“PREPARATION AND EVALUATION OF EXTENDED-RELEASE
MATRIX TABLET OF AN ANTIHYPERTENSIVE DRUG USING
CHITOSAN/CARBOPOL INTERPOLYMER COMPLEX”
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
NISHA RACHEL MATHEWS
DEPARTMENT OF PHARMACEUTICS
PES COLLEGE OF PHARMACY
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
PROFORMA FOR REGISTRATION OF SUBJECTS FOR
1. Name of the candidate and address NISHA RACHEL MATHEWS
P.E.S COLLEGE OF PHARMACY,
2. Name of the institution P.E.S COLLEGE OF PHARMACY
3. Course of study and subject MASTER OF PHARMACY IN
4. Date of the admission 3rd May 2009
5. Title of the topic:
“PREPARATION AND EVALUATION OF EXTENDED-RELEASE
MATRIX TABLET OF AN ANTIHYPERTENSIVE DRUG USING
CHITOSAN/CARBOPOL INTERPOLYMER COMPLEX”
6. Brief resume of the intended work:
6.1 Need for the study:
Carbopol is a cross-linked polymer of acrylic acid with a high molecular weight that forms
a hydrogel in aqueous solutions. It has many advantages as a candidate for an extended-
release tablet matrix. E.g. a good gel-forming ability and mucoadhesive property.
It is difficult to control the drug release rate from the carbopol matrix and correlate the in-
vitro drug release with the in-vivo drug absorption due to its pH sensitivity. pH- dependant
drug release can cause in-vivo variability.
Interpolymer complex (IPC) has attracted considerable interest on account of its unique
characteristics due to a specific interaction between constituent polymers such as hydrogen
bonds, electrostatic interaction, van der waals force, or hydrophobic interactions. Among
them the formation of an IPC between poly(acrylic acid) and chitosan has been reported
due to an electrostatic interaction between the carboxylate group of poly(acrylic acid)as the
polyanionic polymer and the protonated amine group of chitosan as the polycationic
polymer. In a similar manner, the formation of an IPC between carbopol and chitosan
would be expected. This might solve the problem of the pH dependency of carbopol
because carboxyl groups which are the main factors affecting the pH-dependant drug
release, are complexed with chitosan.
The sustained release dosage forms are becoming popular as these have a number of
advantages over conventional dosage frequencies, less fluctuation in circulating blood
levels, increased patient compliance and more uniform effect. The main concept of
sustained drug delivery system are the use of system and techniques for altering and
controlling the absorption, blood levels metabolism, organ distribution and cellular uptake
of pharmacologically active agents. The main aim of a sustained or controlled release
dosage form is to produce an improved therapy by producing a uniform plasma
concentration of drug at steady state and by reducing the ratio of maximum and minimum
plasma levels after each dose. This could be achieved if the release of the drug form the
dosage form is slow first order or slow zero order absorption of drug occurs from the gastro
Antihypertensives are a class of drugs that are used to treat hypertension (high blood
pressure). The fundamental goal of treatment should be the prevention of the important
endpoints of hypertension, such as heart attack, stroke and heart failure. But most of the
antihypertensives have short half life and the usual oral dosage regimen is to be taken two
to four times a day. Its absolute bioavailability is also considerably low. Hence it is
desirable to develop a formulation that will improve the bioavailability as well as control
the release of these drugs. Also to reduce the frequency of administration and to improve
patient compliance, a once-daily matrix-type sustained release drug delivery system of
these drugs is desirable.
6.2 Review of the literature:
Betageri G.V, Deshmukh D.V and Gupta R.B have formulated a hydrogel-forming
bioadhesive drug delivery system for oral administration of didanosine (ddI).
Compressed tablets of ddI using Polyox WSRN-303, Carbopol 974P-NF, and
Methocel K4M as the bioadhesive release rate-controlling polymers were prepared.
