Download preparation and in-vitro characterization of sustained release

“PREPARATION AND IN-VITRO CHARACTERIZATION OF SUSTAINED
RELEASE METFORMIN HCL MATRIX TABLETS USING SYNTHETIC / NATURAL
OR COMBINATION OF POLYMERS”
M. Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Bangalore
Karnataka
By
Ms. DEVARAPALLI L SAROJA., B. Pharm.
Under the Guidance of
MOHAMED RAHAMATHULLA
Associate Professor
DEPARTMENT OF PHARMACEUTICS
EAST WEST COLLEGE OF PHARMACY
BANGALORE – 560091
2010-2012
1
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1
Name of candidate and address
(In Block Letters)
D.L SAROJA,
D/O D.MANIKYALA RAO,
TIRUMALAMPALEM,
DWARAKATIRUMALA MANDAL,
WEST GODAVARI DIST,
ANDHRA PRADESH.
2
Name of the Institute
EAST WEST COLLEGE OF PHARMACY,
BANGALORE -560 091.
3
Course of study and subject:
M.PHARM PHARMACEUTICS.
4
Date of admission of course:
23/07/2010
5
Title of the topic:
“PREPARATION AND IN-VITRO CHARACTERIZATION OF SUSTAINED
RELEASE METFORMIN HCL MATRIX TABLETS USING SYNTHETIC/
NATURAL OR COMBINATION OF POLYMERS”
6
Brief Resume of this intended work:
6.1 Need for the study
6.2 Review of Literature
6.3 Objectives of study
7
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-------
8
List of References
Enclosure-VI
2
9
Signature of the candidate
( DEVARAPALLI L SAROJA)
10
Remarks of the Guide
The proposed work can be carried out in the laboratory.
Protocol is as per university guidelines.
11
Name and designation of
(in block letters)
11.1 Guide
MOHAMED RAHAMATHULLA,
ASSOCIATE 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,
DEPT. OF PHARMACEUTICS,
EAST WEST COLLEGE OF PHARMACY,
11.6 Signature
12
BANGALORE-560 091.
12.1 Remarks of the
Chairman/Principal
12.2 Signature
Prof. K.A. SRIDHAR,
PRINCIPAL,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE - 560 091.
3
ENCLOSURE-I
6) Brief resume of the intended work:
6.1) Need for the study:
Sustained release dosage forms are designed to achieve a prolonged therapeutic effect by continuously releasing
the drug over an extended period of time. Sustained release always follows first order. Whereas, matrix systems
are those where the drug is uniformly dissolved or dispersed in a release-retarding material. Such systems can be
formulated as conventional matrix, or bi or tri-layered matrix systems.1
Matrix is defined as a well-mixed composite of one or more drugs with gelling agent i.e hydrophilic polymers.
Use of hydrophilic matrix alone for extending drug release for highly water soluble drugs is restricted due to
rapid diffusion of the dissolved drug through the hydrophilic gel network. For such drugs it becomes essential to
include hydrophobic polymers in the matrix system. Matrix system is widely used for the purpose of sustained
release. It is the release system which prolongs and controls the release of the drug, which is dissolved or
dispersed.
Two types of matrix systems are:
1. Hydrophilic matrix system.
2. Hydrophobic matrix system.
Matrix tablet as sustained release is a new approach for novel drug delivery system in the field of pharmaceutical
technology. It excludes complex production procedures such as coating and pelletization during manufacturing.
But the drug release rate from the dosage form is controlled mainly by the type and proportion of polymer used
in the preparation.2
Metformin Hydrochloride is hypoglycaemic agent, Chemically it is 1,1–dimethyl biguanide Hcl, Chemical
formula is C4H11N5.Hcl, Molecular weight is 165.63 g/mol, Melting point is 225-232, Daily dose is 0.5 to 2.5g
and 2-3 doses/ day, PKa: 12.4, t1/2: 1.5-3. Duration of action is 6-8 hrs.3 Description: It is a white, crystalline
powder, hygroscopic. Grades are available in crystals, micronized Powder, (50 microns to 400 microns).
