International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 3, Issue 3, 2011

ResearchArticle

DEVELOPMENTANDEVALUATIONOFMUCOADHESIVETABLETSOFCLOTRIMAZOLEAND
ITSCYCLODEXTRINCOMPLEXFORTHETREATMENTOFCANDIDIASIS

A.S.DHAKE*,DATTATRAYAMSHINKARa,SOMASHEKARSHAYLEb,SANJAYBPATILc,CHITRALMSETTYd
*PrincipalandProf.S.M.B.T.CollegeofPharmacy,Dhamangaon,Tal.Igatpuri,Dist.Nashik.Maharashatra,DepartmentofPharmaceutics,
KCTSRGSCollegeofPharmacy,Anjaneri,Nashik,Maharashtra,India,DepartmentofPharmaceutics,V.L.CollegeofPharmacy,Raichur,
Karnataka,India,DepartmentofPharmaceutics,S.N.J.BSSSDJCollegeofPharmacy,Chandwad,Maharashtra,India,Departmentof
Pharmaceutics,SarasawathiCollegeofPharmaceuticalSciences,Yethbarpally,Hyderabad,AP,IndiaEmail:dattshinkar@gmail.com
Received:28March2011,RevisedandAccepted:29April2011

ABSTRACT
Clotrimazoleisanantifungalagentwidelyusedasafirstlinetreatmentfororalcandidiasis.Clotrimazoleisapoorlywatersolubledrug,sosolubility
is mainconstraints forits oral bioavailability.An attempthas been madeto increase itssolubility by complexationwithcyclodextrin and then
formulatingmucoadhesivetabletsofbestformulationwithcyclodextrin.Mucoadhesivetabletformulationswerepreparedbydirectcompression
techniqueusingvariousconcentrationsofHPMCK4M,Carbopol934pona10stationpilotpressusing13mmflatfacedpunches(PPID,Chamunda,
India).All theformulationswereevaluatedfor weightvariation,hardness,thickness,% swellingindex,mucoadhesivestrengthandinvitro drug
release of the drug in simulated saliva solution pH 6.8. In vitro drug release of clotrimazole was best explained by zero order equation and
formulations F1 to F5 were found to be following anomalous diffusion and F6 was found to be following fickian diffusion. The formulations F5
showedmaximumdrugreleasefor12hstudy,thereforethisformulationwasoptimizedbycomplexingtheclotrimazolewithcyclodextrin(1:1
molarratio)whichresultedinincreasethedissolutionrateoftheformulationF6.Thestabilitystudiesshowedthatthereisnodecreaseinthedrug
contentofallformulationsfortheperiodof3months.
Keywords:Mucoadhesivetablet,Clotrimazole,cyclodextrin,HPMC,Carbopol934p.

