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Vol 3, Issue 1, 2011

ResearchArticle

FORMULATIONANDEVALUATIONOFTASTEMASKEDSUSPENSIONOFMETRONIDAZOLE

A.M.SUTHAR*,M.M.PATEL
Lecturer,Dept.ofPharmaceutics,SaraswatiSchoolofPharmacy,Ranela,Mehsana384002,Gujarat;JodhpurNationalUniversity,Jodhpur,
India.Email:ajay_mpharma84@yahoo.com
Received:29Aug2010,RevisedandAccepted:12Nov2010
ABSTRACT
Noncompliance which is mostly associated with bitter taste can lead to worsening of diseased condition The purpose of this research was to
preparepalatableliquidformulationbymaskingtheintenselybittertasteofmetronidazole(MNZ).TastemaskingwasdonebycomplexingofMNZ
withdifferentrasinsKyronT114,KyronT134andIndion234indifferentratios.Preparedsuspensionsweretestedfordrugcontent,invitrodrug
release,tastemasking,stabilitystudy,andmolecularproperties.KyronT134atpH8showedpotentialtopreparepalatableformulationwithMNZ.
Thustoovercometasteproblemoftraditionalpaediatricdosageform,IERisdominatingmethodtopreparepalatableliquidformulationofMNZ.
Keywords:Metronidazole,Tastemasking,Ionexchangeresin,Pediatrics

INTRODUCTION
Children are frequently failed to take medications properly
becauseofunpleasanttasteofmedicament.Noncompliancecan
lead to worsening of diseased condition. Numbers of taste
maskingtechnologieshave beenusedtoaddress theproblemof
patientcompliance.Useofsweeteners,aminoacidsandflavoring
agentsaloneareofteninadequateinmaskingthetasteofhighly
bitter drugs. Coating is more efficient technology for
aggressively bitter drugs even though coating imperfections, if
present, reduce the efficiency of the technique 1. Similarly,
microencapsulation of potent bitter active agents such as
azithromycin is insufficient to provide taste masking of liquid
oralsuspensions 2.
InIonexchange resin(IER)methodweak cationexchangeorweak
anionexchangeresinsareusedfortastemasking,dependingonthe
natureofdrug.Thenatureofthedrugresincomplexformedissuch
that the average pH of 6.7 and cation concentration of about
40meq/Linthesalivaarenotabletobreakthedrugresincomplex
butitisweakenoughtobreakdownbyhydrochloricacidpresentin
the stomach3. Thus the drug resin complex is absolutely tasteless
with no after taste, and at the same time, its bioavailability is not
affected.Childrenundertheageof8aretypicallyprescribedliquid
medicationsbecause ofsmallerstructureofa child'sesophagus 3, 4.
MNZ is a highly bitter drug, used in the treatment of intestinal
protozoal infection like amoebiasis, giardiasis, trichomonas vaginitis
etc4.
MATERIALSANDMETHODS
Materials
Metronidazole benzoate was gift sample from Lincoln
PharmaceuticalsLtd.,(Ahmedabad,India).KyronT104andKyronT
134 was obtained as gift sample from Corel Pharma Chem,
(Ahmedabad, India). Indion 234 was purchased from Ion exchange
Indialimited(Mumbai,India).Sucrose,Sorbitol,Glycerine,Xanthane
gum, Aspartame, Methyl paraben and Mangocandy flavour were
purchased from S. D. Fine chemicals (Mumbai, India). All other
chemicals/solventswereofanalyticalgrade.
Methodology
Purificationofionexchangeresin
ResinswerepurifiedusingthemethodreportedbyIrwinetal. 5.The
resins(5g)werewashedsuccessivelywithdistilledwater,methanol
(50ml),benzene(50ml),methanol(50ml)andseveraltimeswith
distilled water to eliminate organic and color impurities. Then, the
wet resins were activated by 0.1 M HCl 50 ml and washed several
timeswithdistilledwater.Allresinsweredriedovernightinhotair
ovenat500Candkeptinanamberglassvial.

