NEW ANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR THE ESTIMATION OF QUETIAPINE FUMARATE IN MARKETED FORMULATIONS AND DOSAGE FORMS

MASTER OF PHARMACY DISSERTATION PROTOCOL,

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.

BY

MAKADIA AKASH RAMESHBHAI

M.PHARM - I

Under The Guidance Of

MRS. PADMAVATHI P. PRABHU

DEPARTMENT OF QUALITY ASSURANCE.

SRINIVAS COLLEGE OF PHARMACY, MANGALORE – 574143.

2010 – 2012

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME AND ADDRESS OF THE CANDIDATE / MAKADIA AKASH RAMESHBHAI
186-CHITRAKUT DHAM,
B/H I.O.C. QUARTER,
KALAWAD ROAD ,
RAJKOT 360 005.
2. /

NAME OF THE INSTITUTION

/ SRINIVAS COLLEGE OF PHARMACY.
VALACHIL,
FARENGIPETE
MANGALORE-574143,
KARNATAKA.
3. /

COURSE OF STUDY AND SUBJECT

/ MASTER OF PHARMACY IN
QUALITY ASSURANCE
4. / DATE OF ADMISSION OF COURSE / 31/05/2010
5. /

TITLE OF TOPIC

/ NEW ANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR THE ESTIMATION OF QUETIAPINE FUMARATE IN MARKETED FORMULATIONS AND DOSAGE FORMS
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6.0 / BRIEF RESUME OF THE INTENDED WORK:
6.1 NEED FOR THE STUDY:
The modern methods of assessing the purity of the compound are HPLC, GLC ,GC, NMR-MS and GC-MS but they involve high cost. On the other hand, the colorimetric and spectrophotometer methods are easy to operate. Instrumental methods like colorimetric spectrophotometry and fluorimetry are precise but may not give a true assessment of potency or purity of the drug. The limitation in colorimetric methods are the chemical reaction upon which these procedures are based on, that these are instances where compounds do not possess suitable chromogenic properties which can be overcome by modifications such as converting to an absorbing species or is made to react with absorbing reagent, introducing of masking agent, control of pH or use of solvent extraction techniques. Since HPLC being one of the most advanced techniques, estimation was carried out by HPLC.
So the need for the study is to develop, sensitive and accurate spectrophotometric and/or HPLC methods to estimate various pharmaceutical formulations and pharmacologically active compounds.
6.2 REVIEW OF LITERATURE:
Name / Quetiapine fumarate
Ch Chemical Name / 2-[2-(4-dibenzo[b,f][1,4]thiazepine-11-yl- 1-piperazinyl)ethoxy]ethanol hemifumarate