INTRODUCTION
The major disorders of the oral cavity are toothache, periodontal
diseases,dentalcaries,bacterialandfungalinfectionsandaphthous
stomatitis. Candidiasis, commonly called yeast infection or thrush,
occurs commonly in the mucous membranes of the mouth. Oral
thrushreferstotemporarycandidiasisinthemouthofbabies,whilst
if occurring in the mouth or throat of adults, is a fungal infection
(mycosis)ofanyoftheCandidaspecies,ofwhichCandidaalbicansis
the most common1,2. Candida infections of the latter category are
alsoreferredtoascandidemiaandareusuallyconfinedtoseverely
immunocompromisedpersons,suchascancer,transplant,andAIDS
patients, whereas superficial infections of skin and mucosal
membranesbyCandidacausinglocalinflammationanddiscomfortis
commoninmanyhumanpopulations.
Typicalsymptomsofcandidiasisare,Soreandpainfulmouthwith
aburningtongueandalteredtaste.Oropharyngealcandidiasiscan
impair speech, nutritional intake, and quality of life. Although it
affects patients who used antibiotics or corticosteroids for a long
time, it is also commonly people with poor nutrition, specifically
vitaminA,ironandfolatedeficiencies.Worldwide,3040%ofthe
38600000peoplein2005estimatedtobelivingwithHIVarein
need of highly active antiretroviral therapy (HAART) on
Oropharyngeal candidiasis. In Europe, North America, Mexico,
Thailand, and South Africa, oral candidiasisis observed in 5067
% of children, and is considered the most common oral
manifestation of HIV infection. Oropharyngeal candidiasis occurs
in up to 55 % of people with HIV infection and in over 90 % of
those with advanced disease. To prevent and treat the Oral
candidiasis clotrimazole is widely used as first line treatment for
localeffectinthemouth 3,4.
In the present investigation an attempt has been made to
develop controlled release mucoadhesive tablets containing an
antifungal agent, clotrimazole to release the drug
unidirectionalllyinbuccalcavityforextendedperiodsoftimefor
improvement in bioavailability, to reduce the dosing frequency
and to improve the patient compliance for an effective and safe
therapy of oral candidiasis. Since the drug has poor absorption
window orallyand highlylipophilic,thereforeit was planned to
improve its solubility, by forming inclusion complex with
cyclodextrinforoptimizedformulationandtostudytheeffect of
hydrophilic additives like HPMC K4M, and Carbopol 934P on
releaserateofthedrug.
MATERIALSANDMETHODS
Clotrimazolewas agift sample fromUnique Pharmaceutical Pvt. Ltd,
(Mumbai, India). cyclodextrin, Carbopol 934P, talc and mannitol
were obtained from Danmed Pharmaceuticals Pvt. Ltd., (Hyderabad,
India). Magnesium stearate was procured from S.D. Fine chemicals
limited,(Mumbai,India).Othersusedwereofanalyticalreagentgrade.
Preparation and characterization of clotrimazole
cyclodextrincomplex
Equimolar amounts (1:1 molar ratio) of clotrimazole and
cyclodextrin were weighed. Clotrimazole was dissolved in acetone
andkneadedthoroughlywithcyclodextrininacleananddryglass
mortar for 4 h. The paste formed was dried under vacuum for 4 h.
Dried powder was passed through sieve # 120 and stored in a
dessicatoruntilfurtherevaluation.
SolubilitystudyThe solubility of both the drug and clotrimazole
cyclodextrininclusioncomplexwasdeterminedindistilledwater,
methanol, ethanol and phosphate buffer pH 6.8 according to the
methodproposedbyDiezet.al.5.Triplicatereadingsweretakenand
averagewascalculated.
Differential scanning calorimetry Differential Scanning
calorimetrywasusedtoconfirmtheformationofinclusioncomplex.
DSCanalysiswasconductedbyusing(PerkinElmerDSC7,U.S.A.)at
a heating rate of 10/ min over a 30 3000 C or 30 225 C (
cyclodextrin or Clotrimazole) temperature range. A nitrogen purge
was maintained throughout runs and base line optimization was
performedbeforeeachrunrange25mg(3.7mg).
PowderXraydiffractionTheXraypowderdiffractionpatternsof
the samples, clotrimazole, cyclodextrin and clotrimazole
cyclodextrininclusioncomplex,weremeasuredbyusingPhilipsPW
1729/ 1710 Xray diffractometry (Holland) with Cu as anode
material, operated at a voltage of 40 kV, 30 mA. The samples were
analyzedbycontinuousscanintherangeof5500at2angle and
the process parameters were set as scan step size of 0.020 (2),
scansteptimeof0.5sec.
PreparationofmucoadhesivetabletsMucoadhesivetabletswere
prepared by direct compression method. The blended powder was
evaluatedforitsrheologicalcharacteristicsandthencompressedon
10stationpilotpressusing13mmflatfacedpunchestoproducean
approximate weight of 300 mg tablet. The composition of all
formulationsisshownintable1.
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Table1:Compositionofmucoadhesivetabletsofclotrimazole.
Ingredients F1F2F3F4F5F6*
Clotrimazole(mg) 100 100 100 100 100
cyclodextrincomplexequivalentto _ _ _ _ _ 429
100mgdrug
HPMCK4M(mg) 60 60 60 90 90 90
Carbopol934P(mg) _ 60 90 60 90 90
Talc%w/w 6 6 6 6 6 13
Magnesium 3 3 3 3 3 6.5
stearate%w/w
Mannitol(mg) 131 71 41 41 11 21.5
Totaltabletweight(mg) 300 300 300 300 300 650
Theweightoftabletis650mg.
*

