RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES by Egl80C

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									RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
               KARNATAKA, BANGALORE.


                                   ANNEXURE-II

     PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1.   Name of the candidate and address          MUDDUKRISHNA B.S.
                                                I M.PHARMA
                                                DEPARTMENT OF PHARMACEUTICAL
                                                CHEMISTRY
                                                DAYANANDA SAGAR COLLEGE OF PHARMACY
                                                KUMARSWAMY LAYOUT
                                                BANGALORE-560078.

                                                PERMANENT ADDRESS
                                                #20 , VINODA
                                                P&T LAYOUT,
                                                KURUBARAHALLY MAIN ROAD,
                                                VIDYANAGAR,
                                                BANGALORE - 560076


2.   Name of the institution                    DAYANANDA SAGAR COLLEGE OF
                                                PHARMACY,
                                                SHAVIGE MALLESHWARA HILLS,
                                                KUMARSWAMY LAYOUT
                                                BANGALORE-560078.
                                                .

3.   Course of study and subject                MASTER OF PHARMACY IN
                                                PHARMACEUTICAL CHEMISTRY



4.   Date of the admission                      JUNE 2007


5.   Title of the topic
        “FORCED DEGRADATION STUDY OF STEROIDAL DRUG BY
       DEVELOPMENT OF METHOD FOR THE IDENTIFICATION OF
          DEGRADATION PRODUCTS BY SUITABLE ANALYTICAL
                          TECHNIQUE”




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6.
     Brief resume of the intended work

     6.1 Need for the study

     Forced degradation studies on the drug substance are generally done early in the
     development program on a single batch.
     Forced degradation study helps to determine the intrinsic stability of the molecule by
     establishing degradation pathways in order to identify the likely degradation products, and
     to demonstrate specificity when developing stability-indicating methods, particularly
     when little information is available about potential degradation products.
     The purpose of stress testing is to provide evidence on how the quality of a drug substance
     varies with time under the influence of a variety of environmental factors such as
     temperature, humidity, and light, and enables recommendation of storage conditions,
     retest periods, and shelf lives to be established. The main purpose of forced degradation
     studies is to generate degradation products, not to test the stability of the product, thus if
     the conditions initially chosen do not result in degradation, the severity of the conditions
     (i.e., time, temperature, and/or concentration) should be increase. If the substance does not
     react because it is insoluble, organic co-solvents should be used to solubilize the material.

     The two main aspects of drug substance that play an important role in shelf life
     determination are assay of active drug, and degradation products generated, during the
     stability study, the assay of drug substances in stability test sample needs to be determined
     using stability indicating method, as recommended by the International Conference on
     Harmonization (ICH) guidelines and USP-26.

     There are two major analytical approaches to the search for degradation related impurities:
     Chemistry-guided and technique-oriented. The technique-oriented approach involves the
     use of multiple analytical techniques to increase the chances of detecting unknown
     impurities. The chemistry-guided approach involves a scientific evaluation of the possible
     degradation pathways of the drug substance and choosing analytical techniques
     appropriate for the proposed degradation chemistry. The chemistry guided approach
     should involve multiple evaluation points as more information is gathered about the
     conditions leading to degradation and about the structures and spectroscopic
     characteristics of the resulting degradation products that are detected. As degradation
     products and pathways are elucidated, this information is used to re-evaluate the relevance
     of the analytical methods. i.e., if a drug degrades under a certain condition to yield a
     product whose structure indicates that a cleavage has occurred in the parent molecule
     resulting in two products but only one is detected, then the analytical conditions may need
     to be modified or a different analytical technique (or detector) may need to be employed
     as part of the investigation.

     Ideally, a method that resolved and quantitatively detects the parent drug and all the
     degradation products is desired, In reality, Liquid chromatography coupled with Diode
     array detector, Electron spray ionization ion trap mass spectrophotometer is the most
     common analytical technique currently used for detection of degradation and impurities.


