a comparative study for interpenetrating polymeric

8/10/2019 A Comparative Study for Interpenetrating Polymeric

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AfricanJournalofPharmacyandPharmacology,Vol.4(2)pp.035-054,February2010

Availableonlinehttp://www.academicjournals.org/ajpp ISSN1996-08162010AcademicJournals

FullLengthResearchPaper

Acomparativestudyforinterpenetratingpolymeric

network

(IPN)

of

chitosan-amino

acid

beads

forcontrolleddrugrelease

Manjusha

Rani1,

Anuja

Agarwal1,

Tungabidya

Maharana2

and

Yuvraj

Singh

Negi2*

1Department

of

Chemistry,

J.

V.

Jain

College,

Saharanpur

(U.

P.)

India.2PolymerScienceandTechnologyProgram,DepartmentofPaperTechnology,

Saharanpur

Campus,

Indian

Institute

of

Technology,

Roorkee,

Saharanpur

(U.

P.)

India.

Accepted

13

January,

2010

ThepaperaddressesdevelopmentofnovelpHsensitiveinterpenetratingpolymericnetwork(IPN)

beads

composed

of

chitosan-glycine-glutamic

acid

cross

linked

with

glutaraldehyde

and

their

use

for

controlled

drug

release.A

comparative

study

hasbeen

carried

out

on

these

IPN

beads

with

the

beadsthatofchitosan,chitosan-glycineandchitosan-glutamicacidcrosslinkedwithglutaraldehyde.ThebeadswerecharacterizedbyFTIR toconfirm thecross linkingreactionanddrug interactionwithcrosslinkedpolymer

inbeads,scanningelectronmicroscopy(SEM)

tounderstandthe

surface

morphologyand

internalstructureand

DSCto

find

out

thethermalstabilityof

beads.Theswelling

behaviorof

thebeadsatdifferenttimeintervalswasmonitoredinsolutionsofpH2.0andpH7.4.Thereleaseexperimentswereperformed insolutionsofpH2.0andpH7.4at37Cusingchlorpheniraminemaleate(CPM)asamodeldrug.TheswellingbehaviorandreleaseofdrugwereobservedtobedependentonpH,degreeofcrosslinkingandtheircomposition.TheresultsindicatethatthenewlyconstructedcrosslinkedIPNbeadsofchitosan-glycine-glutamicacidmightbeusefulasavehicleforcontrolledreleaseofdrug.Thekineticsofdrugrelease frombeadswasbest fittedbyHiguchismodel inwhichrelease rateislargelygovernedbyrateofdiffusionthroughthematrix.

Key

words:

Cross-linked

beads,

chitosan,

chlorpheniramine

maleate,

glycine,

glutamic

acid,

controlled

drug

release.

INTRODUCTION

Polymersfrom

naturalresourceshavebeenstudiedintherecentpastastheimportant

materialforbiotech-nologicalandbiomedicalapplicationowingtotheiruniquecharacteristicssuchasbiologicalcompatibilitywithnaturalenvironment,non-toxicityandbiodegradability. Deacetylatedproductofchitinprovidesapolysaccharide

(1

4)

2

amino-2

deoxy

-

D

glucan

which

is

known

as

the

chitosan

and

is

one

of

the

wellknown

biodegradable

polymersmetabolizedbyhumanenzymes.Chitosancanbepreparedashydrogelbeads,havingapositivechargeatmetabolicandphysiologicalpH,bioadhesivityandwaterholdingcapacityenhancedintissuesofhumanbodyforextendedperiodoftime.Threedimensionalhydro-

*Correspondingauthor.E-mail:[email protected].

Tel:+91-132-2714328.

philic

polymer

networkofhydrogel

beads

are

capableofretaininglargeamountof

water

or

biofluids.Hydrogelsarethermodynamicallycompatiblewithwaterandexhibitswellinginaqueousmedia.Hydrogelshasresemblancewithnaturallivingtissuesduetotheirhighwaterretentioncapacity.Crosslinkedhydrogelnetworkcanbeobtained

by

cross

linking

chitosan

by

using

a

cross

linker

likeglutaraldehyde.