The effect of polymer concentration on the release profile and in vitro bioadhesion of
the matrix tablets was studied. Tablet formulations with Polyox WSRN-303 (10%) and
Methocel K4M (30%) showed 93 and 90% drug release, respectively, after 12 h.1
Bonacucina G, Martelli S and Palmieri G.F have studied the Rheological,
mucoadhesive and release properties of Carbopol gels in hydrophilic cosolvents. The
aim of this work was to investigate the gelation properties of Carbopol 971 e 974
polymeric systems in water-miscible cosolvents such as glycerine and PEG 400. The
results obtained showed that Carbopol 971 and 974 in PEG 400 gave rise after heating
to gels that show a satisfactory rheological behaviour. Dissolution tests pointed out the
greater release control properties of PEG 400-Carbopol 971 samples. These studies
showed PEG 400-Carbopol systems as a first-rate alternative to traditional water gels.2
Chavasit V, Kienzle-Sterzer C and Torres J.A have studied the formation and
characterization of insoluble chitosan–polyacrylic acid polyelectrolyte complex.
Chitosan and polyacrylic acid mixtures were prepared in different mole ratios and at
different pH values and ionic strengths (0.025–0.300). Complex formation was
detected by turbidity measurement and quantified by weighing the freeze dried pellet
recovered by centrifugation. These studies showed that an electrostatic interaction
between COO– and NH3 + groups was involved in complex formation.3
Chavasit V and Torres J.A have studied the mechanism of complex formation and
potential industrial applications of Chitosan–poly(acrylic acid). The mechanism of
complex formation indicates that pH measurements could be used to monitor the
Cho S.M. and Choi H.K have prepared mucoadhesive chitosan–poly(acrylic acid)
microspheres by interpolymer complexation and solvent evaporation method to prolong
the gastric residence time of the delivery system. Results showed that microspheres
were formed by an electrostatic interaction between the carboxyl groups of the PAA
and the amine groups of the chitosan. Based on their mucoadhesive properties and
morphology, the chitosan-PAA microspheres can be used as a mucoadhesive oral drug
De la Torre P.M, Enobakhare Y, Torrado G and Torrado S have studied the release of
amoxicillin from polyionic complexes of chitosan and poly(acrylic acid) and conducted
the study of polymer/polymer and polymer/drug interactions within the network
structure. The swelling behavior and solute transport in swellable hydrogels were
investigated to check the effect of polymer/polymer and polymer/drugs interactions.
The swelling degree of amoxicillin sodium hydrogels was more extensive when
compared to the swelling degree of amoxicillin trihydrate formulations. It was
concluded that the water uptake was mainly governed by the degree of ionization.6
Gomez-Carracedo A, Alvarez-Lorenzo C, Gomez-Amoza J.L and Concheiro A have
studied the glass transitions and viscoelastic properties of Carbopol ® and Noveon®
compacts. These compacts which differed in cross-linking density and nature and
content in residual solvents, were analysed.7
Koleng J.J and McGinity J.W have investigated the feasibility of using two types of
carbomer (971 and 974) to prepare inhalable dry powders that exhibit modified drug
release properties. These powders offered the potential to reduce dosing frequency and
improve patient compliance.8
Lee I and Peppas N.A have studied the Prediction of polymer dissolution in swellable
controlled-release systems. A new mathematical model was developed to describe the
glassy polymer dissolution process by a thermodynamically compatible penetrant. The
theoretical predictions were verified by available experimental data from the fields of
controlled release and microlithography.9
Meshali M.M, El-Sayed G.M, El-Said Y and Abd El-Aleem H.M have carried out the
Preparation and evaluation of theophylline sustained release tablets. Different
formulations were prepared containing a new sustained-release agent (Carbopol®
974P). Carbopol 974P matrices exhibited release profiles which were best described by
mixed zero-order and Higuchi linear square root of time relationships. This means that
mixed barrier and matrix diffusion-controlled mechanisms were operative.10
Mi F.L, Shyu S.S, Kuan C.Y, Lee S.T, Lu K.T and Jang S.F have formulated the
Chitosan–polyelectrolyte complexation for the preparation of gel beads and controlled
release of anticancer drug. They have also studied the effect of phosphorous
polyelectrolyte complex and enzymatic hydrolysis of polymer. The results indicate that