Evaluationofpowderblend Thickness Thickness of tablet was measured using Vernier

There are many formulations and process variables involved in
mixing step and all these can affect characteristics of blend
produced. Angle of repose, bulk density, true density and percent
compressibilityindexhavebeenmeasuredwhicharegivenintable
3.
Angleofrepose
The friction forces in loose powders can be measured by angle of
repose (). It is an indicative of flow properties of powder. The
powdermixturewasallowedtoflowthrough cutstemfunnelfixed
to a stand at a height (h) from the plane. The angle of repose was
thendeterminedbymeasuringtheheightandradiusoftheheap of
thepowderformed.
=tan1h/r
Where, h = height of heap of powder/granule blend, r = radius of
heapofpowderblend.
Bulkdensity(Db)
It is the ratio of total mass of powder to the bulk volume of the
powder. It was measured by pouring weighed powder into
measuringcylinderandinitialvolumewasnoted.Thisinitialvolume
wascalledthebulkvolume.Fromthisbulkdensitywascalculatedby
according to formula given below. It is expressed in gm/ml and is
givenby
Db=M/Vb
WhereMisthemassofpowderandVbisbulkvolumeofthepowder.
Tappeddensity(Dt)
It is the ratio of total mass of powder to the tapped volume of the
powder.Volumewasmeasuredbytappingthepowderinmeasuring
cylinder for 100 times and then tapped volume was noted. It is
expressedingm/mlandisgivenby
Dt=M/Vt
Where M is the mass of powder and Vt is tapped volume of the
powder.
PercentagecompressibilityIndex
It indicates powder flow properties. It is expressed in percentage
andisgivenby
I=DtDb/Dtx100
Where I is the % compressibility index of the powder, D t is the
tappeddensityofthepowderandDbbulkdensityofthepowder.
Evaluationofmucoadhesivetablets
Weight uniformity Ten tablets were taken and weighed
individually.Averageweightwascalculatedandstandarddeviation
wascomputed.
Hardness Hardness or crushing strength of tablet was measured
usingPfizerhardnesstester.ItisexpressedinKg/cm2.
calipers.Threetabletswereselectedatrandomfromeachbatch.Itis
expressedinmm.
Friability Percentage friability of the tablet was determined by
usingRouchfriabilator.
Swelling studies6,7 The degree of swelling of mucoadhesive
polymer is an important factor affecting adhesive. For conducting
study, threetabletswere weighedindividually (W1) andimmersed
in a petridishes containing simulated saliva fluid (pH 6.75) for
predeterminedtimes(0.25,0.5,1,2,4,8h).Afterimmersiontablets
werewipedoffbytheexcesssurfacewaterbytheuseoffilterpaper
and weighed (W2). The percent swelling index was calculated by
usingthefollowingformulaandresultsweresummarizedintable5.
%SwellingIndex=[W2W1]/W2x100
Where,W1istheinitialweightofthetablet,W2istheweightofthe
tabletaftertheparticularswellingtimeinterval.
SurfacepHThesurfacepHofthetabletswasdeterminedinorder
toinvestigatethepossibilityofanysideeffects,ontheoralcavity.As
acidic or alkaline pH is found to cause irritation to the buccal
mucosa,henceanattempthasbeenmadetokeepsurfacepHcloseto
the neutral pH. Three tablets were allowed to swell for four h in
distilledwaterandpHwasfoundoutbyplacingtheelectrodeofpH
meterjustincontactwiththesurfaceofthetablets.Averageofthree
readingswascomputed.
Drug content uniformity Randomly ten tablets from each batch
were weighed accurately and powdered; the equivalent weight of
100 mg of clotrimazole was taken and made the volume up to 100
ml with methanol in 100 ml volumetric flask and kept aside with
constant shaking for 24 h to extract the total drug present in the
tablet.Thenthesolutionwasfilteredandthevolumewasmadewith
methanol and analyzed for drug content at max of 262 nm.
Averagesoftriplicatereadingsweretaken.
DeterminationofinvitroMucoadhesionstrength8
Mucoadhesive strength of the tablets was conducted on modified
physicalbalance.Theapparatusconsistsofamodifieddoublebeam
physical balance in which the left pan was replaced with a brass
wire,towhichapolypropylenediscwashanged.Anotherpropylene
disc of cm height and cm diameter was placed right below the
suspended disc upon the base of the balance. The right pan was
replacedwithalighterpansothat,theleftpanweighs9.5gmmore
thantherightpan.Thelowerpolypropyleneblock wasintended to
hold the mucosal tissue of goat cheek pouch and to be placed in a
beaker containing simulated saliva solution pH 6.75. Goat cheek
pouch was obtained from abattoir house was kept in a sterile
container containing buffer solution of pH 6.75 until further use.
Then goat cheek pouch was carefully excised, without removing
connective and adipose tissue and washed with simulated saliva
solution. Immediately afterwards the membrane was placed over
the surface of lower polypropylene cylinder and secured. Then
assembly was placed into beaker containing simulated saliva
solution pH 6.75 at 37 2C and tablet was stuck to the lower
surface of polypropylene cylinder with a standard cynoacrylate
adhesive.Theexposedpartofthetabletwaswettedwithadropof
simulated saliva solution, and then a weight of 10 g was placed