Their

properties

depend

mainly

on

thecrosslinkeddensity(theratioofmolesofcrosslinkingagenttothemolesofpolymerrepeatingunits).Formationofhydrogelnetworkrequiresacriticalnumberofcrosslinksperchainand it formsporousstruc-turewhoseporesizedependsuponswellingofbeadswhichinturndependsonexternalenvironment.Currently,chitosanisthepreferred

materialforcon-trolled

drug

delivery

devices

(Machida

et

al.,

1989;

CheinandYie,1983;Yaoetal.,1994;Yujietal.,1996;ChandyandSharma,1992;Chandyand

Sharma,

1993;Houetal.,


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036Afr.J.Pharm.Pharmacol.

Table1.CompositionofIPNbeadsandalignmentofthecolumn(Glutaraldehyde%)

Beadtype Chitosan(g) Glycine(g) Glutamicacid(g) 2%aceticacid(ml) Glutaraldehyde(%)

A1

A2

A3

A4A5

A6

A7

1.0

1.0

1.0

1.01.0

1.0

1.2

-

-

1.0

0.50.5

0.6

0.5

-

1.0

-

0.50.5

0.4

0.5

40

40

40

4040

40

40

12.5

12.5

12.5

12.525.0

12.5

12.5

1985;Miyazakietal.,1981;Leeetal.,1997).Theuse inthedevelopmentoforalsustainedreleasepreparationisbasedontheintragastricfloatingtabletsofchitosan(ShethandTossounian,1984;Inouyeetal.,1988).Moreover,theantacidandantiulcercharac-teristicsofchitosanpreventsorweakendrugirritationinthe

stomach

(Hou

et

al.,

1985).

Therefore,

chitosan

has

greatpotentialfor itsuseasasuitablecarrier incontrolleddrug

deliverysystems.However,therehavebeensomereportsonchitosanbasedbeadscrosslinkedwithglutaraldehyde

asoral

drug

deliverysystemcom-posedofchitosanandoneofthe

aminoacidslike

glycine(GuptaandRaviKumar,2000),glycine,glutamic

acid(KumariandKundu,

2008)andalanine(KumariandKundu,2007)toobtainbeadsfororaldrugdelivery.Ourpresentstudyisanattempttodevelopcrosslinkedbeadscomposedofchitosanandtwoaminoacidsasspacergroupscrosslinkedwithglutaraldehyde

forsustainedreleaseof

chlorpheniraminemaleateasamodeldrug

and

to

compare

it

with

cross

linked

beads

of

chitosan

and

chitosan-amino

acid.

We

have

prepared

four

types

of

beadscrosslinkedwithglutaraldehyde(a)chitosan(b)chitosan-glutamicacid(c)chitosan-glycine(d)chitosan-glycine-glutamicacidhavingdifferentcompositiontoinvestigate the comparative swelling behavior andmodelingdrugreleaseproperties.

MATERIALSANDMETHODS

Chitosan

was

purchased

by

India

Sea

Food,

Kerala

and

was

used

asreceived.Itspercentage

ofdeacetylation

afterdrying

was89%.Chlorpheniraminemaleate(CPM),C16H19ClN2C4H4O4wasobtainedas

agift

sample

fromSarthak

BiotechPvt.

Ltd.,

HSIDC,

Haryana,

India.

Glutaraldehyde,

glycine

and

monosodium

glutamate

wereprocured

from

SD

Fine

Chemicals

Ltd.,

Mumbai,

India,

SiscoResearchLaboratoriesPvt.Ltd.,IndiaandReidalChemicals, India

respectively.Allotherchemicalsusedwereofanalyticalgrade.Doubledistilledwaterwasusedinthroughoutthestudies.

Preparationofsemi-interpenetratingpolymernetwork(IPN)

beads

DifferentIPNbeads(A1-A7)varyingincompositionwereprepared

separately.Theircomposition

isdescribed

in

Table1.

