RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
FORCED DEGRADATION STUDY AND RP-HPLC FOR ESTIMATION, DEVELOPMENT AND VALIDATION OF ATORVASTATIN, GLIMEPIRIDE AND NEVIRAPINE
SYNOPSIS FOR REGISTRATION
Of
M.PHARM DISSERTATION
Submitted to
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA
[pic]
By:-
VISHAL SINGH
IST M.PHARM
[pic]
Department Of Pharmaceutical Chemistry
DAYANANDA SAGAR COLLEGE OF PHARMACY
2009
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
BANGALORE
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
| | | |
|1. |Name of the Candidate |Vishal Singh |
| |and Address |1st M.Pharma |
| | |Department Of Pharmaceutical Chemistry |
| | |Dayananda Sagar College of Pharmacy, |
| | |Kumaraswamy layout, Bangalore – 560 078 |
| | | |
| | |Permanent Address |
| | |B-36/44, C-25, Tulsi nagar, Sarai Nandan, Khojwa, Varanasi(U.P)-221010 |
| | | |
|2. |Name of the Institution |Dayananda Sagar College of Pharmacy, |
| | |Kumaraswamy layout, Bangalore – 560 078. |
| | | |
| | | M. Pharm in Pharmaceutical Chemistry |
|3. |Course of Study and | |
| |Subject | |
| | | |
|4. |Date of Admission |20th JUNE-09 |
| | |
|6.0 |Brief resume of the intended work |
| |6.1 Need for the study |
| |Forced degradation studies on the drug substances 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. 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: |
| | |
| |1. Beata Stanisz and Lukasz Kania, Validation of HPLC method for determination of Atorvastatin in tablet and for monitoring |
| |stability in solid phase. |
| | |
| |2. Wanjari DB et al, Reversed Phase HPLC method for determination of Glimepiride. |
| | |
| |3. Lydia Rabbaa-Khabbaz et al, A simple and sensitive method for Determination of Glimepiride in human serum by HPLC. |
| | |
| | |
| | |
| |4.Fenghe Qui et al, identification of a process impurity formed during synthesis of a nevirapine analogue HIV NNRt inhibitor |
| |using LC/MS and Forced degradation studies. |
| | |
| |5. Vieweg Verlag, Development and Validation of Atorvastatin by LC-ESI-MS and application in bioequivalence Research in healthy |
| |Chinese volunteers. |
| | |
| |6. Zaheed Zaheer et al, Stability-indicating HPLC determination of Atorvastatin calcium in Pharmaceutical dosage form. |
| | |
| |7. Lakshmi K.S.et. al, Development and Validation of liquid chromatographic and UV derivative spectrophotometric methods for the |
| |determination of Metformin, Pioglitazone and Glimepiride in pharmaceutical formulations. |
| | |
| |8. Hohyun Kim et al, Determination of Glimepiride in human plasma by LC-Electrospray ionization Tandem Mass Spectrometry. |
| | |
| |9. Prasada Rao CH et. al, Development and Validation of RP-HPLC method for the estimation of Nevirapine in bulk drug and tablets. |
| | |
| |10. Lakshmi K.S and Rajesh T., Determination of Pioglitazone and Glimepiride in Pharmaceutical formulations and rat plasma by |
| |RP-LC. |
| | |
| |11. Latour S. et al, Validation of a method for the determination of Atorvastatin and its metabolites in human plasma using HPLC |
| |with Tandem mass spectrometric detection. |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| |6.3 – Objective of the Study: |
| |1. Forced degradation study of a drug by :- |
| |a) Thermal Degradation. |
| |b) In acidic media by using 0.1 N HCl & by basic media using 0.1 N NaOH. |
| |c) By oxidation using Hydrogen Peroxide. |
| |d) By neutral degradation 80 OC for 8 hrs. |
| |e) In presence of sunlight for 8 hrs. |
| |2. Development of sensitive method for the identification of degradation products by suitable analytical technique by using HPLC. |
| |The following parameters can be determined for the above said drugs to determine the purity and stability:- |
| |Estimation of the degradation by HPLC method. |
| |Method Development |
| |Validation |
| |Precision |
| |Linearity |
| |Accuracy |
| |Specificity |
| |LOD(Limit of Detection) |
| |LOQ(Limit of Quantification) |
| |vii) Robustness of the method. |
| |3. Degradation of the drug can also be determined by using Mass spectroscopy. |
| | |
| |7.0- Materials and Methods: |
| |Chemicals and reagents:- |
| |● Atorvastatin was obtained from Zydus, Cadila, tablets of Atorvastatin (10 mg) were obtained fro Parke-Davis. |
| |● Glimepiride were obtained as gift samples from Dr. Reddy’s Laboratories, Hyderabad. |
| |● Nevirapine was received as a gift sample from Hetero Drugs Ltd., Hyderabad and was used as such. |
| |● The water, methanol and Ammonium acetate used were of HPLC grade from Qualigens, Merck and glacial acetic acid was of analytical|
| |grade from Fischer Scientific. |
| |HPLC instrument:- |
| |LC system used consisted of pump(Model SHIMADZU; LC-20 AT) with universal loop injector(RHEODYNE 7725 i) of injection capacity 20 |
| |μl. Detector consists of UV- detector SPDZOA: the coloumn used will be Luna C 18 (5 μm,25 cm X 4.6 mm i.d.) phenomenex, USA, at |