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Such a method maximizes the chances of resolving, eluting, and detecting both polar and
non polar degradation products.

Finally forced degradation studies may help facilitate pharmaceutical development as well
in areas such as formulation development, manufacturing, and packaging, in which
knowledge of chemical behavior can be used to improve a drug product.

6.2. Review of the literature

Ravinder J. Singh et.al Developed Sensitive liquid chromatography-tandem mass
spectrometry method for detection of Synthetic Corticosteroids.

Karen M. Alsante et.al Established the role of degradant profiling in active pharmaceutical
ingredients and drug products.

R.Byron et.al Developed a chromatographic method using mass spectral characterization
of budesonide and other structurally related corticosteroids.

Tisovska et.al Developed the HPLC method for the study of glimepride under hydrolytic
stress conditions.

Carla Gennaro et.al Developed HPLC-MS method to investigate the oxidative destruction
pathway of aromatic sulfonate wastes

Baiocchi et.al Developed MS method to study the Dexamethasone transformation products
on light activated titanium dioxide surface.

Kenneth S. Webb et.al done a study of accurate mass measurement of small molecules in
mass spectrometry.

Ashok Kumar et.al done a Characterization and quantitative determination of impurities in
piperaquine phosphate by HPLC and LC/MS/MS,

ICH Guideline, Stability Testing: “Stability Testing of New Drug Substances and
Products,” September 1994.

ICH Guideline, Stability Testing: “Photostability Testing of New Drug Substances and
New Drug Products,” November 1996.

ICH Guideline, “Impurities in New Drug Substances,” July 2000.

Michael G Motto et.al written harmonized guidance for Conducting Forced degradation
studies.




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     6.3. Objectives of the study
        1. Forced Degradation study of Steroidal Drug

        2. Development of Sensitive method for the Identification of Degradation
           products by suitable analytical technique.

7.   Materials and methods:

     7.1 Source of data

     Chemical Abstract and other journals like Journal of Clinical Chemistry, Indian Journal of
     Pharmaceutical Sciences, Journal of Chromatography, Indian Journal of Environmental
     Quality, Journal of American Society for Mass Spectrometry, Guidelines From Food and
     Drug Administration, International Conference on Harmonization and Helinet.


     7.2 Method of collection of data
     Chemicals and other reagents will be purchased from standard companies. The standard
     protocols and ICH and FDA guidelines will be followed for Forced degradation studies
     and method will be developed with the help of various Journals and guidelines for the
     identification of degraded products using liquid chromatography coupled with Diode array
     detector, tandem mass ion trap mass spectrophotometer.

     7.3 Does the study require any investigation or interventions to be
     conducted on patients or other humans or animals?

        NO.



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

        NOT APPLICABLE.
8.   References:
        1. Robert L. Taylor, Stefan K. Grebe, and Ravinder J. Singh Quantitative, Highly
           Sensitive Liquid Chromatography–Tandem Mass Spectrometry Method for
           Detection of Synthetic Corticosteroids, Clinical Chemistry (2004); 50:12: 2345–
           2352




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2. Karen M. Alsante , Akemi Ando, Roland Brown, Janice Ensing, Todd D. Hatajik,
   Wei Kong and Yoshiko Tsuda, The role of degradant profiling in active
   pharmaceutical ingredients and drug products. Advanced Drug Delivery Reviews,
   (2007); 0169-409X

3. Shuguang Hou, Michael Hindle, and Peter R. Byron, Chromatographic and mass
   spectral characterization of budesonide and a series of structurally related
   corticosteroids using LC–MS, Journal of Pharmaceuticals and Biomedical
   Analysis, (2005); 10.1016

4. Petra Kova íková, , , Jií Klime, Jií Dohnal and Lucie Tisovská, HPLC study of
   glimepiride under hydrolytic stress conditions, Journal of Pharmaceuticals and
   Biomedical Analysis, (2004); 10.1016

5. Fabio Gosetti, Valentina Gianotti, Mauro Ravera, and Maria Carla Gennaro,
   HPLC-MS to Investigate the Oxidative Destruction Pathway of Aromatic Sulfonate
   Wastes, Journal of Environmental quality (2005); 34:2328-2333.

