Download enclosure-v

“PREPARATION AND IN-VITRO CHARACTERIZATION OF CARVEDILOL
SOLID DISPERSIONS USING GELITA COLLAGEL/POLOXAMERS”
M. Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Bangalore
Karnataka
By
Ms. Thoodi. Anusha, B. Pharm.
Under the Guidance of
SRIKANTH . A
Assistant Professor
DEPARTMENT OF PHARMACEUTICS
EAST WEST COLLEGE OF PHARMACY
BANGALORE – 560091
2010-2012
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ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1
Name of candidate and address
(In Block Letters)
T.ANUSHA,
D/O RANGARAO,
H.NO:19-70/4
RAMAYAMPET,
MEDAK DIST,
ANDHRA PRADESH STATE.
2
Name of the Institute
EAST WEST COLLEGE OF PHARMACY,
BANGALORE -560 091.
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Course of study and subject:
M.PHARM. PHARMACEUTICS.
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Date of admission of course:
26-07-2010
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Title of the topic:
“PREPARATION, AND IN-VITRO CHARACTERIZATION OF
CARVEDILOL SOLID DISPERSION USING GELITA
COLLAGEL/POLOXAMERS”
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Brief Resume of this intended work:
6.1 Need for the study
6.2 Review of Literature
6.3 Objectives of study
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Enclosure-I
Enclosure-II
Enclosure-III
Materials and Methods:
7.1 Source of data
Enclosure-IV
7.2 Method of collection of data (Including sampling procedure, if any)
Enclosure-V
7.3 Does the study require any investigation or interventions to be conducted on
patients of 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------2
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List of References
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Signature of the candidate
Enclosure-VI
(THOODI ANUSHA)
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Remarks of the Guide
The proposed work can be carried out in the
laboratory. Protocol is as per university guidelines.
Name and designation of
(in block letters)
11.1 Guide
SRIKANTH . A
ASSISTANT PROFESSOR
DEPT. OF PHARMACEUTICS,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
11.2 Signature
11.3 Co-Guide (if any)
------------
11.4 Signature
------------
11.5 Head of Department
Dr. JAGADEESH G HIREMATH,
PROFESSOR,
EAST WEST COLLEGE OF PHARMACY,
BANGLORE-560 091.
11.6 Signature
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12.1 Remarks of the
Chairman/Principal
12.2 Signature
Prof. K.A. SRIDHAR,
PRINCIPAL,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE - 560 091.
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ENCLOSURE-I
6) Brief resume of the intended work:
6.1) Need for the study:
A majority of drug candidates exhibit poor aqueous solubility. These compounds are real challenges for
formulation in terms of development of dosage forms with acceptable solubility. Solid dispersions are one of the
most promising strategies to improve the solubility of poorly water soluble drugs, by reducing drug particle size
to the absolute minimum and drug wettability, solubility can be improved. The melting and solvent evaporation
methods are preferred and used to improve the solubility of solid dispersion. However, surfactans are used to
stabilize the formulation, which prevent drug recrystallization.1 Improving aqueous solubility and slow
dissolution of BCS Class II and Class IV drugs have been investigated extensively. The higher dissolution rates
of solid dispersions can be ascribed to a number of factors which includes: The formation of amorphous of drug
and carriers, cosolvent effect on the drug by water soluble carriers, intermolecular hydrogen bonds between drug
and carrier, local solubilisation effect of carrier at the diffusion layer and reduction of particle size to nearly a
molecular level.2
Carvedilol is non-selective beta blocker used for the treatment of mild to moderate congestive heart failure
(CHF). It blocks beta-1 and beta-2 adrenergic receptors as well as the alpha-1 adrenergic receptors. Carvedilol
used in the treatment of various cardiovascular disorders such as angina pectoris, cardiac arrhythmia and
hypertension. Its oral bioavilibility approximately around 25-35%, because of its first pass metabolism and half
life is about 6-8 h, respectively. Carvedilol is a off-white crystaline powder. Melting point is 114 to 1150C.
Carvedilol practically insoluble in water (0.583 mg/L).3
Hence, there is a need for development of novel solid dispersion to improve the carvedilol solubility and their
in-vitro characterization. The present study is an attempt to overcome the poor aqueous solubility of carvedilol
by using various techniques such as solvent evaporation/spray drying/melt or any appropriate suitable method.
The developed and prepared formulation will be subjected for in-vitro physicochemical characterizations.
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ENCLOSURE-II
6.2) Review of literature:
