Investigation of New Analytical Methods for the Estimation of Darifenacin in Bulk And

“INVESTIGATION OF NEW ANALYTICAL METHODS FOR THE ESTIMATION OF DARIFENACIN IN BULK AND DOSAGE FORMS”.

PROTOCOL

FOR M-PHARM. DISSERTATION

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

PRADEEP V.KHANDELWAL, B. Pharm.,

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

2008 - 2009.

UNDER THE GUIDANCE OF

N.K.SATHISH, M. Pharm.,

ASSISTANT PROFESSOR,

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

BHARATHI COLLEGE OF PHARMACY

BHARATHI NAGARA

MADDUR TQ. , MANDYA-DIST.

KARNATAKA-571422

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

Annexure-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE
AND ADDRESS (IN BLOCK LETTERS) / PRADEEP V.KHANDELWAL
M. PHARM., PART-I
DEPARTMENT OF PHARMACEUTICAL
CHEMISTRY, C/O BHARATHI COLLEGE OF PHARMACY, BHARATHI NAGARA, MANDYA (DIST), KARNATAKA-571422.
2. / NAME OF THE INSTITUTION / BHARATHI COLLEGE OF PHARMACY
BHARATHI NAGARA, KARANATAKA -571422
3. / COURSE OF STUDY AND SUBJECT / MASTER OF PHARMACY IN PHARMACEUTICAL CHEMISTRY.
4. / DATE OF ADMISSION OF COURSE / 30/06/2008
5. / TITLE OF TOPIC / “INVESTIGATION OF NEW ANALYTICAL METHODS FOR THE ESTIMATION OF DARIFENACIN IN BULK & DOSAGE FORMS”.
6. / BRIEF RESUME OF THE
INTENDED WORK
6.1 Need for the study
6.2 Review of the literature
6.3 Objectives of the study /
ENCLOSURE-I
ENCLOSURE-I
ENCLOSURE-I
7 /

MATERIALS AND METHODS

7.1 Source of data

7.2 Method of collection of data

7.3 Does study require any investigations or interventions to conducted on patients or other human or animal? If so, please describe briefly .

7.4 Has ethical clearance been obtained from your institution in case of 7.3

/ ENCLOSURE-II
ENCLOSURE-II
ENCLOSURE-II
ENCLOSURE-II
8 / LIST OF REFERENCES / ENCLOSURE-III
9 / SIGNATURE OF CANDIDATE / (PRADEEP V.KHANDELWAL)
10 / REMARKS OF GUIDE / This Work can be carried out in our College Laboratory
11 / NAME AND DESIGNATION OF
11.1 GUIDE
11.2 SIGNATURE / N.K.SATHISH, M. Pharm.,
Assistant Professor
Department of Pharmaceutical Chemistry,
Bharathi College of Pharmacy,
Bharathi Nagara.
Karnataka-571422
11.3 CO GUIDE (IF ANY)
11.4 SIGNATURE / ------
11.5 HEAD OF DEPARTMENT
11.6 SIGNATURE / Dr. SENTHIL KUMAR G.P., M.Pharm, Ph.D.,
Professor and Head,
Department of Pharmaceutical Chemistry,
Bharathi College of Pharmacy,
Bharathi Nagara.
Karnataka-571422.
12 / 12.1 REMARKS OF THE CHAIRMAN AND PRINCIPAL
FORWARDED FOR APPROVAL
12.2 SIGNATURE / DR. T. TAMIZH MANI Principal, Bharathi College of Pharmacy, Bharathi Nagara. Karnataka -571422

ENCLOSURE – I

6.0. BRIEF RESUME OF THE INTENDED WORK 6.1) General Discussion:-

Darifenacin Hydrobromide is an Antimuscarinic Agent. It is used in the treatment of an over-active bladder. It relaxes the muscle in the wall of the bladder called as destruster muscle by preventing acetylcholine acting on the muscaranic receptors. The molecule has a chiral centre and the S-enantiomer is selected for the analytical method development. The decision is to select the S-enantiomer of the active substance is based on its potency and selectivity. Subsequently, this isomer is to be used for the development of new analytical methods.