Weighedquantityofchitosanandaminoacidweredissolvedin40mlof2%

acetic

acidbyweight

andstirredfor

three

hours

usingmagnetic

stirreratroomtemperature.Thehomogeneousmixturewasextru-dedintheformofdropletsusingasyringeintoNaOH-methanosolution

(1:20

w/w)understirring

condition

at400

rpm.The

beadswerewashedwithhotandcoldwaterrespectively.TheresultantbeadswereallowedtoreactwithglutaraldehydesolutionasgiveninTable1at50Cforabout10min.Finally,thecrosslinkedIPN

beads

were

successively

washed

with

hot

and

cold

water

followedbyairdrying.

Drug

loaded

beads

of

same

composition

were

also

preparedseparatelybyadding

aknown

amount

of

CPM(150mg,

200

mg)respectivelytothechitosan,aminoacidmixturebeforeextrudingintotheNaOH-methanolsolution.

Swellingstudies

Swellingbehaviorofchitosan

beads(A1-A7)werestudiedin

differentpH(2.0and7.4)solutions.Thepercentageofswellingforeachsampleattimetwascalculatedusingthefollowingformula.

Percentageofswelling={(Wt-Wo)/Wo}x100

Where;

Wt

=

weight

of

the

beads

at

time

t

after

emersion

in

thesolution.Wo=weightofthedriedbeads.

Drugloadingassay

Accuratelyweighed(0.1g)drug loadedsamplewaskept in100m

of2%aceticacidfor48h.AftercentrifugationtheCPMinthesupernatant

wasassayedbySpectrophotometerat193.5nm.

Drugreleasestudies

The

drug

release

experimentswere

performed

at37C

under

unstirredconditioninacidic(pH2.0)

andbasic(pH7.4)solution

Beads

(0.1

g)

containing

known

amount

of

the

drug

were

added

tothe

release

medium

(30

ml).

At

pre

decided

intervals,

samples

of

2mlaliquotswerewithdrawn, filteredandassessedby recording theabsorbanceat

193.5nm.

ThecumulativeCPMreleasewasmeasuredasafunctionoftime.

Kineticanalysisofdrugrelease

A fairamountofworkhasbeenincluded in literatureonkineticsof

drug

release

(Agnihotrietal.,2004;Laszlo

etal.,2006).A

largenumber

of

modified

release

dosage

forms

contain

some

sort

ofmatrixsystemandthedrugdissolvesfromthismatrix.Thediffusion


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Ranietal. 037

Figure1(a).Swellingbehaviorofcross linkedA1-A4beadsasa functionoftimeinsolutionpH2.0andpH7.4at37C.

patternofthedrugisdictectedbywaterpenetrationrate(diffusioncontrolled)

andthustheHiguchisequation(Higuchi,

1963)relationshipapplies

Mt/M=kt1/2

Where;Mt/Misthefractionaldrugreleaseattimetandkisa

constantrelated

to

the

structuraland

geometricpropertiesof

thedrug releasesystem.According toHiguchismodel,aninertmatrixshouldprovideasustaineddrugreleaseover

areasonableperiodoftimeandyieldareproduciblestraightlinewhenthepercentageof

drugreleasedisplottedversusthesquarerootoftime.

Characterization

of

IPN

beads

FTIRspectra ofIPNbeads

FTIRspectraofIPNbeadswererecordedusingathermoNicolet

Avatar370FT-IRspectrometersystemusingKBrpellets.

Scanningelectronmicroscopy (SEM)

The

shapeand

surfacemorphology

of

the

beads

were

examined

using

FESEM

QUANTA200

FEG

model

(FEI,

the

Netherlandsmake)withoperatingvoltagerangingfrom200Vto30kV.FESEMmicrographsweretakenaftercoatingthesurfacesofbeadsampleswithathinlayerofgoldbyusingBAL-TEC-SCD-005SputterCoater

(BAL-TECAG,Balzers,Liechtensteincompany,Germany)under

argon

atmosphere.

SEM

was

used

to

perform

textural

charac-terizationoffullandcrosssectionedIPNbeads,magnificationwere

applied

to

each

sample

in

orderto

estimate

the

morphologyand

interiorofthebead.

