A concise review on analytical profile of risperidone
Introduction
Risperidone is a second-generation antipsychotic (SGA) medicine that is used to treat a variety of mood and mental health disorders, such as schizophrenia and bipolar disorder. It's one of the most popular SGAs.1 An excess of dopaminergic D2 and serotonergic 5-HT2A activity is hypothesised to induce schizophrenia and different mood disorders, resulting in over activity of central mesolimbic and mesocortical pathways, respectively. Risperidone inhibits dopaminergic D2 receptors and serotonergic 5-HT2A receptors in the brain, which is considered to lessen over activity.1
Risperidone is a benzisoxazole derivative with antipsychotic property. Risperidone (RIS) chemically known as 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one.2, 3 Figure 1 depicts the chemical structure of RIS.
Figure 1
Chemical structure of RIS
Mechanism of action
Risperidone binds to a variety of receptors, including 5-HT2A/2C serotonin receptors, D2 dopamine receptors, and alpha 1 and H1 receptors. It has no discernible effect on M1 receptors. At D2 and 5-HT2A receptors, its major metabolite (9-hydroxyrisperidone) is almost equal to the parent molecule.2
Pharmacokinetics
Absorption
Well taken in. Risperidone has a 70% absolute oral bioavailability (CV=25%). When compared to a solution, the relative oral bioavailability of risperidone from a tablet is 94% (CV=10%).1
Distribution
The volume of distribution of risperidone is approximately 1 to 2 L/kg.1
Metabolism
Hepatic cytochrome P450 2D6 isozyme metabolises it to 9-hydroxyrisperidone, which has a similar receptor binding affinity as risperidone. N-dealkylation occurs to a lower amount in risperidone.2
Elimination
Risperidone is processed extensively in the liver. Renal clearance of both risperidone and 9-hydroxyrisperidone was reduced in healthy senior adults, and elimination half-lives were longer than in young healthy subjects.2
Pharmacodynamics
Risperidone's main effect is to reduce dopaminergic and serotonergic pathway activity in the brain, which helps to alleviate symptoms of schizophrenia and mood disorders.1
Analytical Account of RIS
For the determination of RIS in bulk and pharmaceutical formulations, an exhaustive literature search found numerous analytical techniques such as UV/Visible Spectrophotometry, HPLC, HPTLC, LC-MS/MS, and bioanalytical approaches. RIS is measured as a single constituent and in combination with Fluoxetine, Olanzapine, Clozapine, Ziprasidone, Haloperidol in various dosage forms and 9-hydroxyrisperidone its active metabolites forms. Figure 2 shows different analytical methods implemented for the estimation of RIS.
Figure 2
Analytical methods of RIS
Bio-analytical method for RIS
Bio-analysis is a sub-discipline of analytical chemistry covering the quantitative measurement of xenobiotics (drugs and their metabolites, and biological molecules in unnatural locations or concentrations) and biotics (macromolecules, proteins, DNA, large molecule drugs, metabolites) in biological systems.4 The summary of the reported bioanalytical methods is shown in Table 1.
Table 1
Bio analytical determination of RIS
|
Sr. No.
|
Drug
|
Sample Matrix
|
Method
|
Column
|
Detection
|
Internal Standard
|
Ref.