Structure-

. HBr

Molecular Formula : - C28H30N2O2.HBr

Nomenclature : - (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl) ethyl]-
3-pyrrolidinyl}-2,2-diphenylacetamide.Hydrobromide.

Molecular Weight : - 507.47g/mol.

Solubility : - Slightly soluble in water (6.03 mg/ml). Its aqueous solubility

has been found to be pH dependent, with a maximum solubility

(8.75 mg/ml) at a pH of 5.0.

Nature : Pale yellow to white powder.

Analytical Functional Group Present:-Amide.

6.2) NEED FOR THE STUDY:

The aim of the present study is to develop simple, easy, economical and the reproducible analytical method for the determination of Darifenacin. Darifenacin is not official in Indian Pharmacopoeia. Several methods have been reported for determination of Darifenacin in biological or pharmaceutical samples. But these are time consuming and expensive.

In the view of the need in the industry for routine analysis of Darifenacin, attempts are being made to develop simple and accurate instrumental methods for quantitative estimation of Darifenacin and extend it for their determination in formulations. Analytical monitoring of a pharmaceutical product or specific ingredients within the product is necessary to ensure its safety, efficacy throughout all phases of its shelf life. Thus there is a need for the development of simple, sensitive, accurate and economical analytical method for effective quantitative estimation of Darifenacin.

Darifenacin is marketed in formulations. So the main aim of the study is to develop the simple and accurate method for the routine analysis of the Darifenacin.

6.3. REVIEW OF THE LITERATURE:-

Kerbusch et al9., developed the pharmacokinetic modeling of Darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism.

Peter.M. et al10., reported the pharmacokinetics –pharmacidynamics relationship between Darifenacin and its hydroxylated metabolites by in- vivo study.

Masuda.Y. et al11., developed and validated the bioanalytical methods for Darifenacin and its metabolites in human plasma by liquid chromatography–tandem mass spectrometry.

K. C. Beaumont et al12., reported the three metabolism routes of Darifenacin by in-vivo study.

Maruyama et al13.,evaluated and reported the effects of Darifenacin for overactive bladder (OAB) treatment on in- vivo muscuranic receptor binding in rat brain by quantitative autoradiography.

Chancellor et al14., reported the behavioral to Darifenacin for overactive bladder treatment by in-vivo study. They also evaluated the health related quality of life.

Augusto Canavesi et al15., reported that pure Darifenacin hydrobromide substantially free of oxidized Darifenacin and salts thereof and processes for the preparation by HPLC method.

6.4. OBJECTIVES OF THE STUDY:-

The present work is aimed to,

1) Develop spectrophotometric method for the estimation of Darifenacin in bulk and dosage forms.

2) Standardize the developed methods.

3) Analyses the marketed formulation for their reliability and accuracy.

Some few analytical methods have been reported for the quantitative estimation of Darifenacin. There is necessity for investigation of new analytical methods for quantitative estimation of Darifenacin in bulk drug and pharmaceutical dosage forms. .In the view of the above fact, planned to develop an accurate, selective, low cost, less time consuming and specific method for the estimation of Darifenacin in bulk and dosage forms.

ENCLOSURE – II

7.0. MATERIALS AND METHODS:-

In the present investigation of newer analytical method development of Darifenacin and bulkdrug formulation. Chemicals and other reagents are analytical grade and purchased from standard companies. The methods will be standadized onUV- Visible spectrophotometer and chromatographic instruments, using calibrated volumetric glass apparatus.

The pure sample of Darifenacin for the research work will be procured from Ranbexy Ltd. Baddi (H.P.).