Thermalanalysis

Thermalgravimetricanalysis(TGA),Differentialthermalgravimetric

(DTG)and

Derivative

thermalanalysis(DTA)were

carried

outsimultaneouslybyusinga(PYRISDiamond).TG/DTAthermalanalyzermodelDSC-7,suppliedbyPerkinElmerand thedatawasprocessedandanalyzedbyPYRISmusemeasureandstandardanalysis

software

(V.3.3U;#.

2002Seiko

instruments

Inc.).

The

sample

was

kept

in

alumina

pan,

the

reference

material

wasaluminapowderandstudywascarriedoutatheatingrateo10C/minunder200ml/min flow rateofairornitrogenatmosphere.Indium

and

gallium

were

usedas

standards

for

temperaturecalibration.

RESULTSANDDISCUSSION

Swellingstudies

The

percentage

swellingofchitosanbeads(A1

-A4)

cross linkedwithglutaraldehyde insolutionofpH2.0and7.4isshowninFigure1(a).Itwasobservedthatswellingrate

followed

order

as

follows

AtpH-2.0 A2


4/20


Figure

1(b).

Swelling

behavior

of

cross

linked

A4-A7

beads

as

a

function

of

time

in

solutionpH2.0andpH7.4at370C.

inacidicsolution

whichmaybeduetothepresenceoffreecarboxylicendsofthechitosan-glutamicacidIPNandthefreecarboxylicendsaremorelikelytobeattackedbybasicsolution.Incaseofchitosan-glycine-glutamicacidbeads,their

rateofswellingwasalsofoundtobehigheratpH2.0thanchitosan-glutamicacidandchitosan-glycinebeadsandatpH7.4,theirrateofswellingisintermediatebetweenchitosan-glutamicacidandchitosan-glycine

beads.

Thus

it

was

concluded

that

over

all

rate

of

swellingwasaffectedbyglycinewhenchitosan-glycine-glutamicacidbeadsweresubjectedtoswellingstudies.Theswelling

behavior

ofthe

cross

linkedchitosan-glycine-glutamicacid

beads(A4

-A7)asa

functionoftimeinsolution

pH

2.0

andpH

7.4has

beenshown

inFigure1(b).

Itwasobserved

that

the

swelling

ratewasdecreasedon

increasingconcentrationofcrosslinkerglutaraldehyde.Theobservedswellingrates

ofA4crosslinkedbeadswerefoundtobehigherthantheswellingratesofA5bead,becauseinA5beadsthehigherconcentrationofglutaraldehydeincreasedthedegreeofcrosslinking,whichdecreasedthedegradationofcross

linked

polymer.

Further,

the

percentage

of

swelling

wasfound

to

be

higher

in

acidic

solution

than

in

basicsolution.Thechangeinaminoacidscomposition,(thatis,

decreaseinglutamicacidconcentrationandincreaseinglycineconcentration)ofcrosslinkedbead(A6)havingsame

concentrationofglutaraldehydeas

compare

toA4bead

hasalso

been

studied

and

observed

thattheincrease

in

concentration

ofglycine

decreased

the

swel-lingpercentageof


acidbeadsinbasicsolutionwhileincreasedinacidicsolution.Thepercentageofswellingof

thecrosslinkedbeads

havingthesameconcentrationofcrosslinkerdecreased(A7A4).ItcanbeexplainedasthepercentageofaminoacidsactingasaspacerincreasedinA4beads(25%)ascomparedtoA7beads(22.7%)andalsochitosanpercentagedecreasedinA4beads(50%)ascomparedtoA7beads(54.5%),theporesizeofA7beadsalsodecreasedand thepenetrationofsolutioninto thebeadsbecomedifficult,whichresult in lesserdegreeofswelling

(Kumari

and

Kundu,

2008).

