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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCE, BANGALORE
KARNATAKA
REGISTRATION OF SUBJECT FOR DISSERTATION
ANNEXURE-II
A.PERMANENT ADDRESS:
1.
NAME OF THE CADIDATE AND
ADDRESS
DEBJIT MUKHERJEE
C/O, SRIKUMAR MUKHOPADHYAY
12, VERNER LANE
BELGHARIA
KOLKATA
WEST BENGAL
PIN-700 056.
B. POSTAL ADDRESS
KRUPANIDHI COLLEGE OF PHARMACY,
CHIKKA BELLANDUR,
CARMELLARAM POST,
VARTHUR HOBLI,
BANGALORE-35.
KARNATAKA.
2.
NAME OF THE INSTITUTE
KRUPANIDHI COLLEGE OF PHARMACY,
CHIKKA BELLANDUR,
CARMELLARAM POST,
VARTHUR HOBLI,
BANGALORE-35.
3.
COURSE OF STUDY AND PROJECT
KARNATAKA.
MASTER OF PHARMACY
(Pharmaceutical Chemistry)
4.
DATE OF ADMISSION TO THE COURSE
13th June 2009
5.
TITLE OF THE PROJECT:
“SYNTHESES, CHARACTERIZATION AND HPLC ANALYSIS OF STRUCTURALLY
RELATED COMPOUNDS OF DOCETAXEL TRIHYRATE”
6.0
BRIEF RESUME OF THE INTENDED WORK:
6.1 Need of study:
Cancer (medical term: malignant neoplasm) is a class of diseases in which a group of cells display
uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of
adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood).
These three malignant properties of cancers differentiate them from benign tumors, which are selflimited, and do not invade or metastasize. Most cancers form a tumor but some, like leukemia, do not.
The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is
oncology.
Anticancer drugs are a well-defined group of drugs, mostly used which are aimed to control the
metastasis.
Docetaxel trihydrate is an antineoplastic agent belonging to the taxoid family. It is prepared by
semi synthetic process beginning with a precursor extracted from the renewable needle biomass of yew
plants.
Docetaxel trihydrate is an anhydrous or trihydrate. The chemical name for docetaxel is (2R,3S)-Ncarboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5-20-epoxy-12,4,7,10,13hexahydroxytax- 11-en-9-one 4-acetate 2-benzoate.
There are two types of Docetaxel products on the market. It is also known as Taxotere. Docetaxel
Trihydrate is a white to almost-white crystalline powder with an empirical formula of C43H53NO14•
3H2O, and a molecular weight of 861.9. Melting point is 186ºC-192ºC.
Impurity is defined as any substance other than the substance of interest, coexisting such as
starting material/ intermediate or that is formed during the manufacture of drugs due to side reactions.
Identification of pharmaceutical impurities is a critical analytical activity in the drug development
process whose goal is to fully elucidate the chemical structures of unknown pharmaceutical impurities
present in either drug substances or drug products above a particular threshold. Knowledge of the
chemical structure of an impurity is essential to assess its toxicological implications and to gain an
understanding of its formation mechanism. Knowledge of the formation mechanism is critical for
improving the synthetic chemical processes and optimizing the drug formulation to reduce or eliminate
the impurity. The study may help to modify the existing manufacturing procedure, to produce a pure
drug with minimum impurities and lesser side effects.
Impurities may arise in the final product by following ways.
a) Impurities closely related to the product and coming from the chemical or biosynthetic route
(During formation of bulk drug)
b) Impurities formed due to spontaneous decomposition of the drugs during storage or on exposure to
extreme conditions.
c) The precursors may be present in the final product as impurities. Therefore, HPLC technique is used
in order to avoid these kinds Of impurities.
In case of unsuccessful identification with standard samples, the reasonable way to determine the
structure of the impurity starts with the investigation of UV spectra, easily obtainable with the aid of the
diode-array detector in case of HPLC and quantification with the help of densitometer.
Regulating authorities such as US FDA, CGMP, TGA, MCA insist on the impurity profiling of
drugs. Hence, studies are required to generate impurity profiles of the drugs. During preparation of
Docetaxel trihydrate, various structurally related compounds are produced as bye products.