Molecular Structure /
Molecular Formula / 2(C21H25N3O2S) C4 H4O4
Molecular Weight / 883.09
Melting Point / 174-176°C
Category Antipsychotic drug.
Pharmacological action [1]
Quetiapine Fumarate has the following pharmacological actions
·  D1, D2, D3, and D4 receptor antagonist
·  5-HT1A, 5-HT2A, 5HT2C, and 5HT7 receptor antagonist
·  α1- adrenergic and α2-adrenergic receptor antagonist
·  H1 receptor antagonist
·  mACH receptor antagonist
Adverse effect
Patients may experience tachycardia. Less common side effects include abnormal liver tests, dizziness, upset stomach, substantial weight gain, a stuffy nose, akathisia, increased paranoia and diabetes.
6.3 REVIEW OF LITERATURE RELATED TO QUETIAPINE FUMARATE
·  Barrett, Holcapek M, Huclova J, Borek VD, Fejt P, Nemec B and Jelínek I.[2] developed a validated, highly sensitive and selective high-pressure liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for the quantitative determination of quetiapine (QUE) in human Na2EDTA plasma with mass spectrometry (MS) detection. Clozapine was employed as an internal standard. Samples were extracted using solid phase extraction. Oasis HLB cartridges and the concentration of quetiapine was determined by isocratic HPLC–MS/MS.
·  Belal F, Elbrashy A, Eid M, Nasr JJ [3] developed a stability indicating reversed phase high performance liquid chromatographic method for analysis of antipsychotic drug quetiapine. Quetiapine was determined in presence of two of its degradation products quetiapine N-oxide and quetiapine lactam. The analysis was carried out using a 250 mm×4.6 mm i.d., 5 µm particle size zorbax SB-phenyl columns. Mobile phase containing a mixture of acetonitrile and 0.02 M phosphate buffer (50:50) at pH 5.5 was pumped at a flow rate of 1 ml/min with UV detection at 254 nm.
·  Bagade SB, Narkhede SP, Nikam DS,Sachde Ck [4] have developed Simple fast and reliable derivative Spectrophotometric method for determination of quetiapine fumarate in pharmaceutical formulation. Second order derivative UV spectroscophotometric methods were developed. Spectrophotometrically, Quetiapine fumarate was determined by measuring the 2D-values at 254.76 nm with 0.1 N HCL as background solvent. Analytical calibration curves were linear within a concentration range from 10 to 30 µg/ml. The developed method was applied to directly and easily to the analysis of the pharmaceutical tablet preparations.
·  Dhaneshwa SR, Patre NG, Mahadik MV [5] , have developed a sensitive, selective, precise, and stability-indicating HPTLC method for quantitative analysis of quetiapine fumarate, both as the bulk drug and in formulations has been established and validated. The stationary phase was silica gel and the mobile phase toluene-methanol 8:2 (v/v).
·  Saracino, Mercolini, Flotta [6] have developed an original HPLC-UV method for the simultaneous determination of the atypical antipsychotic quetiapine and the geometric isomers of the second-generation anti-depressant fluvoxamine. The analytes were seperated on a reversed-phase C8 column (150 mm X 4.6 mm i.d., 5 µm) using a mobile phase composed of acetonitrile (30%) and a 10.5 mM, pH 3.5 phosphate buffer containing 0.12% triethylamine (70%). The flow rate was 1.2 mL min-1 and the detection wavelength was 245 nm.
6.4 OBJECTIVES OF THE STUDY:
Estimation of Quetiapine fumarate is based on the reaction of functional group present in them with a suitable chromogenic agent to form a coloured product which is determined by spectroscopical method. Since Quetiapine fumarate is a one of the newer drug in the market. There are not much methods available for its estimation. It is not official in any Pharmacopoeias.
1.  To determine λmax in different solvent and pH condition for quetiapine fumarate.
2.  To develop simple, selective, rapid, precise and economical analytical method for the estimation of quetiapine fumarate
3.  To validate method in terms of accuracy, precision, linearity, limit of detection, limit of quantitation etc
7.0
8.0 / MATERIALS AND METHODS
7.1 METHODS
The standard drug will be requested from the industries in India depending on the availability of facilities, one of the following method will be applied for the estimation of quetiapine fumarate.
1.  UV Method:
Standard stock solution can be prepared by dissolving 100mg quetiapine fumarate in 100 ml of water and then final volume of both solutions made up to 100 µg/ ml of quetiapine fumarate in volumetric flask. Solutions containing 20 µg/ml of quetiapine fumarate can be prepared and scanned in UV region separately form λmax.
For the compound quetiapine fumarate λmax can be obtained, By dilution of Standard drug in 5,10,15,20 ….50 µg/ml of drug can be prepared and scanned at 200-400 nm. The values of absorbances can be recorded. From this data absorptivity and molar absorbance can be determined for quetiapine fumarate.
2.  HPLC Method:
Mixed solutions consisting of 100 µg/ml of quetiapine fumarate can be prepared in different combinations of solvents using acetonitrile, water, acetone, and methanol. Then eluting the compound solution from column and recording the absorbance parameter by detector. By observing AUC, Peak area we can estimate the amount of drug present in sample.
All the validation parameters such as LOD, LOG, Linearity, Precision and Accuracy can be validated using ICH Q2b guidelines.
The above method likely to change depending on the observations recorded time to time
7.2 SOURCE OF DATA:
a)  Laboratory based studies.
b)  Journals and publications.
c)  From library based books.
d)  Websites www.pubmed.com www.google.com
7.3 METHOD OF COLLECTION OF DATA
1.  Procurement of the drug and marketed formulations.
2.  Solubility determination of Quetiapine fumarate in different solvents and buffers.
3.  Determination of wavelength of maximum absorbance and intensity of absorption in different solvents and buffers for various analytical studies.
4.  Developing and validating analytical method for by UV-Visible spectrophotometer using standard absorptivity value, standard calibration curve, single point and double point standardisation. Developing and validating HPLC method to estimate in bulk and pharmaceutical formulations.
7.4 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTION TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS? IF SO, PLEASE MENTION BRIEFLY.
NOT APPLICABLE
7.5 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION?
NOT APPLICABLE
LIST OF ReferenceS:
1.  http://en.wikipedia.org/wiki/Quetiapine date30/11/2010 time 12:30

2.  Barrett, Holcapek M, Huclova J, Borek VD, Fejt P, Nemec B, Jelinek. Validated HPLC-MS method for determination of quetiapine fumarate in human plasma.

Int J Pharma Biomed Anal 2007; 44(2):498-505.

3.  Belal F, Elbrashy A, Eid M, Nasr JJ. Stability- indicating HPLC method for the determination of quetiapine fumarate. J Liq Chromatogr Rel Techn 2008; 31(9):1283-98.
4.  Bagade SB, Narkhede SP, Nikam DS, Sachde CK.,Development and Validation of UV- spectrophotometric method for determination of quetiapine fumarate in two different dosage tablet. Int. J Chem Tech Res. 2009; 1(4): 898-904.
5.  Dhaneshwa SR, Patre NG, Mahadik MV. Stability-indicating HPTLC method for quantitation of quetiapine fumarate in pharmaceutical dosage form J Acta Chromatogr 2009; 21(1):83-93.
6.  Addolorata SM, Laura M, Giuseppina F, Lawrence AJ, Roberto M, Augusta RM.Simultaneous determination of fluvoxamine isomer and quetiapine fumarate in human plasma by means of high performance liquid chromatography J Chromatogr B 2006;843(2):227-233.
9. / Signature of the candidate / (AKASH MAKADIA)
10. / Remarks of the Guide / The candidate is working under my direct supervision in laboratories of Srinivas College of Pharmacy, Mangalore-574143.
11. / 11.1Name and Designation of Guide
11.2 Signature / MRS PADMAVATHI P PRABHU M.Pharma (Ph.D)
ASSISTANT PROFESSOR,
DEPARTMENT OF QUALITY ASSURANCE,
SRINIVAS COLLEGE OF PHARMACY.
(Mrs. PADMAVATHI P. PRABHU)
11.3 Head of the department
11.4 Signature / PROF. DR. E.V.S SUBRAMANYAM M.Pharma Ph.D
DEPARTMENT OF QUALITY ASSURANCE,
SRINIVAS COLLEGE OF PHARMACY.
(Dr. E.V.S. SUBRAHMANYAM)
12. / 12.1 Remarks of Principal
12.2 Signature / FORWARDED AND RECOMMENDED FOR FAVOURABLE CONSIDERATION.
(PROF. Dr. A.R. SHABARAYA)