SEMstudies

SEMmicrographsofdriedbeads(A1-A7)andtheir

surfacemorphologyareshown inFigures2aandbwhile,thecrosssectioneddriedbeadsandtheirinternastructureareshowninFigures3aandb.ItwasconcludedfromFigures2aandbthatthebeadswerenearlysphericalorsomewhatovalinshapeandtheirapproximatesizevariedfrom1.2to1.8mm.Cross linked

chitosan

amino

acid

beads

(A2

-

A7)

had

rough,

rubbery,fibrous

and

folded

surfaces

as

com-pared

to

chitosanbeads(A1)whichhadrelativelysmooth

surfaces

withfewwrinkles.

Withthe

higherconcentrationof

crosslinker,incaseofA5thechainscomecloser toeachotherandexhibitaregular,fibrousstructureascomparedtoA4having

lower

concentrationof

glutaraldehyde.A7beadsconstituting

higherconcentration

ofchitosan

showedmoreregularfibroussurfacesascomparedtoA4due

tothesmallerconcentrationofspaceraminoacid.Duetothisreasonthechaincameclosertoeachotherdespiteofhavingthesamedegreeofcrosslinker.Theinternal


5/20

Ranietal. 039

Figure2a.SEMphotographsofchitosan-aminoacidcrosslinkedbeads(A1A4)andtheirmorphology

(A1*-A4*).


6/20


Figure2b.SEMphotographs ofchitosan-aminoacidcrosslinkedbeads(A5-A7)andtheirMorphology(A5*-A7*).


7/20

Ranietal. 041

Figure3a.SEMphotographsofcrosssectionedchitosan-aminoacidcross linkedbeads (A1A4)andtheirinternalstructure(A1*-A4*).


8/20

peak

at1384cm wasassignedtoCH3symmetricalde-

deacetylationofchitosan.Peakobservedat2924cm is

NH-stretchingvibrationsin-NH-COCH3 at1639cm o

at1567cm ofthenewlyformedstructurebetweenamino


Figure3b.SEMphotographsofcrosssectionedchitosan-aminoacidcrosslinkedbeads(A5A7)andtheirinternalstructure(A5*-A7*).

structureofbeadsappearedtohavemicroporesaswere

seeninSEM(Figures3aandb).

FTIRstudies

Figure4(a)showstheFTIRspectraofchitosanpowder,

glutamicacid,glycineandA1-A7drugunloadedbeads.An

FTIR

spectrum

of

chitosan

powder

curve

(A)

has

showntwopeaksaround894and1171cm-1corres-

pondingtosaccharidestructure(Yoshiokaetal.,1990).Theobservedpeakat1613cm

-1canbeassignedas

aminoabsorptionpeak.Theabsorptionpeakforamidewereobservedat1639and1319cm

-1andobserved

-1

formationmode(Pengetal.,1994;Sannanetal.,1978).

Abroadbandappearingaround1083cm-1indicated

the>CO-CH3stretchingvibrationofchitosan.Another

broad

band

at

3450

cm-1

wasdue

to

the

amine

N-H

symmetricstretchingvibrationwhichmightbedueto-1

typicalofC-Hstretchingvibration.simultaneouslythe

peakassignedforaminoabsorptionat1613cm-1in

originalchitosanbroadenedordisappearedincrosslinkedbeadsandanewpeakappearingatabout1567cm

-1

due

to

imine

bond

(-C=N-)

which

was

formed

as

aresultofcrosslinkingreactionbetweenaminogroupinchitosanandaldehydicgroup inglutaraldehyde(Bellamy,1980;Leeetal.,1999)incurveA5-A7.Howeverthiswas

due

tothe

overlapping

ofpeaks

correspondingto

-1

theoriginalchitosanwiththatofimino(-C=N-)stretching-1

groupofchitosanandaldehydegroupofglutaraldehyde

inA2-A4.Areactiontakingplaceintheformationof


9/20

correspondingto1567cm was sharpened and distinct

Ranietal. 043

Figure

4(a).