|
|
1
|
RIS
|
Human plasma
|
HPLC
|
Nucleosil C8 column
|
280 nm
|
Diltiazem
|
5
|
|
2
|
RIS
|
Plasma
|
HPLC
|
Cyano column
|
***
|
Remoxipride
|
6
|
|
3
|
RIS
|
Human plasma
|
HPLC-DAD
|
C8 column
|
240 nm
|
Clozapine and Loxapine
|
7
|
|
4
|
RIS
|
Human plasma
|
HPLC-MS/MS
|
Alltima-C18 Column
|
***
|
Paroxetine
|
8
|
|
5
|
RIS
|
Human plasma
|
HPLC
|
Waters XTerra RP-18 column
|
278 nm
|
Clozapine
|
9
|
|
6
|
RIS
|
Human plasma & saliva
|
LC
|
Reversed phase C18 column
|
***
|
Pipamperone
|
10
|
|
7
|
RIS
|
Human plasma
|
LC/MS/MS
|
Betasil C18 column
|
***
|
Methyl risperidone
|
11
|
|
8
|
RIS
|
Human plasma
|
LC–MS/MS
|
Analytical column
|
***
|
Acetonitrile
|
12
|
|
9
|
RIS
|
Rat plasma
|
UPLC-MS/MS
|
BEH C18
|
***
|
Propranolol
|
13
|
|
10
|
RIS & 9-HRIS
|
Human Serum
|
HPLC
|
ODS Hypersil C18
|
285 nm
|
Clozapine
|
14
|
|
11
|
RIS & 9-HRIS
|
Human plasma
|
LC–MS-MS
|
Atlantis HILIC Silica C18 column
|
***
|
Clozapine
|
15
|
|
12
|
RIS & 9-HRIS
|
Human plasma & urine
|
LC–MS/MS
|
Chiralcel OJ column
|
***
|
Methanol
|
16
|
|
13
|
RIS & 9-HRIS
|
Human plasma, urine & saliva
|
MEPS-LC-UV
|
C8 reversed-phase column
|
238 nm
|
Diphenhydramine
|
17
|
|
14
|
RIS & 9-HRIS
|
Human plasma
|
DLLME-LC-MS/MS
|
Ascentis® Express C18 chromatographic column
|
***
|
Clozapine
|
18
|
|
15
|
RIS & 9-HRIS
|
Plasma
|
LC-MS/MS
|
C18 column
|
***
|
Clozapine
|
19
|
|
16
|
RIS, FLX & 9-HRIS
|
Rat plasma
|
UPLC-MS/MS
|
ACQUITY UPLC BEH C18 column
|
***
|
Olanzapine
|
20
|
|
17
|
OLZ, RIS, 9-HRIS, CLZ, HAL & ZIP
|
Rat plasma
|
LC/ESI-MS/MS
|
Waters AtlantisTM dC-18
|
***
|
Midazolam
|
21
|
UV-Visible spectroscopy method for RIS
To date, lots of spectrophotometric methods have been accounted for the determination of RIS alone. This review compiles three papers describing spectrophotometric methods for determination of alone RIS. The details of Spectrophotometry determination of basic principle, sample matrix, lambda max, solvent linearity range and the correlation coefficient are summarized in Table 2.
Table 2
Spectrophotometric methods used for determination of RIS
|
Sr. No.
|
Drug
|
Matrix
|
Solvent
|
Lambda Max (nm)
|
Linearity (μg/mL)
|
Correlation coefficient (R2)
|
Ref.
|
|
1.
|
RIS
|
Pure form & pharmaceutical dosage forms
|
Methanol
|
240 and 280 nm
|
20 to 60 μg/ml
|
0.99
|
22
|
|
2.
|
RIS
|
Bulk &Tablets Formulation
|
0.1N HCl
|
238 nm
|
2-12 μg/ml
|
0.999
|
23
|
|
3.
|
RIS
|
Bulk drug & Pharmaceutical formulation
|
0.1N HCL
|
280 nm
|
2 to 6 μg/ml
|
0.99
|
24
|
HPLC method for RIS
The specificity of the HPLC method is excellent and simultaneously sufficient precision is also attainable. However, it has to be stated that the astonishing specificity, precision, and accuracy are attainable only if wide-ranging system suitability tests are carried before the HPLC analysis. For this reason, the expense to be paid for the high specificity, precision, and accuracy is also high.25 The summary of the reported HPLC methods is shown in Table 3.
Table 3
Summary of HPLC methods for the determination of RIS in a single and combined dosage form
|
Sr. No.
|
Drug name
|
Column
|
Mobile phase
|
Lambda max (nm)
|
Linearity (μg/mL)
|
Retention time (min)
|
Flow rate (mL/min)
|
Detector
|
Ref.
|
|
1.
|
RIS
|
C18 column
|
Acetonitrile-potassium dihydrogen phosphate (45:55, v/v, pH 6.5; 0.05 M)
|
237 nm
|
1–100 μg/mL
|
6 min
|
1.0 mL/min
|
PDA
|
26
|
|
2.