New method will be planed depending upon the chemical nature (functional group, chromophore, polarity etc.) of Darifenacin.

7.1) SOURCE OF DATA:

The preliminary data required for the experimental study is obtained from

CD-Rom search available at national center for scientific information (NCSI), Indian institute of Sciences, Bangalore.
Scientific Journals.
Analytical chemistry Books.
Bharathi College of Pharmacy Library.
Internet Sources.
Scientific abstracts.
RGHUS Library, Bangalore.

8. E-Library in Bharathi College of Pharmacy.

7.2) METHODS OF COLLECTION OF DATA:

The preliminary data required for the experimental study is obtained from,

1. CD-Rom search available at National Center of Scientific Information (NCSI), Indian institute of Sciences, Bangalore, Bharathi College of Pharmacy Library, Scientific abstracts, Journals, Internet sources and Relevant Books.

2. The data will be collected by Laboratory investigation and Recording the data.

7.3 Does the study require any investigation or interventions to be conductedon

patients or other humans or animals?

-NO-

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

- NOT APPLICABLE -

ENCLOSURE - III

8.0. REFERENCES:-

Block J.H., Beale J.M., Jr. Wilson And Grisvold’s Text Book Of Organic Medicinal And Pharmaceutical Chemistry, 11th edition, 315-316, 330-331.
Williams D.A. Lemke T.L., Foye’s Principles of Medicinal Chemistry, 5th.
Windholz M. The Merk Index,Tenth Edition,Merk,USA,753.
Beckett, A.H.and Stenlake J.B., Practical Pharmaceutical Chemistry, Fourth Edition, Part Two, CBS, New Delhi,302-303

5. Christen G.D. Analytical Chemistry. 6th Edition, John Wiley and Sons, 2003 p. 1.

Skoog D.A.,Holler F.J.,Nieman T.A.. Principles of Instrumental Analysis.5th Edition, Eastern Press, Bangalore, 2004, p. 1, 674,695.
Ashutosh Kar, Pharmaceutical Drug analysis, New Age International, New Delhi, 293-313.

8. Gurudeep R Chatwal,Anand S.K.,Instrumental Methods Of Chemical

Analysis, Himalaya Publishing House 2.149-2.177.

9. Kerbusch T., et al., “Assessment of the in-vivo relative potency of the hdroxylated

matabolide of Darifenacin for the reduction of salivary flow using a population

pharmacokinetics – pharmacodynamic meta analysis”. Annual meeting of the

opulation approach group in Europe. 2003,12,437.

10. Milligan T., Karlsson P.A., Kerbusch M. O., “Pharmacokinetic-pharmacodynamic

Relationship to Darifenacin”, British Journal of clinical Pharmacology, 2004, 57,

2, 170-180.

11. Masuda Y. ,Kanayama N.,Manita S.,Ohmori S. and Tsuyoshi, “Bioanalytical

methods for Darifenacin”, Journal of Chromatography B, 2007, 853 (1-2), 70-

79.

12. Beaumont K.C;Cussans N.J; Nichols D.J; Smith D.A. “Metabolism routes of

Darifenacin.” Pharmacology Toxicology, Xenobiotica, 1998, 28(1), 63-75 .

13. Maruyama S, Tsukada H, Nishiyama S, Kakiuchi T, Fukumoto D, Oku N,

Yamada “Effects of Darifenacin for overactive bladder”.Life

Sciences.2006,80(2),127-132.

14. Chancellor M B, Kianifard F, Beamer E, Mongay L, Ebinger U, Hicks G,

Delconte. “A Behavioural to Derifenacin for OAB”. Int Journal, Clin Pract.

2008,62(4), 606– 613.

15. Canavesi A., Merli V., Daverio P. , Vailati A.“Pure darifenacin hydrobromide

substantially free of oxidizeddarifenacin and salts thereof and processes for the

preparation of Darifenacin”. Kenyon & Kenyon Llp.2008,646, 915.