solubility is freely soluble in water, practically insoluble in acetone, ether, chloroform and dichloromethane in
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water, slightly soluble in ethanol (95%).4 The main mechanism of action is reduction of hepatic glucose output
largely by inhibiting hepatic gluconeogenesis. Metformin Hydrochloride also slows intestinal absorption of
sugars and improves peripheral glucose uptake and utilization. A very important property is its ability to reduce
hyperlipidemia lipoprotein (LDL) and very-low-density lipoprotein (VLDL) cholesterol concentrations falls,
and high-density lipoprotein (HDL) cholesterol rises.5
Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion:
Metformin Hcl has an oral bioavailability of 50-60% under fasting conditions and is absorbed mainly from small
intestine. Peak plasma concentrations (Cmax) are reached within 1-3hrs with immediate-release and 4-8hrs with
extended release. The plasma protein binding of Metformin Hcl is negligible, as reflected by its very high
apparent volume of distribution. Metformin Hcl is not metabolized. It is cleared from the body by tubular
secretion and excreted unchanged in urine. Renal clearance is approximately 3.5 times greater than creatinine
clearance, which indicates that tubular secretion is the major site for Metformin Hcl elimination. The average
elimination half-life is 6.2hrs.6 The adverse effects are abdominal discomfort, anorexia, nausea, metallic taste and
mild diarrhoea, metformin Hcl is effective in the treatment of polycystic ovary disease.7
The aim of present study is to prepare the sustained release Metformin Hydrochloride matrix tablets using
synthetic/ natural/ combination of polymers using wet granulation or dry granulation technique. And to evaluate
In-vitro release rate studies.
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ENCLOSURE-II
6.2) Review of literature:
Bhusan Samal et al., have developed sustained release zidovudine matrix tablets by employing various
proportions of hydrophilic polymers like NaCMC, HPMC, eudragit (Eu-Ll55), xanthan gum alone or in
combination with hydrophobic polymer ethyl cellulose. Tablets were prepared by wet granulation method.
Preformulation and post formulation studies were performed and were found to be within the limits. In-vitro
dissolution studies were also performed using USP 2 dissolution apparatus but combination of two polymers
xanthan gum combined with EC, NaCMC, and HPMC in different ratios shows zero order kinetics with 80-97%
of drug release but in the presence of NaCMC the drug released in 12hrs were in the range of 75-85% and shows
zero order. It has also showed good entrapment efficiency 96-106% of drug. Drug polymer interaction was
studied by FT-IR Spectroscopy. From the above study it was concluded that stable formulation can be developed
by incorporating both hydrophilic and hydrophobic polymers in a definite proportion so that sustained release is
maintained for an extended periods of time.8
Bhagawat et al., have investigated sustained release matrices of verapamil hcl using glyceryl monostearate and
stearic acid as waxy materials. Tablets were prepared by melt granulation technique. This formulation was
performed to study the effect of waxes at different drug: polymer ratios on the release profile of drug from matrix
formulations using glyceryl monostearate, stearic acid and both waxes in combination. Preformulation and post
formulation studies were performed and were found to be within the limits. An In-vitro dissolution study was
also performed and was analyzed by UV Spectrophotometer. The study showed that release of drug from
matrices prepared from combination of both waxes gets more retarded than from glyceryl monostearate and
stearic acid alone. Also study reveals that as concentration of waxes increases, release of drug from matrices
decreases. Among entire formulations combination of verapamil hydrochloride and glyceryl monostearate
showed the drug release 87.17±144%. From the studies it was concluded that glyceryl monostearate and stearic
acid were approximate waxy materials that can be utilized as matrix forming agent in melt granulation technique
to sustain the release of water soluble drug such as verapamil hydrochloride.9
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Rahman et al., have investigated various grades of HPMC matrix systems as oral sustained release using
diclofenac sodium as drug. Drug delivery systems used diverse grades of HPMC (Methocel K100M, K100LV,
K4M, K15M) in order to investigate the effect of various grades of this polymer on release mechanism from
matrix tablets. Tablets were prepared by direct compression method. Preformulation and post formulation studies
were performed and were found to be within the limits. In-vitro dissolution study was also performed using
paddle method. The highest percentage of drug release within 8hrs is 91.09% obtained from the formulation
containing methocel K100LV. At a fixed polymer level, drug release from the higher viscosity grades (K100M)
was found to be slower when compared to lower viscosity grades (K100LV). The drug content of all the
formulations was between 100.32- 100.33% indicating the presence of an acceptable amount of drug in all