|
RIS
|
C18 column
|
Methanol: acetonitrile (80 : 20, v/v)
|
280 nm
|
10–60 μg/mL
|
3.35 ± 0.01
|
1 mL/min
|
PDA
|
27
|
|
3.
|
RIS
|
Hypersil ODS C-18 column
|
Methanol-acetonitrile-phosphate buffer (0.02 M) (65 : 20 : 15, v/v/v)
|
238 nm
|
1.0–10 mg/ml-1
|
6.16 min
|
1.0 ml/min-1
|
***
|
28
|
|
4.
|
RIS
|
Waters Xterra RP8 column
|
(10 mM potassium dihydrogen phosphate, pH 3.5± 0.05): acetonitrile: methanol (65:20:15)
|
276 nm
|
5-45 μg/mL
|
12 min
|
1.0 mL/min
|
UV
|
29
|
|
5.
|
RIS
|
Gemini C-18
|
Methanol: acetonitrile: 50 mM potassium dihydrogen orthophosphate (80:10:10 v/v)
|
234 nm
|
1-11 μg/ml
|
2.5 min
|
1.3 ml/min
|
UV/VIS
|
30
|
|
6.
|
RIS
|
Lichrosorb RP C 18 column
|
Methanol:0.05M potassium dihydrogen phosphate pH 7 (65:35 (v/v))
|
280 nm
|
25–500 μg/ml−1
|
***
|
1 ml/min−1
|
DAD
|
31
|
|
7.
|
RIS
|
Purosphere STAR RP-18e
|
Water: glacial acetic acid 0.50 %: triethylamine 0.80 %: acetonitrile (65.00: 0.32: 0.52: 34.16, v/v)
|
294 nm
|
25.00 μg/mL to 250.00 μg/mL
|
***
|
1 mL/min
|
DAD
|
32
|
|
8.
|
RIS & HPD
|
XBridge C18
|
Methanol: triethyl amine Buffer (60::40) and the pH of triethylamine adjusted to pH2.5 using orthophosphoric acid
|
260 nm
|
2-10 μg/ml & 8-40 μg/ml
|
1.82 min & 4.42 min
|
1.0 ml/min
|
PDA
|
33
|
HPTLC method for RIS
Thin-layer chromatography is a popular technique for the analysis of a wide variety of organic and inorganic materials, because of its distinctive advantages such as minimal sample clean-up, a wide choice of mobile phases, flexibility in sample distinction, high sample loading capacity and low cost. R. B. Patel et. al established HPTLC method development and validation for analysis of risperidone in formulation and in-vitro release study. TLC was carried out by stationary phase silica gel 60 F254 plates with methanol-ethyl acetate 8.0:2.0 (v/v) as mobile phase. The linearity range for risperidone was 100-600 ng per band. The developed method was successfully applied for determination of risperidone in formulation.34
Conclusion
The present review article provides comprehensive data of various analytical and bioanalytical methods developed for RIS alone and in combinations. For analysis purpose, different analytical methods have been reported that includes HPLC, HPTLC, UV spectroscopy, LC-MS/MS etc. The method along with their details concerning the mobile phase, stationary phase, retention time, etc., have been summarized in tabular form that will more helpful for the researchers for further analytical m3ethod development for estimation of RIS in dosage form and pure form. In the future, enlisted data can be used for the development of analytical methods bio-analysis of RIS in pharmaceutical and biological formulations. Finally, it presents an opportunity for greater information on what has already been done and what new methods and changes can be developed to get a better estimation of RIS.
Abbreviations
RIS - Risperidone
USA — United states of America
DA — Food and drug administration
UV/VIS - Ultra violet/visible spectroscopy
HPLC — High-performance liquid chromatography
HPTLC — High-performance thin layer chromatography
LC-MS/MS — Liquid chromatography-mass spectroscopy-mass spectroscopy
SGA — Second-generation antipsychotic
DNA — Deoxyribonucleic acid
RP — Reverse phase
nm — Nanometer
µg/mL — Micro gram per Milliliter
PDA - Photo diode array
TLC — Thin layer chromatography
Conflict of Interest
None.
Acknowledgments
Authors are thankful to TSPM’s, Trimurti Institute of Pharmacy, Paldhi (Bk) — 425 103, Jalgaon, Maharashtra, India for providing necessary library facilities.
