RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1. / NAME OF THE CANDIDATE AND ADDRESS / Mr. SHAKTISH TELSANGDEPARTMENT OF PHARMACEUTICS,
K.L.E. SOCIETY’s COLLEGE OF PHARMACY,
J. N. M. C. CAMPUS, NEHRU NAGAR,
BELGAUM – 590010, KARNATAKA.
2. / NAME OF THE INSTITUTION / K.L.E. SOCIETY’s COLLEGE OF PHARMACY,
J. N. M. C. CAMPUS, NEHRU NAGAR,
BELGAUM – 590010, KARNATAKA.
3. / COURSE OF STUDY AND SUBJECT / MASTER OF PHARMACY IN
PHARMACEUTICS
4. / DATE OF ADMISSION TO COURSE / JUNE 2008
5. / TITLE OF THE TOPIC:
“ENHANCEMENT OF SOLUBILITY AND DISSOLUTION PROPERTIES OF GRISEOFULVIN BY NANOCRYSTALLIZATION TECHNIQUE”
6. / BRIEF RESUME OF THE INTENDED WORK:
6.1 NEED FOR THE STUDY:
Formulation of poorly water soluble drug is a general interactable problems in pharmaceutical field especially those compounds poorly soluble in both aqueous and organic media. It is difficult to resolve this problem using conventional formulation approaches, so many drugs are abandoned early in their discovery1.
A substantial factor that prevents the development of such substances (poorly soluble) is limited dissolution rate2. According to Noyes-Whitney law the dissolution velocity dc/dt depends on the saturation solubility Cs of drug.
There are two basic approaches to overcome the bioavailability problems of these drugs.
• Increased saturation solubility (eg. By complex formation)
• Increase of dissolution velocity
The first approach has limited success. A much more straight forward way in increasing the dissolution velocity by increasing the surface area of drug powder i.e. micronization leading to mean particle sizes of approximately 3-5 μm. However many of new drug compound show such a low solubility that micronization does not lead to a sufficient increase in bioavailability after oral administration3.
There are various approaches to solubilize poorly soluble drugs, such as inclusion complexes with cyclodextrins, formation of mixed micelles and liposome formulation. However, these approaches have proved to be inefficient as evidenced by the low number of marketed products4.
Nowadays an alternative approach is being applied that is nanonisation. The drug powder is transferred to drug nanocrystals3. Nanocrystal is a new carrier free colloidal drug delivery system with a particle size ranging from 100-1000 nm, and is thought as a viable drug delivery strategy to develop the poorly soluble drugs, because of their simplicity in preparation and general applicability.
The drug nanocrystal production techniques are classified as ‘bottom up’ methods and ‘top down’ methods. The bottom up methods, such as the precipitation technique, mean that nanocrystals can be constructed from the molecules; however, the top down methods such as pearl milling and homogenization techniques, mean that the nanocrystals can be disintegrated
step by step from the coarse powder1.
The main production technologies currently in use to produce drug nanocrystals yield as a product a dispersion of drug nanocrystal in liquid. However, the most convenient dosage form for patient is a dry product e.g. tablet, capsule, etc3.
Griseofulvin is an antifungal agent and chemically classified under hetrocyclic benzofuran5. It is extracted from Penicillium griseofulvum. It is useful in the treatment of dermatophytosis, ring worm infections and other fungal infections. Bioavailability of griseofulvin is 25-70% which is highly variable because of its low water solubility6 (0.2mg/ml)7.
Considering the above mentioned factors the present study is undertaken to provide an alternative drug delivery system with improved dissolution rate for griseofulvin in the form of nanocrystals which will overcome the inherent drawbacks of existing dosage form and with added benefits like;
· Decreased particle size
· Increased surface area
· Increased aqueous solubility
· Increased dissolution velocity
· Increased stability
6.2 REVIEW OF LITERATURE
Literature review for undertaking the study was done by referring to various national and international journals, published articles in various official standard books and referring to various websites on the internet.
During last 10-15 years, the formulation of drugs as nanocrystals has rapidly evolved into a mature drug delivery strategy, with currently 5 products in market. The major characteristics of these systems are rapid dissolution velocity, enabling bioavailability enhancement after oral administration. Recent advances with respect to nanosuspension stabilization, miniaturization of nanosuspensions production, further nanosuspension solidification is discussed8.
Nanosuspensions are first prepared by wet communition in the presence of stabilizers followed by spray drying which converts them into dried particles from which compacts are prepared. The aggregates formed during spray drying can be slowly redispersed into nanoparticles in water. It was found that stress to break and indentation hardness was only slightly higher in nanoparticulate system9.
Nanocrystals were prepared by emulsion solvent diffusion method by using cyclodestrins as stabilizers. Surfactant free nanocrystals of indomethacin were prepared, the effect of changing type and concentration of cyclodextrins on the formulation of indomethacin nonocrystals were investigated. Dispersions were freeze dried to characterize shape, size, nanoparticle yield, crystallinity and dissolution behavior of obtained particles were studied10.
Controlled crystallization during freeze drying (a novel bottom up process) was used to improve the dissolution behavior of lipophilic drug. Finofibrate was taken as model drug and the dissolution behavior was strongly increased. Tablets prepared form crystallized dispersion showed better dissolution when compared to tablets prepared from physical mixtures11.