formulations.10
Patil et al., have investigated sustained release matrix tablets of furosemide using natural polymers such as
pectin, guar gum, and xanthan gum. Various preformulation and post formulation studies were performed and
were found to be within the limits. In-vitro dissolution studies were also evaluated. Among the entire
formulations tablet containing guar gum has exhibited greater swelling index than those with pectin and xanthan
gum. The swelling index was calculated with respect to time. As time increases swelling index also increases
because weight gain by the tablet was increased proportionally with rate of hydration up to 8hrs. A direct
relationship was observed between swelling index and drug concentration. Based on all results obtained, it is
possible to design oral sustained release matrix containing furosemide.11
Deore et al., have investigated sustained release matrix tablets of tramadol hydrochloride using glyceryl
palmitostearate prepared by melt granulation or by direct granulation. Preformulation and post formulation
studies were performed and were found to be within the limits. In-vitro dissolution study was also performed
using USP 2 dissolution apparatus. Drug release from the tablets prepared by melt granulation was found to be
less when compared to that of direct compression from the equivalent formulation made by melt granulation. FTIR study has determined that there was no interaction between drug and polymer. The study showed that glyceryl
palmitostearate is an appropriate waxy matrix former for sustained release of water-soluble drug such as
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tramadol hydrochloride. From the study it was concluded that matrix tablets prepared by melt granulation
technique were far superior to those prepared by direct compression of the physical mixture.12
Chakrahari et al., have investigated sustained release matrix tablets of losartan potassium using HPMC, EC,
xanthan gum as polymers. Tablets were prepared by wet granulation method and formulated using different drug
and polymer ratios. Various preformulation and post formulation studies were performed and were found to be
within the limits. In-vitro dissolution study was also evaluated using USP 2 dissolution apparatus. From drug
release it was observed that increase in polymer concentration induce a decrease in release rate. The drug release
rate from xanthan gum matrix was found to be less as compared to HPMC K100M. Whereas formulation
containing EC has shown higher drug release as compared to formulation containing HPMC K100M and xanthan
gum. The use of gel forming methocel K100M was found to be successful in achieving the sustained drug release
for 10hrs. The kinetics of drug release was best explained by zero order equation. From FTIR and DSC studies it
was confirmed that there was no incompatibility between drug and various polymers.13
Khandai et al., have investigated sustained release matrix tablets of propranolol hydrochloride using both
hydrophilic and hydrophobic polymers. And also investigated the effects of both hydrophilic and hydrophobic
polymers on In-vitro drug release. Tablets were prepared by direct compression method using different
concentrations of HPMC and EC. Preformulation and post formulation studies were performed and were found
to be within the limits. In-vitro dissolution test was also evaluated using USP 2 dissolution apparatus from that it
was observed that 10% of each polymer in combination was able to produce desired formulation which release
more than 90% of drug in 12hrs. From the studies it was cleared that matrices undergo both swelling and erosion
at the same time after placing them in dissolution media. So, both swelling and erosion occurs simultaneously in
the matrix which helps in constant release of the drug from the matrices. Combination of both hydrophilic and
hydrophobic polymers can be used to produce the matrix tablet than using a single type of polymer. FT-IR
studies suggested that there was no interaction between pure drug and polymers and their combination used in
the study.14
8
ENCLOSURE-III
6.3) Objective of the study:
The present study is planned with the following objectives:
 To develop sustained release matrix tablet by dry granulation/ wet granulation/ by direct compression
Technique.
 Selection of appropriate polymers for the preparation of sustained release matrix tablets of Metformin
Hydrochloride.
 To perform precompressional parameters for granules like:
a. Angle of repose b. Bulk density c. Tapped density d. Carr’s index e. Hausner’s ratio.
 To perform post compression parameters like:
a. Hardness b. Friability c. Weight variation d. Content uniformity
 The developed formulations will be carried to study the drug and polymer interaction by FT-IR or DSC.
 To evaluate In-vitro release rate profile for the prepared formulation
9
ENCLOSURE-IV
7) Materials and Methods:
Materials:
Drug
: Metformin Hydrochloride
Polymers: Different grades of hydroxy propyl methyl cellulose (HPMC) /ethyl cellulose (EC)/eudragit /carbopol/
chitosan/ Poly vinyl pyrolidine (PVP) /xanthan gum/ guar gum and/or other appropriate polymers,
which will be used for preparation of formulations during the course of the study.