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a the expand ded cap, left forr 10 minutes to bind tablet withh Wherre,Mt/M=fraactionofdrugreleeased,K=kinetic constant,t=
mucinandthewe
m eightwasremoveed.Theweightso ontherighthand d releassetime,n=thediiffusionalexponeentfordrugreleasse.
side were slowlyy added in an in ncrement of 0.5 g till the tablet
separates from the mucosal su urface/ membraane. The weight Stability studies11,12 The stability studies of formulated tablets
required for compplete detachmen nt is noted (W1) (W19.5G)) givess were carried out at temperature of 40C/75% relatiive humidity
fo
orce required for
f detachment expressed in weightw in gramss. (RH) for 3 months, to
o investigate the influence of temp
perature and
Procedure
P was repeated for tw wo more tabletts. Average wass relativ
vehumidityonthhedrugcontent.
computedandrec
c corded. RESU
ULTSANDDISCUSSION
Solub
bilitystudy
The solubility
s of clottrimazole and its cyclodextrin complex, in
variouussolventslikew water,ethanol,meethanolandpH6 6.8phosphate
bufferrs was found to o be 0.076 mg/m mL in distilled water,
w 91.66
mg/m mLinethanoland d100.29mg/mL inmethanol,0.10 02mg/mLin
pH 6.8. The solubility ty of clotrimazolle cyclodextrin n, 1:1 molar
ratio, in water was foound to be 0.657 mg/mL, which is almost 8.6
timessincreaseofsolub bilitythaninwateerasshownintab ble2.

Table2:Solubillityofclotrimazo
oleandclotrima
azole
cyclo
odextrininclusioncomplex
Wate
er(mg/ml) Ethanol Methanol Phospphate
(mg/ml) (m
mg/ml) buffe
erpH6.8
(mg//ml)
Drug Drug: Drug Drrug Drug
cyclodextrin
complex
Fig.1:Mucoadhessivetestassembly (1:1molar
ratio)
Where,
W A polyprropylene disc, B
B Teflon block, C Right pan, D 0.076
6 0.657 91.66 10
00.29 0.102
2
mucosaltissueof
m goatcheekpoucch,Ebeakerconttainingsimulated d

