Formulation and Evaluation of Floating Tablets Containing the Nsaid S As a Drug

“Study of Formulation of Dexamethasone Sodium Phosphate Injection to Stabilize The Product to Avoid Particulate In The Formulation On Aging”

DISSERTATION PROTOCOL

SUBMITTED TO RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA.

BY MAHENDRA SINGH RATHORE M.PHARM, PART-I DEPARTMENT OF PHARMACEUTICS (2008-2010) RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA. ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

6.1. BRIEFNAME OFRESUME THE CANDIDATE OF THE INTENDEDMAHENDRA WORK: SINGH RATHORE AND ADDRESS (IN BLOCK NARGUND COLLEGE OF PHARMACY, LETTERS) DATTATREYANAGAR, II MAIN, 100 FT RING ROAD, BSK III STAGE, BANGLORE-85 KARNATAKA. 6.1 NEED FOR THE STUDY: Dexamethasone Sodium Phosphate Injection, IP is a synthetic adrenocortical steroid 2. anti-inflammatoryNAME OF THE INSTITUTION drug. Dexamethasone NARGUNDSodium Phosphate COLLEGE Injection, OF PHARMACY, IP 4 mg/mL is a DATTATREYANAGAR, II MAIN, sterile solution for intravenous, intramuscular, intra-articular, intralesional and soft tissue 100 FT RING ROAD, BSK III STAGE, administration[1]. BANGLORE-85 KARNATAKA. Dexamethasone Sodium Phosphate Injection, IP has a rapid onset but short duration of action when compared with less soluble preparations. Because of this, it is suitable for

3. theCOURSE treatment OF STUDYof acute ANDdisorders responsiveMASTER to adrenocortical OF PHARMACY steroid IN therapy, such as SUBJECT Primary or secondary or Acute adrenocorticalPHARMACEUTICS insufficiency.It is also used in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful,Shock unresponsive to conventional therapy etc.,[2,3] TH 4. CurrentlyDATE OF DexamethasoneADMISSION OF Sodium Phosphate5 MAY is also 2008 available for oral administration. COURSE However its bioavailability followed by oral administration is poor. Hence Dexamethasone Sodium Phosphate injections are currently considered as important. But formation of particulates in Dexamethasone Sodium Phosphate injections IP during and 5. TITLE OF TOPIC “Study of Formulation of Dexamethasone after storage for 6 months has been reported. The present study is aimed to study the Sodium Phosphate Injection to Stabilize The formation of particulates in Dexamethasone SodiumProduct Phosphate to Avoid injectionsParticulate IP In during The and Formulation On Aging” after storage for 6 months. Many samples of Dexamethasone Sodium Phosphate injections that failed to meet strength requirements; This is a problem with the shelf-life stability of dexamethasone sodium phosphate injections. This problem may be because, it is highly hygroscopicity or its polymorphic form or may be due to its interactions with glass containers or degradation by oxidation [3,4,5,6]. 6.2 REVIEW OF LITERATURE :

The stability of sterile dexamethasone acetate suspensions and dexamethasone sodium phosphate injections that had been stored in hospital pharmacies across the United States was studied. Through a voluntary FDA drug stability program, all hospital pharmacies in the United States were asked in October 1981 to complete a response card indicating information about the sterile dexamethasone acetate suspensions and dexamethasone sodium phosphate injections they had in stock. All samples that failed to meet strength requirements showed evidence of degradation by oxidation. Sterile dexamethasone acetate suspensions appear to be stable when stored under actual marketplace conditions, but there is a problem with the shelf-life stability of dexamethasone sodium phosphate injections made by some manufacturers[1,2,3] 2. The stability of 10 mg/mL dexamethasone sodium phosphate injection was evaluated using a validated, stability-indicating liquid chromatographic method during 91 days storage in glass and 55 days storage in plastic syringes with rubber plungers. Analysis of samples for leachates on day 101 failed to demonstrate any contamination. However, re-analysis of the syringes following 18 months storage indicated contamination by a number of compounds. The results indicate that sorption of dexamethasone phosphate to the syringe barrel or plunger did not occur to a clinically important degree. However after 101 days there was no measurable contamination of the dexamethasone phosphate solution, although after 18 months considerable contamination was observed [1,3]. 3. High – performance liquid chromatography studies were performed to determine whether dexamethasone sodium phosphate is degraded either in vials or in an infusion pump at 37 (degrees) C a period of weeks [2,3,4].