Binders: Different grades of micro crystalline cellulose (MCC), methyl cellulose, ethyl cellulose, poly ethylene
glycol, poly vinyl alcohols, poly vinyl pyrolidine,
gelatin, gums, starch, sucrose and other appropriate binders, which will be used during the course of
study.
Diluents: Different grades of lactose, sucrose, micro crystalline cellulose, starch, calcium carbonate, di and tri
basic calcium phosphate, and other appropriate diluents, which will be used during the course of
study.
Glidants: Magnesium stearate, talc, stearic acid and other appropriate glidants, which will be used during the
course of study.
Methods: Sustained release matrix tablets will be prepared by direct compression/dry granulation/wet
granulation technique and evaluated for In-vitro drug release.
7.1) Source of data:
Data is collected from:

Research publications.

Internet sources.

International and Indian journals.

Textbooks and references.
10
ENCLOSURE-V
7.2 Method of collection of data: (Including sampling procedure, if any)
 Evaluation of preformulation parameters like angle of repose by fixed funnel method, bulk density by
tapping method, Tapped density, Carr’s index and hausner’s ratio will be calculated by applying the
formulas.
 Post compression parameters like hardness using monsanto hardness tester, friability with roche
friabilator will be performed. Weight variation and drug content will be performed according to the
procedure and calculated by applying the formulas.
 FT-IR or DSC studies will be carried to study the drug and polymer interaction for the prepared
formulations.
 Standard curve will be estimated according to the procedure and will be measured by UV
Spectrophotometer at specified wave length.
 In-vitro release studies will be carried out using USP 2 dissolution apparatus.
11
ENCLOSURE- VI
8) List of references:
1. Brahmankar DM, Sunil B. Jaiswal. Bio pharmaceutics and pharmacokinetics, A Treatise. Vallabh Prakashan,
ind. 2009;41.
2. Modi AS, Gaikwad PD, Bankar VH, Pawar SP. Sustained release drug delivery system, A Review. Int J
Pharma Res Dev 2011;2(12):147-48.
3. Tripathi KD, essentials of medical pharmacology. 6thed, Jaypee publications, ind. 2008;268
4. Indian pharmacopeia 2007;1,2:154,1358.
5. Lipincott william and wilkins, Pharmacology. 4thed, Wolters kluver publications Ltd. 2009;293.
6. Goodman and Gilman’s, the pharmacological basis of therapeutics. 10thed, MC Graw-Hill Medical publishing
division. 2001;1705.
7. Rang and Dale’s, pharmacology. 6thed, Churchill living stone elsevier. 2007;405.
8. Samal BH, Srinivas SA, Dey S, Sharma H. Formulation and evaluation of sustained release zidovudine matrix
tablets. Int J Pharm Sci 2011;3(2):32-41.
9. Bhagwat AD, Kawtikwar SP, Sakarkar MD. Sustained release matrices of verapamil hydrochloride using
glyceryl monostearate and stearic acid. Res J Pharm Tech 2008;1(4):405-09.
10. Rahman MMD, Roy S, Das CS, Jha MK, Begum T, Ahsan QMD et al., Evaluation of various grades of
HPMC matrix systems as oral sustained release drug delivery systems. J Pharm Sci Res 2011;3(1):930-38.
11. Patil UK, Jain S, Yadav SK. Preparation and evaluation of sustained release matrix tablets of furosemide
using natural polymers. Res J Pharm Tech 2008;1(4):930-38.
12. Deore RK, Kavitha K, Theetha GT. Preparation and evaluation of sustained release matrix tablets of
tramadol hydrochloride using glycerl palmitostearate. Trop J Pharm Res 2010;9(3):275-81.
13.Chakrahari R, Shanmugan S, Sundaramoorthy S, Ayyappan T, VetriChelvan T. Formulation and evaluation
of sustained release matrix tablets containing losartan potassium. Int J Pharm Tech Res 2011;3:526-34.
12
14. Khandai M, Chakraborty S, Sharma A, Panda D. Development of propranolol hydrochloride matrix tablets:
An investigation on effects of combination of hydrophilic and hydrophobic matrix formers using multiple
comparision analysis. Int J Pharm Sci Rev Res 2010;2(1):1-7.
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