Literature review for understanding the study was done by referring to various national and international
journals, published articles in various official standard books and referred to various websites.
Planinsek et al., have prepared the carvedilol solid dispersion by solvent evaporation method using porous
Sylysia (SiO2) in a vacuum evaporator. The impregnated carriers were characterized using nitrogen-adsorption
experiments, X-ray diffraction, wettability measurements, attenuated total reflectance FTIR spectroscopy and
thermal analysis. They have reported that significant improvement of drug release with prepared solid dispersion
when compared to dissolution of pure carvedilol or its physical mixtures with sylysia. Their results showed that
when the drug precipitated in a thin layer within the carrier the dispersion retained a high specific surface area,
micropore volume and drug-release rate from the solid dispersion. Their results also suggested that the
amorphous form of carvedilol showed improved wettability and weak interactions between the drug and carrier
in the solid dispersion was contributed to improve the dissolution.4 (2011)
Potluri et al., have investigated on solid dispersion (SDs) of carvedilol by using Gelucire (50/13) prepared by
solvent evaporation method. The solubility of carvedilol showed linear increase with increasing the
concentrations of Gelucire. They have characterized solid dispersion of physicochemical characteristics by using
differential scanning calorimetry and X-ray diffractometry. Their obtained results showed that transformation of
crystalline form of drug to amorphous form was confirmed by scanning electron micrographs. Further, fourier
transform infrared spectroscopy results suggested that there was no drug carrier interaction observed. Dissolution
parameters such as mean dissolution time, dissolution efficiency and drug release rate, results suggested that
improved in the dissolution characteristics for SDs when compared with physical mixture and pure drug. Thus
SDs of carvedilol in Gelucire (50/13) showed enhanced solubility and dissolution rate compared to pure drug.5
(2011)
Kumar et al., have prepared carvedilol solid dispersion by polyethylene glycol (PEG) by using different
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superdisintegrants like Ac-Di-sol and SSG and they have prepared the fast dissolving tablets with dry granulation
method. They have characterized formulation for the physicochemical and in-vitro release studies.6 (2011)
Rathinaraj et al., have prepared and evaluated the sustained release solid dispersion of nimodipine using
retarding polymers by solvent evaporation technique. They have used ethyl vinyl acetate (EVA), eudragit (EURL-100) and etylcellulose (EC) as polymers. Solid state and drug polymer interactions was investigated by
infrared spectroscopy (I.R) and confirmed the absence of any possible interactions. In-vitro drug release study
was conducted by using 900 ml of dissolution media (acetate buffer pH 4.5) at 75 RPM at 37±0.50C,
respectively. The percentage drug release results revealed that 99.2% with EC, 95.2% with (EU-RL-100) &
89.34% with EVA, respectively.7 (2011)
Elbary et al., have investigated on the surface solid dispersion (SSD) strategy using glibenclamide as a model
drug. The drug was solubilized by surfactants and/or polymers then adsorbed onto the surface of extremely fine
carriers to increase its surface area and to form the SSD. The prepared solid dispersions were characterized by
using differential scanning calorimetry, X-ray diffraction, infrared spectroscopy, scanning electron microscopy
and in-vitro drug release. DSC and X-ray diffraction studies showed a decrease in the melting enthalpy and
reduced drug crystallanity and consequently indicated that no drug interactions with the carriers by infrared
spectroscopy (I.R). They have carried out a bioequivalence study by using six male human volunteers. In their
bioequivalence study they have compared best prepared formulation with marketed tablets. Finally they have
concluded that surface solid dispersion may serve as a successful strategy for enhancing solubility of poorly
water soluble drugs.8 (2011)
Patil et al., have prepared solid dispersion of gliclazide with polyethylene glycol 6000 by fusion method. They
have carried out in-vitro dissolution study of gliclazide, its physical mixture and solid dispersion to demonstrate
the effect of PEG 6000. Analytical techniques of FT-IR spectroscopy, differential scanning calorimetry and Xray diffractometry were carried out to characterize the drug in the physical mixtures and solid dispersions. The
FT-IR results suggested that there was no interaction between gliclazide and PEG 6000 when prepared as a solid
dispersion. DSC and XRD study indicated that the drug was converted into amorphous form. They have reported
that dissolution studies of solid dispersion and physical mixture showed greater improvement in drug release