FTIR

spectra

of

glutamic

acid

(A),

glycine

(B),

chitosan

powder

(C)

and

drug

unloaded

cross

linkedbeads(A1-A7).

cross-linkisasfollows

-NH2 + O=HC- -N=CH-

Amino aldehyde imino(Chitosan) (Glutaraldehyde) (Crosslink)On increasingtheglutaraldehydeconcentration, thepeak

-1

inA5.AllthecurvesA1toA7showedadditionalpeaksofaminoacid.

FTIRspectral

dataof

drug

loadedbeads

inFigure4b

were

usedtoconfirmthechemicalstabilityofCPM inchitosanaminoacidbeads.FTIRspectraofpureCPMdrug(curveD)andCPM loadedcross-linkedbeads(A1-A7) inFigure4bwerecomparedwithdrugunloadedcross-linkedbeads(A1-

A7)

inFigure4a.


10/20

bandataround864cm duetoaromaticC-Clstretching.


Figure

4(b).

FTIR

spectra

of

pure

CPM

drug

(D)

and

drug

loaded

cross

linked

beads

(A1

-

A7).

CPMhasshowncharacteristicbandat2966and2917cm

-1

due

to

aliphaticC-Hstretching.

The

band

at

1619and1588cm

-1duetoC=Nstretchingvibration.While

thoseof1476and1432cm-1areduetoaromaticC=C

stretchingvibration.CPMhasalsoshowncharacteristic-1

Whendrugwasincorporatedintothe crosslinked

chitosan-aminoacidbeads,alongwithallthecharacteris-

ticband

ofthe

crosslinked

chitosan

and

amino

acidsadditionalbandhave

appearedduetothepresenceofCPMinthematrix.ItindicatesthatCPMhasnotundergoneanychemicalchangewithinthebeads.

THERMALANALYSIS

TGAexperimentswerecarriedoutonchitosan,glutamic


11/20

by

chitosan

powder

(curve

A)

below

100C

due

to

loss

of

Ranietal. 045

Figure5(a).TGcurvesforchitosanpowder(A),glutamic acid(B),glycine(C)anddrugunloadedcrosslinkedbeads(A1-A7).

acid,glycineandcrosslinkeddrugunloadedbeadsA1-

A7

and

the

curve

obtained

are

presented

in

Figure5awhichclearlyshowsthatapproximately10%

weight

loss

o

freewater.Afterthis,weightlossremainsconstantupto

249C.Asuddenweightlossisobservedafter249Cand


12/20


Figure

5(b).

TG

curves

for

pure

CPM

drug

(D)

and

drug

loaded

cross

linked

beads

(A1-A7).

thetotalweightlossat400Cisabout60%,whereaspurechitosancross linkedbeads (A1)showsweight lossafter200Candweightlossat400Cisapproximately46%,

lesser

than

chitosan

powder

thisshows

thatcrosslinkingofchitosanwithglutaraldehydeincreases

itsthermalstability.Similarly,chitosan-glutamicacid,

chitosan-glycineand

chitosan-glycine-glutamicacidbeadsshowweight lossat400Cabout50,43,and45%respectivelywhichclearlyindicatethatchitosanaminoacidspecially,

chitosan-glycine-glutamicacidbeadsareasthermallystableaschitosanbeads(A1)andthermalstabilityofchitosan-glycine-glutamicacidbeadsisgreaterthanchitosan-glutamic

acid

beads

and

slightly

lesser

than

thatofchitosan-glycinebeads.TG

curvesfor

CPMmodel

drug

(curve

D)and

drugloaded

crosslinked

beads

(A1

-

A7)

are

shown

in

Figure5b.CPMdruglostabout67%weightbetween208and274C(curveD)whichwasduetothedecompositionof


13/20

Ranietal. 047

Figure6(a).DTGcurves forchitosanpowder(A),glutamicacid(B),glycine(C)anddrugunloaded

cross

linked

beads

(A1

-

A7).

ofdrug

above

itsmeltingpoint.