The work involves the use of various separation techniques such as column chromatography,
preparative TLC, HPLC to isolate the impurities produced during the synthesis of Docetaxel trihydrate.
HPLC method will be developed to separate and identify the related impurities of bulk drug.
6. 2 Review of Literature
 Marij J.P. Weltersa C et al (1994) have reported as The growth inhibiting effect of docetaxel.1
 S.B. Kaye et al (1994) have reported as Activity of Docetaxel in Small Cell lung cancer2.
 M.C Bissery et al (1995) have reported as Preclinical Pharmacology of Docetaxel.3
 Dravecz f et al (1997) have reported the Drug impurity profiling stratergies.4
 Cesare Bumma et al (1999) have reported as Docetaxel in combination with epirubicin in
metastatic breast cancer: pharmacokinetic interactions.5
 Daniel Guénard et al (2000) have reported as Synthesis of 5(20)deoxydocetaxel, a new active
docetaxel analogue. 6
 Alfred Goodman Gilman et al (2001) have reported The Pharmacological Basis of
Therapeutics.7
 Xiao-Tian Liang et al (2001) have reported as Synthesis of the 2a-benzoylamido analogue of
docetaxel. 8
 Francoise Gue´ritte et al (2005) have reported the Synthesis and biological activities of
docetaxel analogue with a peptide side chain at C30.9
 Europian Pharmacopoeia (2005) have reported as Pharmacological activity of some Docetaxel
Trihydrate derivative and impurities.10
 R Vasu Dev et al (2006) have reported as Isolation and characterization of impurities in
docetaxel.11
 B. Mallikarjuna Raoa et al (2006) have reported as a stability-indicating HPLC assay method for
docetaxel.12
 Anand C, Burman et al (2007) have reported as Isolation and characterization of degradation
impurities in docetaxel drug substance and its formulation.13

Yongzhou Hua et al (2007) have reported as Synthesis and evaluation of water-soluble
docetaxel prodrugs-docetaxel esters of malic acid.14
 Armando Córdova et al (2008) have reported the Catalytic asymmetric synthesis of the
docetaxel side chain.15
 Yi Qub et al (2008) have reported as Synthesis and biological evaluation of novel 30-N-tertbutylsulfonyl analogues of docetaxel.16
 Guo-Qiang Lin et al (2009) have reported as Design, synthesis and biological evaluation of
novel fluorinated docetaxel analogues.17
6.3 Objective of study:
The present work is an attempt to:
1. To synthesize Docetaxel trihydrate and structurally related compounds.
2. To identify the impurities present in the desired compound.
3. To Characterize by IR, NMR Mass Spectroscopy.
4. To develop HPLC analysis method for the title compound.
7.0 MATERIALS AND METHOD
7.1 Source of Data
Data will be obtained from internet facilities, literature and related articles from libraries of
Krupanidhi College of Pharmacy and Indian Institute of Sciences, Bangalore.
Data from observations and inference will be collected on the basis of experiments to be carried
out during the course of research in laboratories of Krupanidhi College of Pharmacy and CIPLA
Pvt. Ltd, Bangalore.
7.2 Scheme of synthesis:
a) Synthesis of Docetaxel trihydrate :
b)
c) Catalyst screen for the enantioselective reactions between phenyl -N -Boc-imine and alpha
oxyaldehyde
d) Direct organocatalytic assymmatric Mannich reactions between N-Boc-protected imines and
alpha - oxyaldehydes
e) Scheme1. Reagents and conditions
Step 1
g) Step 2
Docetaxel
→Following structurally related compounds of Docetexal Trihydrate will be synthesised in similar
manner by manupulating reaction3
A.
C.
B.
D.
A. 1,7,10 trihydroxy-9-oxo-5,20- epoxytax-11-ene-2,4, 13-tril-4-acetate 13-[(2R,3S)-3-{(1,1dimethylethoxy)carbonyl}amino-2-hydroxy-3-Phenylpropanoate]-2-methyl but-2-enolate] (2-odesbenzoyl-2-o-tiglyldocetaxel).