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when compared to that of the pure drug. They have observed mechanisms for increase in dissolution rate may be
concluded that, reduction of crystallite size, solubilization effect of the carrier, absence of aggregation of drug
crystallites, improved wettability and dispersbility.9 (2011)
Bobe et al., have prepared solid dispersion of atorvastatin by using mannitol, PEG 4000 and PVP-K30. The
prepared solid dispersions were characterized by using fourier transform infrared spectroscopy (FTIR),
differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and also analysed the solubility
and in-vitro dissolution. Their results suggested that solid dispersion prepared with polyethylene gylcol
(PEG4000) showed the presence of amorphous form confirmed by characterization studies and also it had shown
enhanced solubility with improved dissolution rate. They have concluded that dissolution rate of atorvastatin can
be enhanced to considerable extent by solid dispersion technique with PEG.10 (2011)
Onoue et al., have prepared crystalline solid dispersion of tranilast (CSD/TL) by wet-melting technique with
aim of improving physicochemical and pharmacokinetic properties. Physicochemical properties of the prepared
formulations were characterized by laser diffraction and dynamic light scattering for particle size analysis,
scanning electron microscope for morphplogical analysis and powder X-ray diffraction and differential scanning
calorimetry for crystallanity assessment. They have reported that TL particles in CSD/TL appeared as a
crystalline nature with diameter of 122 nm and CSD/TL exhibited marked improvement in the dissolution
behavior as compared to crystalline TL was investigated.11 (2010)
Kapadia et al., have prepared dispersion granules using a hot melt granulation technique which involved
preparation of a homogenous dispersion of valsatron in gelucire-50/13 melt, followed by its adsorption on to the
surface of aeroperl-300 pharma®, an inert adsorbent. The dispersion granules were characterized by FTIR, DSC,
XRD and SEM analysis. Their results showed partial drug excipient interactions revealed by FTIR spectrum,
retention of amorphous form of valsatran was observed by DSC and XRD. Their studies also revealed that
homogeneity and surface adsorption of the gelucire-50/13 melt on aeroperl-300pharma® was observed by SEM,
which lead to enhancement of solubility. They have finally concluded that in-vitro dissolution rate of these
tablets were significantly better in comparison with marketed formulation.12 (2009)
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Choi et al., have investigated on felodipine solid dispersion in presence of various carriers by solvent wetting
method. The results of X-ray diffraction and thermal analysis indicated that the drug was amorphous state when
PVP, HPMC and poloxamer were used as carriers. They have observed dissolution rates of felodipine in PVP,
HPMC or poloxamer solid dispersions were much faster than those for the corresponding physical mixtures.
However, dissolution profiles were depends upon the carrier used, the dissolution rate of felodipine increased
slowly for solid dispersions prepared by using HPMC, whereas rapid initial dissolution rates were observed for
solid dispersions prepared by using PVP or poloxamer. They have concluded that no significant changes in
crystal form was observed by X-ray diffraction or thermal analysis and no significant changes in dissolution rate
was observed when sorbitol and mannitol were used as carriers.13 (2006)
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ENCLOSURE-III
6.3) Objective of the study:
The present study is planned with the following objectives:
1. Selection of appropriate carriers for the preparation solid dispersions for carvedilol
2. To prepare the carvedilol containing solid dispersion by solvent evaporation/ eutectic/microwave/spray
drying/ or any other appropriate suitable method.
3. To evaluate the physicochemical characterization of prepared solid dispersions.
4.
To estimate the drug content in solid dispersions.
5.
To study the in-vitro drug release aspects.
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ENCLOSURE-IV
7) Materials and Methods:
Materials:
Drug
: Carvedilol
Polymers: Gelita collagel/Poloxamer or any other appropriate polymers, which will be used for the preparation
of solid dispersion formulations during the course of study.
Methods:
Initially, preparation of solid dispersions of carvedilol with different polymers will be carried out any one of the
following different method. viz., solvent evaporation/ melt technique/ spray drying technique or any other
appropriate technique. Subsequently, one/two methods will be optimized.
7.1) Source of data:
The reaserch and review articles and text book references have been collected from the below
mentioned
sources, respectively.

