Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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-12,4,7,10,13hexahydroxytax- 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.