B. 1,7 ,-dihydroxy-9,10-dioxo-5 , 20- epoxytax-11-ene 2 ,4,13–triyl-4-acetate 2 benzoate 13[{(2R,3S)-3-[{(1,1-dimethoxyethoxy)carbonyl}amino]-2-hydroxy-3-phenylpropanoate](10-dehydroxy10-oxodocetaxel).
C. 1,7,10-trihyroxy-9-oxo-5,20-epoxytax-11-ene-2,4,13-triyl-4-acetate 2benzoate13-[(2R,3S)3[{(1,1-dimethoxyethoxy)carbonyl}amino]-2-hydroxy-3-phenylpropanoate](7-epi-docetaxel).
D. 1,7-dihydroxy-9,10-dioxo-5,20-epoxytax-11-ene-2,4,13-triyl 4-acetate 2 benzoate 13[(2R,3S)-3-phenylpropanoate](10-dehydroxy-10-oxo-7-epi-docetaxel).
7.3 Method of characterization:
Characterization of the synthesized compounds will be performed by using modern analytical
Techniques like UV, IR, NMR, and Mass spectroscopy, TLC.
HPLC analytical method will be developed to analyze the impurities of Docetaxel trihydrate.
7.4 Method of Screening:
Not Applicable.
7.5 Does the study require any investigation or interventions to be carried out on patients or other
humans or animals?
No.
8. LIST OF REFERENCES:
1) Bou.dewijn J.M. Braakhuisa, Arie Kegelb, Marij J.P. Weltersa’C, The growth inhibiting effect of
docetaxel (Taxotere) in head and neck squamous cell carcinoma xenografts, Cancer Letters, 1994 ;
30 (8) : P 1058-1060.
2) J.F. Smyth, I.E. Smith, C. Sessa, P. Schoffski, J. Wanders, H. Franklin and S.B. Kaye, Activity of
Docetaxel (Taxotere) in Small Cell lung cancer, European Journal of Cancer, 1994 ; 30 (8) : P 10581060.
3) Cancer and tumor therapy and antineoplastic agents, www.wikimipia.com/cancer therapy, and M. C.
Bissery, Preclinical Pharmacology of Docetaxel, European Journal of Cancer. 1995 ; 31(4) : S1-S6 .
4) Gorog S, Babjak M, Balogh G, Brilik J, Csehi A, Dravecz f, Drug impurity profiling stratergies,
Talanta, 1997; 44(9) : 1517-1526.
5) Maurizio Ceruti a, Valentina Tagini a, Valeria Recalenda a, Silvia Arpicco a, Luigi Cattel a, Mario
Airoldi b, Cesare Bumma b, Docetaxel in combination with epirubicin in metastatic breast cancer:
pharmacokinetic interactions, Il Farmaco, 1999 ; 54 (11-12) : 733-739.
6) Joëlle Dubois, Sylviane Thoret, Françoise Guéritte and Daniel Guénard, Synthesis of 5(20) deoxy
docetaxel, a new active docetaxel analogue, Tetrahedron Letters 2000 ;41(18): 3331–3334.
7) Joel G.Hardman, Lee E. Limbird, Alfred Goodman Gilman’s , The Pharmacological Basis of
Therapeutics, 2001; (10) : 1381-1389.
8) Wei-Shuo Fang, Qi-Cheng Fang and Xiao-Tian Liang. Synthesis of the 2a-benzoylamido analogue
of docetaxel, Tetrahedron Letters 2001;42: 1331–1333.
9) Anne-Laure Larroque, Joe¨lle Dubois, Sylviane Thoret, Genevie`ve Aubert,Daniel Gue´nard and
Franc¸oise Gue´ritte, Synthesis and biological activities of docetaxel analogue with a peptide side chain
at C30, Bioorganic & Medicinal Chemistry Letters 2005 ; 15(1) : 4722–4726
10) Europian Pharmacopoeia, Docetaxel Trihydrate derivative and impurities 2005; (6.6): P.5236-5238
11) R Vasu Dev a, J. Moses Babu a,., K. Vyasa, P. Sai Ramb, P. Ramachandra b, N.M. Sekhar b, D.N.