References
Risperidone is a second-generation antipsychotic medication used to treat a number of mental health disorders including schizophrenia, bipolar mania, psychosis, or as an adjunct in severe depressionhttp://go.drugbank.com/drugs/DB00734
N Spooner
Dried blood spot sampling for quantitative bioanalysis, time for a revolutionBioanalysis2010211178110.4155/bio.10.153
S M Foroutan
A Zarghi
A Shafaati
Rapid high performance liquid chromatographic determination of risperidone in human plasmaIran J Pharm Res201051377010.22037/IJPR.2010.650
X Zhang
X Zhao
C Zhang
L Yang
X Xiong
Y Zhou
.
Validation of an LC-MS-MS method for the determination of risperidone and 9-hydroxyrisperidone in human plasmaChromatographia2010711110152310.1016/j.jchromb.2008.04.041
M De Meulder
B M Remmerie
R De Vries
L L Sips
S Boom
E W Hooijschuur
.
& Timmerman PM. Validated LC-MS/MS methods for the determination of risperidone and the enantiomers of 9-hydroxyrisperidone in human plasma and urineJ Chromatography B2008870181610.1016/j.jchromb.2008.04.041
R Mandrioli
L Mercolini
D Lateana
G Boncompagni
M A Raggi
Analysis of risperidone and 9-hydroxyrisperidone in human plasma, urine and saliva by MEPS-LC-UVJ Chromatography B201187921677310.1016/j.jchromb.2010.11.033
Gks Alcantara
L A Calixto
B A Rocha
F B Júnior
A De Oliveira
C M De Gaitani
A fast DLLME-LC-MS/MS method for risperidone and its metabolite 9-hydroxyrisperidone determination in plasma samples for therapeutic drug monitoring of patientsMicrochem J20201561104894
N Vanwong
S Prommas
A Puangpetch
Y Hongkaew
N Nuntamool
C N Nakorn
.
Development and validation of liquid chromatography/tandem mass spectrometry analysis for therapeutic drug monitoring of risperidone and 9-hydroxyrisperidone in pediatric patients with autism spectrum disordersJ Clin Lab Anal201630612364610.1002/jcla.22009
E Ezzeldin
N F Abo-Talib
M H Tammam
UPLC-Tandem Mass Spectrometry Method for Simultaneous Determination of Fluoxetine, Risperidone, and Its Active Metabolite 9-Hydroxyrisperidone in Plasma: Application to Pharmacokinetics Study in RatsJ Anal Methods Chem20172017518708410.1155/2017/5187084
G Zhang
A V Terry Jr
M G Bartlett
Liquid chromatography/tandem mass spectrometry method for the simultaneous determination of olanzapine, risperidone, 9-hydroxyrisperidone, clozapine, haloperidol and ziprasidone in rat plasmaRapid Commun Mass Spect20072169208
M A Raggi
F Bugamelli
C Sabbioni
M A Saracino
C Petio
HPLC-DAD determination of plasma levels of the antipsychotic risperidone and its main metabolite for toxicological purposesJ Separation Sci20052832455010.1002/jssc.200401939
M Z Huang
J Z Shentu
J C Chen
J Liu
H L Zhou
Determination of risperidone in human plasma by HPLC-MS/MS and its application to a pharmacokinetic study in Chinese volunteersJ Zhejiang Univ Sci B2008921142010.1631/jzus.B0710439
P T Vergara
J Sepulveda
C V Plessing
Pharmacokinetic study of risperidone: application of a hplc method with solid phase extractionJ Chilean Chem Soc2011561606910.4067/S0717-97072011000100019
M Aravagiri
S R Marder
T V Putten
K K Midha
Determination of risperidone in plasma by high-performance liquid chromatography with electrochemical detection: application to therapeutic drug monitoring in schizophrenic patientsJ Pharm Sci1993825447910.1002/jps.2600820503
M A Saracino
A De Palma
G Boncompagni
M A Raggi
Analysis of risperidone and its metabolite in plasma and saliva by LC with coulometric detection and a novel MEPS procedureTalanta2010814-515475310.1016/j.talanta.2010.02.067
J Bhatt
G Subbaiah
S Singh
Liquid chromatography/tandem mass spectrometry method for the simultaneous determination of olanzapine, risperidone, 9-hydroxyrisperidone, clozapine, haloperidol and ziprasidone in rat plasmaRapid Commun Mass Spectrom200620621091410.1002/rcm.2914https://doi.org/10.1002/rcm.2537
C Kousoulos
Y Dotsikas
Y L Loukas
Turbulent flow and ternary column-switching on-line clean-up system for high-throughput quantification of risperidone and its main metabolite in plasma by LC-MS/MS: application to a bioequivalence studyTalanta2007722360710.1016/j.talanta.2006.10.049
R A Rub
S Beg
I Kazmi
O Afzal
W H Almalki
S Alghamdi
.