Internet.

Pharmaceutical poster presentation.

Research publications.

International and Indian Journals.

Textbooks and reference books.
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ENCLOSURE-V
7.2 Method of collection of data: (Including sampling procedure, if any)

Standardization of carriers with drug for preparation of solid dispersions.

Determination of solubility by using water bath shaker

Estimation of drug content in the developed formulations.

In-vitro drug release studies.
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ENCLOSURE- VI
8) List of references
1. Vasconcelos T, Sarmento B, Costa P. Solid dispersions as stratergy to improve oral bioavailability of
poor water soluble drugs. Drug Discov Today 2007;12:23-24.
2. Saharan VA, Kukkar V, Kataria M, Gera M, Choudhury PK. Dissolution enhancement of drug. Int J
Health Res 2009;2(2):107-24.
3. Tripathi KD. Essentials of Medical Pharmacology. 6th edition, 2008, chapter 10,143-44. Jaypee
publications.
4. Planinsek O, Kovacic B, Vrecer F. Carvedilol dissolution improvement by
preparation of solid
dispersions with porous silica. Int J Pharm 2011;406:4-48.
5. Potlluri RHK, Bandari S, Jukanti R, Veerareddy PR. Solubility enhancement and physicochemical
characterization of carvedilol solid dispersion with gelucire 50/13. Arch Pharm Res 2011;34:51-57.
6. Kumar KB, Kumar SS, Chandu LM, Rao MK, Prasanth KSV. Formulation development and evaluation
of fast dissolving tablet of carvedilol using super disintegrants and solid dispersion technique. Int J
Adv Pharm Res 2011;2(2):45-51.
7. Rathinaraj SB, Rajveer CH, Choudhury PK, Sheshrao GB, Shinde GV. Studies on dissolution behaviour
of sustained release solid dispersions of nimodipine. Int J Pharm Sci 2011;3(1):77-82.
8. Elbary AAA, Salem HF, Maher ME. In-vitro and in-vivo evaluation of gilbenclamide using surface solid
dispersion approach. Br J Pharmacol Toxicol 2011;2(1):51-62.
9. Patil MP, Gaikwad NJ. Characterization of gliclazide-polyethylene glycol solid dispersion and its effect
on dissolution. Braz J Pharm Sci 2011;47:161-66.
10. Bobe KR, Subrahmanya CR, Suresh S, Gaikwad DT, Patil MD, Khade TS et al. Formulation and
evaluation of solid dispersion of atorvastatn with various carriers. Pharma Globale 2011;2(1):1-6.
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11. Kawabataa Y, Yamamotoa K, Debarib K, Onouea S, Yamada S. Novel crystalline solid dispersion of
tranilast with high photostability and improved oral bioavailability. Eur J Pharm Sci 2010;39:256-62.
12. Shrivastava AR, Ursekar B, Kapadia CJ. Design, optimization, preparation and evaluation of dispersion
granules of valsartan and formulation into tablets. Curr Drug Deliv 2009;6:28-37.
13. Kim EJ, Chun MK, Jang JS, Lee IH, Lee KR, Choi HK. Preparation of a solid dispersion of felodipine
using a solvent wetting method. Eur J Pharm Biopharm 2006;64:200-05.
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