salivasolutionpH
H6.75,FMucoadh hesivetablet.
Differrentialscanning
gcalorimetry

The DSC
D thermogram ms (fig 2) of clottrimazole and cyclodextrin
n vitro release study9 In vitro dissolution stud
In dies were carried
d showsacharacteristicc,sharp,endothermicfusionpeak kat149.47C
out
o in USP XXIV type
t II apparatuss (Electrolab, Mum
mbai) under sinkk corresponding to its melting
m point (Arrea of peak = 866 553.675 mJ
conditions.
c The dissolution
d mediuum was 500 ml simulated salivaa and enthalpy
e H = 14
44.237 J/g) and aa broad endothermic peak at
solutionpH6.75aat370.5Cwith hstirringspeedo of100rpmfor12 2 117.4
44C respectively. The therm mogram of clotrrimazole
h.Thesamplesw
h werewithdrawnaat0,1,1.5,2,2.5,,3,4,5,6,7,8,99, cycloddextrin complex shows persistence of the cyclo odextrin peak
10,11and
1 12 hrs.. 1mlofsamples werewithdrawn n atintervalsand
d butissshiftedtoalow
wertemperature~ ~105C,andthe endothermic
replaced by equiv valent amount of fresh dissolutio on medium. Thee peak of clotrimazole has
h diminished in n its size (Area of
o the peak =
amountofdrugre
a eleasedinthedisssolutionmedium mwasanalyzedbyy 112.7
78 mJ) and the eenthalpy has red duced (H= 30.46 64 J/g). This
Ultra
U violet (UV) spectrophotomeeter at 262 nm. Drug released in n indicaatesthat,eventhoughnotattributtabletoinclusion ncomplexbut
cumulativepercen
c ntagefromdiffereentformulationsversustimeweree certaiinlyshowsastro ongerinteractionbetweenclotrim mazoleand
comparedwhichi
c isgiveninfigure4 4. cycloddextrininsolidsttate13.
Innvitrodrugrele easekineticsIn nthepresentwo ork,dataobtainedd
frrominvitroreleaasestudieswere fittedtovarious kineticequationss
too find the mechaanism of drug reelease from the controlled
c releasee
mucoadhesivetab
m blets.
Zeroorderequa
Z tionTherateoffreleaseofdrug canbe described
d
mathematicallyas
m sfollows:
Rateofrelease=d
R dCs/dt=k(1)
Where,
W Cs = Conncentration of drug
d present in the matrix, K =
=
actori.e.,reactionrateconstant,t=
proportionalityfa
p =time.
SinceCsisaconst
S tant,xamountoffdrugreleasedisdescribedas
dx/dt=k
d (2)
In
ntegrationofequ
uation
X
X=kt+Constant (3)
AplotofxVstre
A esultsinastraighttlinewithaslopee=k
The
T value of k would
w indicate the amount drug released
r per unit
tiimeandtheinterrceptofthelineaattime0isequaltoconstanttothee
equation.
e
Korsemeyers
K eqquation10 It is a simple empirrical equation to
o
describe
d general solute behavior from controlled release polymerr
matrices:
m
Fig.2:DSCThermog gramsofA)Clotrrimazole,B)Cy
yclodextrin
Mt/M=Kxtn
M andC)ClottrimazoleCycllodextrincomplex

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PowderXraydiffraction
The X ray diffraction patterns of clotrimazole and cyclodextrin
indicate thats both is in its crystalline form. The kneaded
clotrimazole cyclodextrin complex exhibits significant diminution
(fig 3) of the diffraction peaks, suggesting that the complex is less
crystalline. This reduction in its crystallanity is attributed to the
kneadingtreatment,isclearlyevidentforpurecyclodextrin while
clotrimazoledoesnotshowthiseffect.Itisalsoevidentthatheights
of the diffraction peaks of complex have reduced indicating
reduction degree of crystallanity in the case solid inclusion
complex14.
Evaluationofpowderblend
Angleofrepose
Theangleofreposefortheentireformulations(F1toF6)blendwas
foundtobeintherange29.05to31.99beforeaddingglidentsand
similarly studies were conducted after adding glidents showed
reducedangleofreposeintherange25.64and29.86.
PercentagecompressibilityIndex
Compressibility index was found to be in the range of 11.56 % to
14.73 %. All formulations showed good flow properties which are
givenintable3.