Mohan Reddyb, N. Srinivasa Raob, Isolation and characterization of impurities in docetaxel, Journal
of Pharmaceutical and Biomedical Analysis. 2006 ; 40(3) : 614–622.
12) B. Mallikarjuna Raoa,., Arpita Chakraborty a, M.K. Srinivasu a, M. Lalitha Devi a,P. Rajender
Kumarb, K.B. Chandrasekhar c, A.K. Srinivasan d, A.S. Prasad d, J. Ramanathamd, A stabilityindicating HPLC assay method for docetaxel, Journal of Pharmaceutical and Biomedical Analysis
2006 ; 41(2) : 676–681.
13) Dinesh K. Rajesh S T, Santosh K, Deolia, Moloy M, Rama M, Anand C. Burman,.”Isolation and
characterization of degradation impurities in docetaxel drug substance and its formulation”. Journal
of Pharmaceutical and Biomedical Analysis. 2007 ; 43(4) : 1228–1235.
14) Wenting Du,a Lan Hong,b Tongwei Yao,b Xiaochun Yang,cQiaojun He,c Bo Yangc and
Yongzhou Hua, Synthesis and evaluation of water-soluble docetaxel prodrugs-docetaxel esters of
malic acid, Bioorganic & Medicinal Chemistry 2007; 15(18) : 6323–6330
15) Pawel Dziedzic, Jan Vesely, Armando Córdova, Catalytic asymmetric synthesis of the docetaxel
(Taxotere) side chain; organocatalytic highly enantioselective synthesis of esterification-reation ahydroxy-b-amino acid, Tetrahedron Letters. 2008 ; 49(47) : 6631–6634.
16) Bowen Ke a, Yong Qin a, Fengyan Zhao b, Yi Qub, Synthesis and biological evaluation of novel
30-N-tert-butylsulfonyl analogues of docetaxel, Bioorganic & Medicinal Chemistry Letters 2008 ; (18):
4783–4785
17) Hong-Fu Lu a, Xun Sun a, Liang Xu b, Li-Guang Lou c, Guo-Qiang Lin, Design, synthesis and
biological evaluation of novel fluorinated docetaxel analogues, European Journal of Medicinal
Chemistry. 2009 ; 44(2) : 482-491.
9.
Signature of student:
10.
Remarks of the Guide
“SYNTHESIS, CHARACTERIZATION AND HPLC ANALYSIS OF STRUCTURALLY
RELATED COMPOUNDS OF
DOCETAXEL TRIHYRATE” To be undertaken by
Mr. Debjit Mukherjee has been discussed and to be worked out under my direction and supervision
as the official guide. The work is feasible having potential which can be exploited for the field of bulk
drug Chemistry. This work can be carried out in the research laboratories of Pharmaceutical
Chemistry at Krupanidhi College of Pharmacy, Bangalore. Hence the project is recommended for
clearance and approval
11.0
Name and Designation of guide:
11.1 Guide:
Dr. Amit Kumar Das.
Principal
Krupanidhi College of Pharmacy,Bangalore.
11.2 Signature:
11.3 Co-Guide:
Dr. BH Koti Reddy.
(R&D) CIPLA Pvt.Ltd.
Bommasandra -Jigni Link Road industrial area
Bommasandra ,Bangalore- 560099.
11.4 Signature:
11.5 Head of the Department:
Dr. Amit kumar Das
Dept of Pharmaceutical Chemistry
Krupanidhi College of Pharmacy
Bangalore-35.
11.6 Signature of HOD:
12.0
12.1 Remarks of Principal:
The Program and the research work that Mr. Debjit Mukherjee is undertaking has potential
implication in the field of bulk drug Chemistry and the work can be carried out in the research
laboratories of Pharmaceutical Chemistry at Krupanidhi College of Pharmacy and CIPLA
Laboratory, Bangalore.
Hence this project is recommended for clearance and approval.
12.2 Signature of Principal:
Dr. Amit Kumar Das
Principal
Krupanidhi College Of Pharmacy
Bangalore-35.