the chitosan-polyphosphoric acid gel bead is a better polymer carrier for the sustained
release of anticancer drugs in simulated intestinal and gastric juice medium than the
chitosan-tripolyphosphate gel beads.11
Ranjani V. Nellore, Gurvinder Singh Rekhi, Ajaz S. Hussain, Lloyd G. Tillman and
Larry L. Augsburger have developed metoprolol tartrate extended-release matrix tablet
formulations for regulatory policy consideration. Several grades and levels of
hydroxypropyl methylcellulose (Methocel K4M, K15M, K100M and K100LV), fillers
and binders were studied. The results of this study led to the choice of Methocel
K100LV as the hydrophilic matrix polymer and fluid-bed granulation as the process of
choice for further evaluation of critical and non-critical formulation and processing
C.G.T. Neto, J.A. Giacometti, A.E. Job, F.C. Ferreira, J.L.C. Fonseca and M.R. Pereira
have studied the Thermal analysis of chitosan based networks. In this work two kinds
of material were studied: chitosan cross-linked with glutaraldehyde and in a blend with
PEO. It was observed by thermogravimetry that the water-polymer interaction will be
different for the cross-linked material compared to the blend, according to the specific
Peppas N.A and Sahlin J.J have designed a simple equation for the description of solute
release. A methodology is presented for general analysis of the release behavior of
controlled release systems using a coupled diffusion/relaxation model.14
Shieh J.J and Huang R.Y.M have carried out the pervaporation with chitosan
membranes using blend membranes of chitosan and polyacrylic acid and comparison of
homogeneous and composite membrane based on polyelectrolyte complexes of
chitosan and polyacrylic acid for the separation of ethanol-water mixtures were studied.
It was found that all membranes are highly water-selective.15
Vendruscolo C.W, Andreazza I.F, Ganter J.L.M.S, Ferrero C and Bresolin T.M.B have
formulated Xanthan and galactomannan (from M. scabrella) matrix tablets for oral
controlled delivery of theophylline. . The drug release decreased with the increase of
polymer concentration and all formulations at 25% w/w of gums showed excessive
sustained release effect. The release mechanism was a combination of diffusion and
Wang H, Li W, Lu Y and Wang Z have cerried out the studies on chitosan and
poly(acrylic acid) interpolymer complex. Preparation, structure, pH-sensitivity, and salt
sensitivity of complex-forming poly (acrylic acid): chitosan semiinterpenetrating
polymer network were also studied. Evidence from infrared spectra proved the
formation of polyelectrolyte complex through electrostatic interaction between NH+3
groups from CS and COO- groups from PAA.17
Zhong Z and Guo Q have studied the Interpolymer complexes and miscible blends of
poly(N-vinyl-2-pyrrolidone) with novolac resin and the effect of crosslinking on related
behaviour. The nature of the solvent has a profound influence on the degree of
interpolymer association. It was found out that the driving force in the formation of the
interpolymer complexes between novolac and PVP is the hydrogen-bonding interaction
between the hydroxyl of the novolac and the proton-accepting groups of PVP.18
6.3 Main objectives of the study:
The objective of the present study is as follows:
1. To formulate matrix tablets containing chitosan and carbopol interpolymer complex.
2. To characterize the interpolymer complex by FTIR and DSC.
3. To carry out the drug release profile of the various formulations.
4. To carry out the evaluation of the drug dissolution mechanism.
7. Materials and methods:
7.1 Source of data
The data will be obtained on experimental work,
a) Formation of the interpolymer complex.
b) In-vitro drug release study and evaluation of the IPC.
The data will be obtained from the literature survey.
7.2 Method of collection of data(including sampling procedures if any)
The data will be collected from the formulation studies, in vitro evaluation, and characterization of
the interpolymer complex by FTIR, DSC, and turbidity measurements.
7.3 Does the study require any investigation or interventions to be Conducted on patients or
other humans or animals?
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
8. List of references:
1. Betageri GV, Deshmukh DV, Gupta RB. Oral sustained release bioadhesive tablet
formulation of didanosine. Drug Dev Ind Pharm. 2001;27:129-36.
2. Bonacucina G, Martelli S, Palmieri GF. Rheological mucoadhesive and release
properties of Carbopol gels in hydrophilic cosolvents. Int J Pharm. 2004;282:115-30.