Melting

point

ofCPM

is134Candsuchahuge loss inweightwasnotshownbydrug loadedbeadsA1-A7.Thisconcluded that thedrugisquitestablewithinthebeads.DTGthermogramsofpurechitosan,glutamicacid,glycineandcrosslinkedbeadsA1-A7arepresentedinFigure6a.Theseindicated

the

rate

of

weight

loss

for

chitosan

powder

washighest

at

290C

and

cross

linked

chitosan

beadsshowed

lesserrateofweightlossat244C.Oncomparing

A1 -A4

beads

it

can

be

concluded

that

chitosan-glutamicacid-glycinebeadswerefoundtobemoststableasthelossweightathighesttemperature(271C)ascomparedtochitosanbeadsat244C,chitosan-glutamicacidbeadsat249Candchitosan-glycinebeadsat268C.DTGcurves

for

CPMdrugand

drugloadedcrosslinkedbeadsareshown

inFigure6b.CurveDforpure

CPM

drug

have


14/20


Figure6(b).DTGcurvesforCPMdrug(D)anddrugloadedcrosslinkedbeads(A1-A7).

peaksforweightlossat134,207and256C.

ThecomparisonofdrugunloadedbeadsA1-A7in

Figure

6a

and

drug

loaded

beads

A1

-

A7

in

Figure

6b

showed

almost

similar

peaks

with

same

rate

of

weight

lostalsoproveddrugstability

inthepolymericmatrix.DTA

thermograms

forpure

chitosan,

glutamicacid,glycineand

cross

linked

drug

unloadedbeads

(A1-A7)arepresentedinFigure7a.Thermogramsforchitosanpowdershowedoneendothermicpeakat65Cduetolossoffreewaterandoneexothermicpeakat296Cduetochemicaltransformation.Glutamicacidgivestwoandglycinegivesoneendothermicpeakintheirthermograms.While incaseof(A1-A4)beadsonlyoneexothermicpeakisobserved.Itwasconcludedthatchitosan-

glycine-glutamicacidbeadsarethemoststableasinthermograms forA1-A4beadsexothermicpeakmoves

towards

higher

temperature

(240

to

274C).

DTA

thermograms

for

pure

CPM

drug

and

drug

loaded

beads

A1-A7are

represented

in

Figure7(b).

Incase

ofCPMdrug(curve

D)one

endothermicpeakand

one

exothermicpeakwereobserved.Oneat134Cwhichcorrespondstomelting

processand

otherat254C

to

chemicatransformation.Drugloadedbeads(A1-A7)showedalmostsimilar

thermogramsinwhichnopeakswereobservedat134and254Cindicatingtheamorphousdispersionofdruginto thebeads(AgnihotriandAminabhavi,2006;Kulkarnietal.,2007).


15/20

Ranietal. 049

Figure

7(a).DTAcurvesfor

chitosanpowder(A),glutamicacid(B),glycine(C)anddrugunloadedcrosslinkedbeads(A1-A7).

Drugloadingassay

When(1g)drugloadedsamplewaskeptin100ml

2%

aceticacid,thetotaldrugreleasedafter48hwasfoundtobe78gand142gforthebeadsincorporatedwith

150and200mgofCPMrespectively.

Drugreleasestudy

Figures8aand

bshowsthereleaseprofileof

CPM


16/20


Figure7b.DTAcurvesforCPMdrug(D)anddrugloadedcrosslinkedbeads(A1-A7).

fromchitosanbeads(78gofdrugloadedbead)atvarioustime

intervalsin

acidic(pH2.0)and

basic(pH7.4)

at

37C.

There

wasa

burstrelease

initiallyfor

thefirsthourinbothacidicandbasicmediafollowedbyamoderatereleasefornextfourhoursandfinallyanalmost

constant

releaseofCPM

fromthe

matrixforthestudiedperiodof48h.Theamountandpercentage

ofdrug

releasedfollowedtheorderofswellingofbeads.Itisbecause

the

release

rate

depends

on

swelling

of

thebeads.

It

was

noticed

that

drugrelease

waspHdependentandfollowedthefollowingorderinacidicandbasicmedium

AtpH2.0 A2


17/20

Figure8(a).ReleaseofCPMforA1-A4beads(78gCPM

loadedbeads)vstimeinsolutionpH2.0andpH7.4at37C

Figure8(b).ReleaseofCPM forA4 -A7beads(78gCPM

loadedbeads)vstimeinsolutionpH2.0andpH7.4at37C.