Poorly water soluble drugs such as nifidipine possess poor dissolution characteristics. To overcome this problem nifidipine loaded nanoparticles were prepared using high pressure homogenization. The nanoparticles were characterized in terms of size, morphology and redispersion characteristics following water removal. Crystalline state evaluation before and following particle size reduction was also conducted through DSC, PXRD to evaluate transformation to amorphous state during homogenization process12.
6.3 OBJECTIVES OF THE STUDY
1. Preformulation studies.
2. Preparation of griseofulvin nanocrystals by controlled crystallization/emulsion solvent diffusion method or any other suitable method.
3. Characterization of nanocrystals for following parameters.
i. Physical Characterization
a) Particle size and size distribution.
b) Surface Morphology.
c) Zeta potential (Surface charge)
d) Crystal characteristics
e) Nanocrystal yield
ii. In-Vitro drug release.
iii. Stability studies at different conditions of temperature and relative humidity.
7. / MATERIALS AND METHODS
Drug : Griseofulvin
Method : Preparation of griseofulvin nanocrystals by controlled crystallization/emulsion solvent diffusion method or any other suitable method.
7.1 SOURCE OF DATA:
This data is obtained from the prepared nanocrystals based on the laboratory experiments and evaluation technologies and also from published literature.
7.2 METHOD OF COLLECTION OF DATA: By conducting laboratory experiments and approved analytical methods (Including sampling Procedure if any).
A. Preparation of standard curve.
B. Formulation of nanocrystals.
C. Evaluation of nanocrystals.
1) Particle size analysis (PCS/SEM).
2) Nanocrystals morphology
3) Crystal characteristics
4) Nanocrystal yield
5) Zeta potential (Zetameter)
6) Stability study (by statistical data)
D. In vitro drug release studies.
7.3 Does the study require any investigations or invention to be conducted on patients or other human or animals? If so, please mention briefly.
No
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
No
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8. / REFERENCES:1. Gao L, Zhang D, Chen M. Drug nanocrystal for the formulation of poorly soluble drugs and its application as a potential drug delivery system. J Nanopart Res 2008;10:845-62.
2. Douroumis D, Fahr A. Nano-and micro-particulate formulations of poorly water-soluble drugs by using a novel optimized technique. Eur J Pharm Biopharm 2006;63:173-5.
3. Nanocrystals of poorly soluble drugs for oral administration [Online]2007. [cited 2008 Nov 25]; Available from:
URL:http://userpage.fu-berlin.de/~mpharm2/Download/pdf/nanopure.pdf
4. Akkar A, Namsolleck P, Blaut M, Rainer H, Muller. Solubilizing poorly soluble antimytotic agents by emulsification via a solvent free process. AAPS Pahrm Sci Tech 2004;5(1):1-6.
5. Block JH, Beale JM. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chaemistry 11th ed. Philadelphia, Lippincott Williams & Wilkins. 2004:p.238
6. Tripathi KD. Essentials of Medical Pharmacology. 10th ed. New Delhi: Jaypee Brothers Medical Publishers; 2008. p.760-1.
7. Florey K. Analytical Profiles of Drug Substances; (vol-8). New York: Academic Press Inc. 1979. p.234.
8. Eerdenbrugh BV, Mooter GVd, Augustijns P. Top-down production of drug nanocrystals: Nanosuspension stabilization, miniaturization and transformation into solid particles. Int J Pharm 2008;364:64-75.
9. Lee j. Drug nano- and microparticles processed into solid dosage forms: physical properties. J Pharm Sci 2003;92(10):2057-67.
10. Makhlof A, Miyazaki Y, Tozuka Y, Takeuchi H. Cyclodextrins as stabilizers for the preparation of drug nanocrystals by the emulsion diffusion method. Int J Pharm 2008;375:280-5.
11. Waard Hde, Hinrichs WLJ, Frinjlink HW. A novel bottom up process to produce drug nanocrystals: controlled crystallization during freeze drying. J Control Release 2008;128:179-83.
12. Hecq J, Deleers M, Fanara D, Vranckx H, Amighi K. Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement nifidipine. Int J Pharm 2005;299:167-77.
9. / SIGNATURE OF CANDIDATE
10. / REMARKS OF THE GUIDE
The above information is true to the best of my knowledge and the work will be done under my guidance.
11. / 11.1 NAME AND DESIGNATION OF GUIDE / SHRI. P.M.DANDAGI.M.Pharm.
ASSOCIATE PROFESSOR,
Department of Pharmaceutics K.L.E.Society’s College of Pharmacy,
Belgaum.
11.2 SIGNATURE
11.3 CO-GUIDE (IF ANY)
11.4 SIGNATURE
11.5 HEAD OF THE DEPARTMENT / Dr. F. V. MANVI M. Pharm., Ph.D
PRINCIPAL,
PROFESSOR AND HEAD,
K.L.E. Society’s College of Pharmacy,
J. N. M. C. Campus, Nehru Nagar,
Belgaum – 590010, Karnataka.
11.6 SIGNATURE
12. / 12.1 REMARKS OF THE CHAIRMAN AND PRINCIPAL
The above mentioned information is correct and I recommend the same for approval.
12.2 SIGNATURE / Dr. F. V. MANVI M. Pharm., Ph.D
PRINCIPAL,
K.L.E. Society’s College of Pharmacy,
J. N. M. C. Campus, Nehru Nagar,
Belgaum – 590010, Karnataka.
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