3. Chavasit V, Kienzle-Sterzer C, Torres JA. Formation and characterization of an
insoluble polyelectrolyte complex: chitosan-polyacrylic acid. Polym Bull. 1988;19:223-
4. Chavasit V, Torres JA. Chitosan-poly(acrylic acid): mechanism of complex formation
and potential industrial applications. Biotechnol Prog. 1990;6:2-6.
5. Cho SM, Choi HK. Preparation of mucoadhesive chitosan-poly(acrylic acid)
microspheres by interpolymer complexation and solvent evaporation method II. Arch
6. de la Torre PM, Enobakhare Y, Torrado G, Torrado S. Release of amoxicillin from
polyionic complexes of chitosan and poly(acrylic acid). Study of polymer/polymer and
polymer/drug interactions within the network structure. Biomaterials. 2003;24:1499-
7. Gomez-Carracedo A, Alvarez-Lorenzo C, Gomez-Amoza JL, Concheiro A. Glass
transitions and viscoelastic properties of Carbopol® and Noveon® compacts. Int J
8. Koleng JJ, McGinity JW. Carbomer. In: Kibbe, A.H. (Ed.) Handbook of Pharmaceutical
Excipients, 3rd ed. Pharmaceutical Press, London, UK. 2000:79-82.
9. Lee I, Peppas NA. Prediction of polymer dissolution in swellable controlled-release
systems. J Control Release. 1987;6:207-15.
10. Meshali MM, El-Sayed GM, El-Said Y, Abd El-Aleem HM. Preparation and evaluation
of theophylline sustained release tablets. DrugDev Ind Pharm. 1996;22:373-6.
11. Mi FL, Shyu SS, Kuan CY, Lee ST, Lu KT, Jang SF. Chitosan-polyelectrolyte
complexation for the preparation of gel beads and controlled release of anticancer drug.
I. Effect of phosphorous polyelectrolyte complex and enzymatic hydrolysis of polymer.
J Appl Polym Sci. 1999;74:1868-79.
12. Nellore RV, Rekhi GS, Hussain AS, Tillman LG, Augsburger LL. Development of
metoprolol tartrate extended-release matrix tablet formulations for regulatory policy
consideration. J Control Release. 1998;50:247-56.
13. Neto CGT, Giacometti JA, Job AE, Ferreira FC, Fonseca JLC, Pereira MR. Thermal
analysis of chitosan based networks. Carbohyd Polym. 2005;62:97-103.
14. Peppas NA, Sahlin JJ. A simple equation for the description of solute release. III.
Coupling of diffusion and relaxation. IntJ Pharm. 1989;57:169-72.
15. Shieh JJ, Huang RYM. Pervaporation with chitosan membranes.II. Blend membranes of
chitosan and polyacrylic acid and comparison of homogeneous and composite
membrane based on polyelectrolyte complexes of chitosan and polyacrylic acid for the
separation of ethanol-water mixtures. J Membr Sci. 1997;127:185-202.
16. Vendruscolo CW, Andreazza IF, Ganter JLMS, Ferrero C, Bresolin TMB. Xanthan and
galactomannan (from M. scabrella) matrix tablets for oral controlled delivery of
theophylline. Int J Pharm. 2005;296:1-11.
17. Wang H, Li W, Lu Y, Wang Z. Studies on chitosan and poly (acrylic acid) interpolymer
complex. I. Preparation, structure, pH-sensitivity, and salt sensitivity of complex-
forming poly (acrylic acid): chitosan semiinterpenetrating polymer network. J Appl
Polym Sci. 1997;65:1445-50.
18. Zhong Z, Guo Q. Interpolymer complexes and miscible blends of poly(N-vinyl-2-
pyrrolidone) with novolac resin and the effect of crosslinking on related behaviour.
Polym Int. 1996;41:315-22.
9. Signature of the candidate:
(NISHA RACHEL MATHEWS)
10. Remarks of the guide: Recommended
11. Name And Designation of:
11.1 Guide Dr.Satish C.S
Department of Pharmaceutics
P.E.S College of Pharmacy
11.5 Head of the department Mr. S.J Shankar
Asst.Professor & Head,
Department of Pharmaceutics,
P.E.S. College of Pharmacy,
12. 12.1 Remarks of the Chairman and Prof.Dr.S.Mohan,
Prnicipal: Director and Principal,
P.E.S College of Pharmacy,