Fig.3:PowderXraydiffractionpatternsofA)Clotrimazole,B)CyclodextrinandC)ClotrimazoleCyclodextrincomplex.
[

Table3:Flowpropertiesofpreparedmucoadhesivetabletsofclotrimazole
Fcode Compressibilityindex(%) Truedensity Bulkdensity Angleofrepose(o)
gm/ml gm/ml BeforeaddingglidentsAfteraddingglidents
F1 11.56 0.360 0.318 29.95 26.39
F2 12.9 0.383 0.330 29.05 26.74
F3 13.53 0.404 0.346 29.65 25.84
F4 14.73 0.371 0.315 30.75 26.56
F5 12.96 0.357 0.310 30.19 26.56
F6 13.5 0.557 0.468 31.99 29.86

Evaluationofmucoadhesivetablets
Prepared controlled release mucoadhesive tablets were then
evaluated for various physical properties like swelling studies,
surfacepH,drugcontentuniformity,invitromucoadhesivestrength,
friability, thickness, hardness, weight variation and all the
observationsaresummarizedintable4.
Weight variation The weight of the formulated tablets of
clotrimazole(F1toF5)wasfoundtobeuniformwithlowstandard
deviationvaluesfrom284.752.64mgto294.52.34mgandthe
weight formulated tablets of the clotrimazole cyclodextrin
complex (F6) was found to be 669.1 2.98 mg. The prepared
formulations comply with the weight variation test as per IP. The
resultsaregivenintable4.
Thickness The thickness of the tablets was found to be uniform,
between 2.03 0.084 mm to 2.57 0.018 mm for (F1 to F5) and
5.750.06mmforF6.
HardnessThehardnessofthetabletswasfoundtobeF1through
F6wasfoundtobe3.240.185Kg/cm2to4.220.17Kg/cm2which
indicating good binding and satisfactory strength of tablets to
withstand stress during transportation and also may offer good
adhesiontomucosa.
Friability test The percent friability for formulations (F1 to F5)
wasfoundtobe0.52%to0.98%and1.23%(F6).The%friability
was less than 1% for all formulations except formulation F6
ensuringthattabletsweremechanicallystable.
DrugcontentThemaximumdrugcontentforallformulationswas
found to be 99.14 0.35 mg and minimum drug content from all
formulations was found to be 95.87 0.31 mg. The results were
withinpharmacopoeiallimits.
In vitro mucoadhesive strength The maximum mucoadhesive
strengthofalltheformulations(F1toF6)wasfoundto be43.32
1.69 gm and minimum mucoadhesive strength was found to be
27.61 0.82 gm. It indicates that as the content of HPMC K4M or
Carbopolwasincreasedthemucoadhesivestrengthwasfoundtobe
increased.SimilarlyinformulationF6thepresenceofcyclodextrin
complexdoesnotinfluencesthemucoadhesivestrengthoftablets.
SurfacephThesurfacepHofallformulationswasfoundto6.14
0.007to7.050.071.TheacceptablepHofthesalivaintherangeof

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57
5 and surface pH of all the tablets was with
hin limits. Hencee, formu
ulationsmaynotproduceanyirrittationtothebuccalmucosa.

