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

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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 | |

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5. Title of the topic:-

“DEGRADATION STUDY AND RP-HPLC FOR ESTIMATION, DEVELOPMENT AND VALIDATION OF ATORVASTATIN, GLIMEPIRIDE AND NEVIRAPINE”.

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