& Ahmed FJ. Systematic development of a bioanalytical UPLC-MS/MS method for estimation of risperidone and its active metabolite in long-acting microsphere formulation in rat plasmaJ Chromatography B2020116012243310.1016/j.jchromb.2020.122433
K M Kirschbaum
S Finger
F Vogel
R Burger
M Gerlach
P Riederer
LC with column-switching and spectrophotometric detection for determination of risperidone and 9-hydroxyrisperidone in human serumChromatographia2008673321410.1365/s10337-007-0506-1
G A Vasagam
A A Smith
C H Nawas
M S Kumar
A K Muthu
R Manavalan
Development of analytical method for Risperidone by UV Spectrophotometry using methanol as a solvent. Scolars Research Library “Der pharma chemica20102309315
M S Kumar
A A Smith
G A Vasagam
A K Muthu
R Manavalan
Development of analytical method for risperidone by UV spectrophotometryInt J Pharm Sci Res2010121226
S Kulkarni
G Chhabra
M Shivani
Development and validation of UV spectrophotometric method for the determination of risperidone in bulk and tablets formulationInt J Pharm Chem Res20121215
M R Siddiqui
Z A Alothman
N Rahman
Analytical techniques in pharmaceutical analysis: A reviewArabian J Chem201710114092110.1016/j.arabjc.2013.04.016
G K Anthony
Development and Validation of RP-HPLC method for simultaneous estimation of Risperidone and Haloperidol in tablet dosage formsInt J Pharm Drug Anal20146665961
S Mennickent
M D Diego
B Liser
L Trujillo
Stability indicating HPLC method for quantification of risperidone in tabletsJ Chilean Chem Soc20186334150410.4067/s0717-97072018000304150
S L Baldania
K K Bhatt
R S Mehta
D A Shah
RP-HPLC Estimation of Risperidone in Tablet Dosage FormsIndian J Pharma Sci2008704494710.4103/0250-474X.44601
Z R Dedania
R R Dedania
N R Sheth
J B Patel
B Patel
Stability indicating HPLC determination of risperidone in bulk drug and pharmaceutical formulationsInt J Anal Chem2011201112491710.1155/2011/124917
D Svirskis
J T Sejdic
S Garg
A stability indicating HPLC method for the determination of electrochemically controlled release of risperidoneJ Chromatogr Sci20114910780510.1093/chrsci/49.10.780
A P Suthar
S A Dubey
S R Patel
A M Shah
Determination of Risperidone and forced degradation behavior by HPLC in tablet dosage formInt J Pharm Tech Res20091356874
Z A El-Sherif
B El-Zeany
O M El-Houssini
High performance liquid chromatographic and thin layer densitometric methods for the determination of risperidone in the presence of its degradation products in bulk powder and in tabletsJ Pharm Biomed Anal20053659758110.1016/j.jpba.2004.07.014
S S Imam
M Aqil
M Akhtar
Y Sultana
A Ali
Optimization of mobile phase by 3 2-mixture design for the validation and quantification of risperidone in bulk and pharmaceutical formulations using RP-HPLCAnal Methods201461282810.1039/C3AY41562G
R B Patel
B G Patel
M R Patel
K K Bhatt
HPTLC method development and validation for analysis of risperidone in formulations, and in-vitro release study.Acta Chromatographica20102245496710.1556/AChrom.22.2010.4.5