Table4:Ev
valuationofphyssicalcharacterissticsofmucoadh
hesivetabletsco
ontainingclotrim
mazole
Fco
ode Weig
ght Ha
ardness Thickness Friability Drugconttent Bioadh
hesive S
SurfacepHSD

mgS
SD Kg
g/cm2SD mmSD (%) mgSD streng
gth
gmSDD
F1 293.1
12.04 3.1
180.13 2.570.01 0.92 99.140.35 27.61
0.82 6.530.03
6
F2 286.5
52.19 3.2
240.18 2.250.02 0.76 97.280.41 31.46
1.94 6
6.610.10
F3 288.3
31.88 3.5
520.07 2.290.02 0.52 95.870.31 32.44
1.54 6
6.690.04
F4 288.8
82.37 3.6
660.18 2.330.05 0.68 96.540.28 35.20
2.02 6
6.580.04
F5 284.7
72.64 3.3
380.01 2.330.07 0.59 97.680.23 43.32
1.69 6
6.650.07
F6 669.1
12.98 4.2
220.17 5.750.06 1.23 96.690.59 43.15
1.67 7
7.050.07
SDstandarddevi
S ation,wheren=3
Swellingstudies
S Appropriatesw wellingbehavioroofbuccaladhesivee Swelling studies indiccate that the sw
welling index of the
t (F6) was
system is essentiaal for uniform an
nd prolonged rellease of the drugg foundd tobe higherfolllowed byF5 > F3
F > F4 > F2> F1
1.Swelling of
and
a effective mucoadhesion.
m T
The % swelling index of alll tabletts increases withh time due to increase in conteent of either
fo
ormulationswasfoundtointheraangeof16.65%tto77.05%for8h h. HPMC CorCarbopolassshownintable5.

Table5:Swellingstudie
esfordifferentf
formulationsofc
clotrimazolemu
ucoadhesivetablet.
Fcode
F %swellingindex
0.25h 0.5h
h 1
1h 2h 4h 8h
F1
F 16.65 25.62
2 3
32.99 38.37 54.41 66.966
F2
F 17.06 28.27
7 3
35.53 42.51 56.21 68.933
F3
F 17.88 28.56
6 3
36.00 42.60 57.17 69.477
F4
F 18.84 27.96
6 3
37.27 43.43 56.99 69.344
F5
F 21.22 30.37
7 3
38.77 45.16 57.84 70.344
F6
F 16.36 31.87
7 4
40.92 48.32 71.84 77.055

In
nvitrodrugrele easestudyThe invitrodrugreleeasestudiesweree ofinv
vestigationdonettostudytheeffecctoflevelsofHPMCK4Mand
carriedoutinUSP
c PXXIVtypeIIapp paratusforallforrmulations(F1to o Carboopol934Ponreleeaseprofileofclo
otrimazolefromttheswellable
F6).
F The tablet was observed to t be intact butt swollen for alll matriices.
fo
ormulationsupto o12handerosio onofsmallerpartticleswasstarted d
after5hupto12
a 2hforallformulaations.Theresulttsofdrugreleasee Theooveralldataoninvitrodissolutionstudiescloselyin
ndicatedthat,
studies are indicaate that a polymmer concentration n has substantiaal thefoormulationF5waasfoundtobetheebestwithhighp percentageof
effect
e ondrug rellease from the tabletsasshown in nfigure 4.The in
n F was selected to formulate
drug release. Therefore formulation F5
vitrocumulativea
v amountofdrugreleaseforformullationsF1,F2,F3 3, formu ulation F6 with clotrimazole: cyclodextrin
co
omplex (1:1)
F4andF5at12h
F hshowed62.80% %,65.09%,66.57 7%,64.60%,and d molarr ratio showed 87.67% of the drug
d released in
n 12 hrs. By
70.53
7 % respecttively. The conceentration of Carrbopol 934P hass incorp poratingcyclod dextrintheamouuntof drugreleassewasfound
greatereffectond
g drugreleasethan nconcentrationH HPMCK4M,which h to bee increased in fo
ormulation F6 as
a shown in figu ure 4, which
indicaates that these formulations arre capable of achieving the
maybeduetoles
m sserpermeability yofformer.Thisffindingisinfavorr
objecttiveofthisinvesttigation.