AtpH7.4 A3


18/20

%drugrelease


Figure9a.ReleaseofCPMforA1-A4beads(142gCPMloadedbead)vs.timeinsolutionpH2.0andpH7.4at37C.

Figure9b.ReleaseofCPMforA4-A7beads(142gCPM loaded

bead)vs.timeinsolutionpH2.0andpH7.4at37C.

thekineticdataofdrugrelease.Linearplotsofpercent

cumulativeamountreleaseversussquarerootoftimeisshowninFigure10demonstratingthatthereleasefromthecrosslinkedpolymericmicrospherematrixisdiffusioncontrolled

and

obeys

the

Higuchis

model

(Jameela

et

al.,

1998).Theconstantk,presentedinTable2wascalculated

fromtheslopeof

the

linear

portion

of

plotof

percentageof

cumulative

drug

released

versusthesquarerootoftime.Thevalueof

k

forthereleaseprocess

has

beenfound tobe lower insolutionofpH7.4 than insolutionofpH2.0exceptforA2beads.However,thevaluesweresmallerwhichindicatemildinteractionbetweenthedrugandpolymericmatrices(Orientietal.,1996;Ganza-Gonzalezetal.,1999).

Figure10a.PlotsshowingdrugreleaseprofilefromA1-A4beads

(78gCPM

loaded)

in

solutionpH2.0

andpH

7.4

by

fitting

the

Higuchis

equation.

A4pH2 A5pH2 A6pH2 A7pH2

A4pH7.4

A5pH7.4

A6pH7.4 A7pH7.4

60

50

40

30

20

10

0

0

1 2

3

t1/2

Figure10b.Plotsshowingdrugreleaseprofile fromA4-A7beads

(78

g

CPM

loaded)in

solution

pH

2.0

and

pH

7.4

by

fitting

theHiguchisequation.

Conclusion

Theobservationsofthepresentstudyhaveshownthat


acid

beads

posses

a

pHdependentswellingbehavior. Itcanbeusedsuccessfullyfortheformulationofcontrolleddrugdeliverydevices.Theyhaveoptimumentrappingcapacityforthestudieddrugsandprovideasustainedreleaseofdrugsforextendedperiodswhichmakethemappropriatefordelivery

of

drug

at

a

controlled

rate.

ACKNOWLEDGEMENT

Authorsaregrateful

to

Prof.B.Gupta,

Bioengineering


19/20

Ranietal. 053

Table2.ResultsofdrugreleasemechanismbyfittingdatainHiguchismodelforCPMloadedbeads.

pH2.0 pH7.4

Beads

type

CPMloadedbeadswith

78g 142g 78g 142g

K S.D. R K S.D. R K S.D. R k S.D R

A1

A2

A3

A4

A5

A6

A7

.15

.12

.19

.26

.22

.28

.21

.013

.011

.019

.030

.025

.031

.024

.99

.99

.99

.99

.99

.99

.99

.13

.10

.19

.20

.195

.20

.19

.015

012

.021

015

015

.011

.015

.99

.99

.99

.99

.99

.99

.99

.074

.24

.058

.10

.078

.061

.085

.055

.027

.048

.089

.081

.048

.052

.98

.99

.97

.99

.95

.98

.99

.081

.198

.064

.083

.078

.061

.085

.01

.021

.074

.083

.086

.083

.087

.99

.99

.99

.99

.99

.98

.99

Figure

10c.

Plots

showing

drug

release

profile

from

A1-

A4

beads(142

g

CPM

loaded)in

solution

pH

2.0

andpH7.4byfittingtheHiguchisequation.

Figure10d.Plotsshowingdrugreleaseprofile fromA4-A7

beads(142gCPM loaded)insolutionpH2.0andpH7.4

byfittingtheHiguchisequation.

Laboratory,TextileDepartment,

IIT,

Delhi

forgiftingchitosansampleandtechnicalhelp.

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