| |ambient temperature. |
| | |
| |7.1- Source of Data: |
| |Chemical abstracts & other journals like:- |
| |● Indian Journal of Pharmaceutical sciences |
| |● Indian Journal of Chemistry |
| |● Pharmaceutical Bulletin |
| |● European Journal of Chemistry |
| |● Journal of pharmaceutical and biomedical analysis |
| |● Indian journal of environmental quality |
| |● Advanced drug delivery reviews. |
| | |
| |7.2 - Method of collection of data: |
| |Chemicals & other reagents will be collected 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. The products will be purified as per standard protocols. |
| | |
| |7.3 - Does the study require any investigations or interventions to be conducted on |
| |patients or other humans or animals? If so, Please describe briefly. |
| | |
| |No. |
| | |
| |7.4 – Has ethical clearance been obtained from your Institution in case of 7.3? |
| | |
| |Not applicable. |
| | |
| |8.0 List of References: |
| | |
| |1. Beata Stanisz and Lukasz Kania, Validation of HPLC method for determination of Atorvastatin in tablet and for monitoring |
| |stability in solid phase. Acta Poloniae pharmaceutica-drug research. 2006; 63 (6): 471-76. |
| | |
| |2. Wanjari DB and Gaikwad NJ, Reversed Phase HPLC method for determination of Glimepiride. Indian Journal of Pharmaceutical |
| |Sciences. 2005; 67: 253-55. |
| | |
| |3. Lydia Rabbaa-Khabbaz, Rita Abi Daoud, Dolla Karam-sarkis and Antoine Zoghbi, A simple and sensitive method for Determination |
| |of Glimepiride in human serum by HPLC. Journal of Liquid Chromatography & related Technologies. 2005; 28: 3255-63. |
| | |
| |4. Fenghe Qui, Scott Pennino, Carl A. Busacca and Daniel L. Norwood, Identification of a process impurity formed during synthesis |
| |of a nevirapine analogue HIV NNRt inhibitor using LC/MS and Forced degradation studies. Boehringer Ingelheim Pharmaceuticals Inc. |
| |2009. |
| | |
| |5. Vieweg Verlag, Development and Validation of Atorvastatin by LC-ESI-MS and application in bioequivalence Research in healthy |
| |Chinese volunteers. Chromatographia. 2007; 65: 737-41. |
| | |
| |6. Zaheed Zaheer, Farooqui M.N, Mangle A.A and Nikalje A.G, Stability-indicating HPLC determination of Atorvastatin calcium in |
| |Pharmaceutical dosage form. African Journal of Pharmacy and Pharmacology. 2(10): 204-10. |
| | |
| |7. Lakshmi K.S, Rajesh T, Sharma S and Lakshmi S, Development and Validation of liquid chromatographic and UV derivative |
| |spectrophotometric methods for the determination of Metformin, Pioglitazone and Glimepiride in pharmaceutical formulations.Der |
| |Pharma Chemical. 2009; 1(1): 238-46. |
| | |
| | |
| |8. Hohyun Kim, Kyu Young Chang, Hee Joo Lee and Sang Beon Han, Determination of Glimepiride in human plasma by LC-Electrospray |
| |ionization Tandem Mass Spectrometry. Bull. Korean Chem. Soc. 2004; 25: 109-14. |
| | |
| |9. Prasada Rao CH, Channabasavaraj KP, Lakshmi Aswini G, Development and validation of RP-HPLC method for the estimation of |
| |Nevirapine in bulk drug and tablets, J Pharm. Sci. & Res. 2009; 1(2): 78-82. |
| | |
| |10. Lakshmi K.S, Rajesh T and Shrinivas Sharma, Determination of Pioglitazone and Glimepiride in Pharmaceutical formulations and |
| |rat plasma by RP-LC. International Journal of PharmTech Research. 2009; 1: 496-99. |
| | |
| |11. Latour S, Bradley T and Madi M, Validation of a method for the determination of Atorvastatin and its metabolites in human |
| |plasma, using HPLC with Tandem mass spectrometric detection. Bioanalytical Laboratory, Algorithme Pharma. |
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|9. |Signature of the candidate | |
| | |(VISHAL SINGH.) |
| | | |
|10. |Remarks of the Guide: | |
| | | |
|11. |Name and Designation of: | |
| |11.1 Guide: |Dr. V. Murugan |
| | |Professor and principal |
| | |Dept of Pharmaceutical Chemistry |
| | |Dayananda Sagar College of Pharmacy, |
| | |Kumaraswamy layout, Bangalore – 78. |
| | | |
| |11.2 Signature: | |
| |11.3 Co-Guide: |Mr. Pavan Kumar.P. |
| | |Senior Lecturer, |
| | |Department of pharmacology |
| | |Dayananda Sagar College of Pharmacy, |
| | |Kumaraswamy layout, Bangalore – 78. |
| |11.4 Signature | |
| | | |
| |11.5 Head of the Department: |Dr. V. Murugan |
| | |Professor and principal |
| | |Dept of Pharmaceutical Chemistry |
| | |Dayananda Sagar College of Pharmacy, |
| | |Kumaraswamy layout, Bangalore – 78. |
| | | |
| |11.6 Signature | |
| | | |
|12. |12.1 Remarks of the Chairman and Principal | |
| | | |
| | |Dr. V. Murugan |
| | |Professor and principal |
| | |Dept of Pharmaceutical Chemistry |
| | |Dayananda Sagar College of Pharmacy, |
| | |Kumaraswamy layout, Bangalore – 78. |
| | | |
| |12.2 Signature | |
-----------------------
5. Title of the topic:-
“DEGRADATION STUDY AND RP-HPLC FOR ESTIMATION, DEVELOPMENT AND VALIDATION OF ATORVASTATIN, GLIMEPIRIDE AND NEVIRAPINE”.
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