Fig.4:Drugreleaseprofileforcontrollledreleasemuccoadhesivetable
etsofclotrimazo
ole

Kinetic
K treatmen nt to dissolution n data Dissolution data from thee ulationswasbest explainedby
releasseofclotrimazoleeinalltheformu
batcheswasfitted
b dtozeroorderan ndKorsemeyerP Peppasmodeland d zero order equation, as the plots showed highest regression
th
he results are sh
hown in table 6. The
T value of releease exponent (n)) wed by Korsemeyer Peppas
correlation coefficient (r) and follow
was
w found to be
b a polymers used and the physicochemicaal modeel.Agoodcompliaancewithzeroorderequation(av verage=0.99)
propertiesofthed
p drugmoleculeitsself.Itwasfoundthatinvitrodrugg indicaates that drug release from alll formulations were nearly

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IntJPharmPharmSci,Vol3,Issue3,2011,159164

independent of drug concentration in tablets. The next best fit was
KorsemeyerPeppasmodel(average=0.99).Thecalculateddiffusion
exponent (n) were found between 0.41 to 0.64 which indicates a
combinationofdiffusionandswellingcontrolledreleasemechanism
and drug release was highly influenced by swelling and gradual
erosionofthetablets.Itwasconcludedinastudythatformulations
(F1 to F5) exhibited anomalous (non fickian) diffusion and
formulationF6exhibitedFickiandiffusion.
Stability studies The stability studies were carried out for all
formulations according to ICH guidelines at temperature of 40C
with75%relativehumidity(RH)for3months.Theresultsshowed
thattherewasnoconsiderabledifferenceindrugcontentasshown
intable7.
CONCLUSION
The current studies are aimed at successful development and
optimization of mucoadhesive tablets of clotrimazole for the local
treatmentoforalcandidiasiswithhighregulationofthereleaserate.
Based on the in vitro dissolution studies, it was found that
formulation (F5) showed maximum drug release in 12 hrs.
Therefore this formulation was optimized by complexing the
clotrimazole with cyclodextrin (1:1 molar ratio) which was
resulted in increase the dissolution rate of the formulation (F6).

Table6:Drugreleasekineticparametersforcontrolledreleasemucoadhesivetabletsofclotrimazole
Formulation Zeroorderplot KorsemeyersPeppasplot Mechanismofdrugrelease
r nr
F1 0.990 0.410.983 anomalous(nonfickian)diffusion
F2 0.988 0.560.997 anomalous(nonfickian)diffusion
F3 0.980 0.620.997 anomalous(nonfickian)diffusion
F4 0.986 0.640.996 anomalous(nonfickian)diffusion
F5 0.970 0.610.995 anomalous(nonfickian)diffusion
F6 0.992 0.50.995 fickiandiffusion

Table7:Dataofstabilitystudiesofmucoadhesivetabletformulationsat40C/75%RH
Timeindays F1 F2 F3 F4 F5 F6
DC(mg) DC(mg) DC(mg) DC(mg) DC(mg) DC(mg)
0 99.14 97.28 95.87 96.54 97.68 97.68
1 98.68 97.10 95.26 95.78 97.36 96.68
3 97.89 96.69 95.02 95.26 97.01 96.00
7 97.36 96.05 94.87 95.00 96.65 95.69
15 96.89 95.85 94.12 94.58 96.05 95.12
30 96.02 94.75 94.03 94.01 95.69 94.13
45 95.56 94.25 93.45 93.85 95.00 93.01
60 95.01 94.00 93.01 93.10 94.12 92.56
90 94.58 93.45 92.16 92.25 93.00 91.36

Stability studies were performed for all formulations as per ICH
guidelines,fordrugcontent.Theformulationsshowednosignificant
variations in the drug content and they were stable for specified
time period. It was concluded that the mucoadhesive controlled
release tablets of clotrimazole may be a good choice to bypass the
extensive hepatic first pass metabolism with clotrimazole alone
tablets and clotrimazole with cyclodextrin to improve the
bioavailabilityofdrugthroughbuccalmucosa.
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