IUPAC Name: “3-(2-Chloroethyl)-2-methyl-6, 7, 8, 9- tetrahydro-4H-pyrido-(1, 2-a)-pyrimidin-4-one “  
Risperidone Related Compound G
CAS No:  152542-00-2
Molecular Weight: 413.49 (base) 449.95 (HCl salt)
IUPAC Name: 3-[2-[4-(4-Fluoro-2-hydroxybenzoyl)piperidin-1-yl]ethyl]-2-methyl-6, 7, 8, 9-tetrahydro-4H-pyrido[1, 2-a]pyrimidin-4-one HCl
Risperidone IH Impurity 3 (Quaternary Salt)
CAS No:  N/A
Molecular Weight: 601.75
IUPAC Name: 4-(6-fluorobenzo[d]isoxazol-3-yl)-1, 1-bis(2-(2-methyl-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido[1, 2-a]pyrimidin-3-yl)ethyl)piperidin-1-ium 
Risperidone N-Oxide
CAS No:  832747-55-4
Molecular Weight: 426.48
IUPAC Name: 3-[2-[4-(6-Fluoro-1, 2-benzisoxazol-3-yl)-1-oxido-1-piperidinyl]ethyl]-6, 7, 8, 9- tetrahydro-2-methyl-4H-pyrido[1, 2-a]pyrimidin-4-one  
Risperidone Difluorobenzyol impurity
CAS No:  106266-04-0
Molecular Weight: 261.7
IUPAC Name: 4-(2, 4-Difluorobenzoyl)-piperidine HCl  
Bicyclorisperidone
CAS No:  2231638-02-9
Molecular Weight: 538.4
IUPAC Name: 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 
Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole
CAS No:  84163-77-9
Molecular Weight: 220.24 g/mol
IUPAC Name: 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole

Risperidone is an antipsychotic second-generation medication to treat mental health disorders which include treating schizophrenia, bipolar disorder, psychosis, and irritability related to autsim.   Risperidone is sold under the brand name Risperdal and it is available as a generic medication.  Risperidone is marketed through the regulated and non-regulated markets and the impurities are determined as per the different pharmacopeia. Impurities of Risperidone have been isolated and purified by synthetic chemical methods and analytical techniques and are reported in the pharmacopeia.

References:

  1. “Risperidone”. The American Society of Health-System Pharmacists. Archived from the original on 2 December 2015. Retrieved 1 December 2015
  2. FDA Approved Drug Products: Risperdal (risperidone) for oral use by the American Society of Health-System Pharmacists. Archived from the original on 2 December 2015. Retrieved 1 December 2015
  3. “Risperdal- risperidone tablet Risperdal M-Tab- risperidone tablet, orally disintegrating Risperdal- risperidone solution”. DailyMed. Archived from the original on 30 April 2017. Retrieved 31 December 2019
  4. Schatzberg AF, Nemeroff CB (2009). The American Psychiatric Publishing textbook of psychopharmacology (4th ed.). Washington, D.C.: American Psychiatric Pub. p. 627
  5. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.
  6. “Respiridone”. The American Society of Health-System Pharmacists. Archived from the original on 13 April 2011. Retrieved 3 April 2011
  7. “Electronic Orange Book”. Food and Drug Administration. April 2007. Archived from the original on 19 August 2007. Retrieved 24 May 2007
  8. “Okedi EPAR”. European Medicines Agency (EMA). 15 December 2021. Archived from the original on 3 March 2022. Retrieved 2 March 2022
  9. https://www.ema.europa.eu/en/documents/assessment-report/okedi-epar-public-assessment-report_en.pdf