6. Paola Calza, Ezio Pelizzetti, Mariacarla Brussino, and Claudio Baiocchi, Ion Trap
   Tandem Mass Spectrometry Study of Dexamethasone Transformation Products on
   Light Activated TiO2 Surface, American Society for Mass Spectrometry. Published
   by Elsevier Science Inc., (2001); 1044-0305/01.

7. Anthony W. T. Bristow and Kenneth S. Webb, Intercomparison Study on Accurate
   Mass Measurement of Small Molecules in Mass Spectrometry, American Society
   for Mass Spectrometry. Published by Elsevier Science Inc., (2003); 1044-0305/03.

8. Vaijanath G. Dongre, Pravin P. Karmuse, Pradeep D. Ghugare, Mukesh Gupta,
   Bipin Nerurkar, Chirag Shaha and Ashok Kumar, Characterization and quantitative
   determination of impurities in piperaquine phosphate by HPLC and LC/MS/MS,
   Journal of Pharmaceutical and Biomedical Analysis, (2007); 0731-7085.

9. FDA, “International Conference on Harmonization: Stability Testing of New Drug
   Substances and Products,” Federal Register 59 (183), 48753–48759 (22 September
   1994) (ICH Q1A).

10. FDA, “International Conference on Harmonization: Draft Revised Guidance on
    Q1A(R) Stability Testing of New Drug Substances and Products,” Federal Register
    65 (78), 21446–21453 (21 April 2000) [ICH Q1A(R)]. This revised guideline
    reached Step 4 of the ICH process on 8 November 2000.

11. FDA, “International Conference on Harmonization: Guideline for the Photostability
    Testing of New Drug Substances and New Drug Products,” Federal Register 62
    (95), 27115–27122 (16 May 1997) (ICH Q1B) and References 1 and 2.




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12. FDA, “International Conference on Harmonization: Guideline on Impurities in
    New Drug Substances,” Federal Register (Notices) 61 (3), 371–376 (4 January
    1996) (ICH Q3A) and FDA, “International Conference on Harmonization: Draft
    Revised Guidance on Impurities in New Drug Substances,” Federal Register
    (Notices) 65 (140), 45085–45090 (20 July 2000) [ICH Q3A(R)]. ICH Q3A(R)
    currently is at Step 3.

13. Available Guidance and Best Practices for Conducting Forced Degradation Studies
    Dan W. Reynolds, Kevin L. Facchine, June F. Mullaney, Karen M.Alsante,Todd
    D.Hatajik, and Michael G Motto, Pharmaceutical Technology (2002)




                              Page 6 of 7
9.   Signature of the candidate:
                                                              [MUDDUKRISHNA B.S]

10. Remarks of the guide:



11. Name and Designation of:

     11.1 Guide
                                            Dr. Murugan .V
                                            Professor and Principal
                                            Department of Pharmaceutical Chemistry
                                            Dayananda Sagar college of Pharmacy
                                            Banglore-78



     11.2 Signature

     11.3 Co-Guide                           Dr. Suresh Venkatram
                                             CEO & Technical Director,
                                             Star Drugs and Research Laboratory
                                             No.15A, 1st Floor, The Presidency,
                                             St. Marks Road, Bangalore – 01.
     11.4 Signature

     11.5 Head of the department            Dr. Murugan .V
                                            Professor and Principal
                                            Department of Pharmaceutical Chemistry
                                            Dayananda Sagar college of Pharmacy
                                            Banglore-78.
     11.6 Signature

12. 12.1 Remarks of the Chairman and Principal:


                                            Dr. Murugan .V
                                            Professor and Principal
                                            Department of Pharmaceutical Chemistry
                                            Dayananda Sagar college of Pharmacy
                                            Banglore-78

     12.2 Signature




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