4. Dexamethasone Sodium Phosphate Injection, USP has a rapid onset but short duration of action when compared with less soluble preparations. Because of this, it is suitable for the treatment of acute disorders responsive to adrenocortical steroid therapy. This is also used in Hypercalcemia associated with cancer, Rheumatic disorders, Congenital adrenal hyperplasia, Nonsuppurative thyroiditis Hypercalcemia associated with cancer, Rheumatic disorders etc [5,6,7].

6.3 OBJECTIVES OF THE STUDY: The present study is aimed at the stability study of Dexamethasone sodium phosphate injection which includes the 1. Study of Dexamethasone sodium phosphate Polymorphism , 2. To study its interactions with glass containers upon storage, 3. stability studies due to its hygroscopic characteristics and its degradation due to oxidation etc., Finally study of reasons for formation of particulates in Dexamethasone Sodium Phosphate injections and to improve the Shelf-life stability of Dexamethasone sodium phosphate injections.

MATERIALS AND METHODS: Materials 1. Dexamethasone Sodium Phosphate is a water-soluble inorganic ester of dexamethasone. It occurs as a white to yellow crystalline powder, is odorless or has a slight odor of alcohol, is exceedingly hygroscopic, and is freely soluble In water (25 mg/ml - clear to slightly hazy, colorless solution), Ethanol (96%), Slightly soluble in Chloroform and Practically insoluble in Ether. 2. Water for injection and other organic solvents etc. 3. Preservative like Parabens and benzyl Alcohol etc.,

7.1. Source of Data 1. Library: Nargund college of pharmacy 2. e-library: Nargund college of pharmacy 3. The data will be collected by Laboratory investigation and Recording the data.

7.2. Method of Collection of Data 1. Data on drug will be collected through literature survey and from physiochemical data base such as Solubility in various solvents, pH of the drug solution and compatibility of the drug with various formulation additives. 2. Polymorphism studies using O-XRD method, Crystallography techniques and Thermal analysis. 3. Spectrophotometery analysis of the preparations. 4. Formulation compatibility studies using DST techniques. 5. Solubility studies using Co-solvents like Poly Ethylene glycol, Propylene glycol, Di Isosorbide, etc. 6. Stability studies as per ICH guidelines.

7.3. Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.

-NO-

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

- NOT APPLICABLE-

8. LIST OF REFERENCES: 1. Kroin,s Jeffrey, Schaefer, B S S Richard, Penn, MD D Richard, “ Chronic Intrathecal Administration of Dexamethasone Sodium Phosphate: Pharmacokinetics an Neurotoxicity in an Animal Model.” “Neurosurgery Jan.2000 46(1): 178-183. 2. Coffman HD, Crabbs WC, Joachims GL,Kolinski RE,and Page DP, “, Stability of sterile dexamethasone acetate suspensions and daxamethasone sodium phosphate injection submitted by U.S.hospitals” “ American Journal of hospital Pharmacy” vol.40: 2165-2169. 3. N Mahesh, J Jusko Williom and Samtani, “Stability of dexamethasone sodium, phosphate in rat plasma” “ Internationl Journal of Pharmaceutics” 2005 July 27. 4. V Dilova, V Zlatarova, N Spirova, K Filcheva, A Pavlova, P Grigorova, “Study of insolubility problems of dexamethasone and digoxin : cyclodextrin complexation. ” Int. J. of Pharmaceutics, vol.25: 216-219. 5. DW Law, S Law, SE Walker, J Iazzetta,” Dexamethasone phosphate stability and contamination of solution stored in syringe” “J.Pharma Sci.Technol. 1996 Aug. 6. G Della Porta, SF Ercoline, L Parente, E Reverchon “ Corticosteriod Microparticals produced by susperitical assisted atomization process optimization, product characterization, and in vitro performance.” “J Pharma Sci.2006 Sep: 95(9): 2062-76. 7. The Indian Pharmacopoeia 1996 VOL.1; 233. 9. Signature of the candidate

MAHENDRA SINGH RATHORE

10. Remarks of the Guide

RECOMMENDED FOR DISSERTATION WORK

11. Name & Designation of (in block letters)

11.1 Guide Mr. SATEESHA S.B. LECTURER M.PHARMACY NARGUND COLLEGE OF PHARMACY, DATTATREYANAGAR, II MAIN, 100 FT RING ROAD, BSK III STAGE, BANGLORE-85 11.2 Signature KARNATAKA

12. Name & Designation of (in block letters)

12.1 Co- Guide K.M Prasad, DGM (Works) Karanataka Antibiotics and Pharmaceuticals Limited, No, 14, II Phase, Peenya Industrial Area, Bangalor- 560058 12.2 Signature 13. 13.1 Remarks of the RECOMMENDED FOR DISSERTATION WORK Principal

13.2 Signature.

PROF. M.S HARISH Principal Nargund college of Pharmacy