Preparationofdrugresincomplex6,7,8
Drugresincomplexwerepreparedbybatchprocess.Step1:Weigh
alltheingredientaccurately.Nowaddweightedquantityofresinin
specific quantity of water and stir it for 15 min. under mechanical
stirrer.Step2:NowaddweightedquantityofMNZintostep1&stir
it for 4 to 5 hr. continuously under stirrer. Step 3: Take specific
quantityofwaterboilitdissolvesugar&filterit.Nowcoolthesyrup
atroomtemperatureandaddsorbitolandglycerininit&addinto
step2undercontinuousstirring.Step4:Takewater&addxanthane
gumandstirittoformapaste.Addthispasteinstep3slowlyunder
stirring. Step 5: Take warm water dissolve methylparaben,
propylparaben&aspartameintoit&addintoabovesolutionunder
stirring.Step6:Nowaddcoloring,flavoringagentinstep5&make
volume of suspension up to required quantity by using purified
water,pHofresinsolutionwasadjustedto8byusing1MKOH.
CharacteristicsofMNZresinates
a)Determinationofdrugcontentinresonates9.
MNZ resinate (200 mg) was placed in a beaker to which 0.1N HCl
(50ml)wasaddedforelutingMNZfromtheresinate.Thevolumeof
eluate was measured and assayed for the content of MNZ by
spectrophotometryatwavelengthof277nm.
b)Invitroreleaseofsuspension9,10
Dissolution studies of above samples were performed using USP
XXIIIapparatustype2.Suspensionequivalentto400mgofthedrug
were added to the dissolution medium (500 ml 0.1N HCl at a
temperature of 370C 0.50C), which was stirred with a rotating
paddle at 50 rpm. At suitable time intervals, 10 ml samples were
withdrawn,filtered(0.22m),dilutedandanalyzedat277nmusing
UVspectrophotometer.
c)Determinationofviscosity
The viscosity of gel was determined at ambient condition (DV III+,
BrookfieldProgrammableRheometer)usingadequateamountofthe
sample.
d)Tasteevaluation
Thetasteofsuspensionwascheckedbypanelmethod 11. Thestudy
protocol was explained and written consent was obtained from
volunteers. For this purpose, 10 human volunteers were selected.
About 5 ml suspension containing 200 mg of drug was placed on
tongueandtasteevaluatedafter15seconds.
e)Assayofsuspension
Take10mlofsuspensionin100mlvolumetricflask&makeupthe
volume up to 100 ml with 0.1N HCL. Now take 2 ml solution from
flask&addinto200mlvolumetricflask.Makeupthevolumeupto

Sutharetal.
IntJAppPharm,Vol3,Issue1,2011,1619
200 ml with 0.1 N HCL filter it & measure the absorbance at
wavelength277nminU.V.Spectrophotometer11,12.

Drug loading were very less compare to other resins at same

condition.PanelmethodindicatesinsufficienttastemaskingofMNZ
byusingIndion234[table3].

f)Sedimentationvolume13

Forpreparationofresinates,batchmethodwaspreferredbecauseof
its convenience. Equilibrium was reached within 6 h. The high
affinityofresinstohydrogenionscanyieldfastdesorptionofbound
ions when they are exposed to an acidic environment such as the
stomach. When the pH is lower than 4, the resin exists in the free
state.16Therefore,drug/resincomplexformationneedstobecarried
out at pH 6 or higher. Higher concentration of competing ions at
lower pH may inhibit the interaction of resins. At pH 8 maximum
loadingofMNZwasseenontoKyronT114,KyronT134andIndion
234(data notshown). Effect of drug:resinratioon % drug content
pergramofresinateareshownin[table2].Resultsshowsthatusing
kyron T114 and kyron T134 maximum drug loading were
observed at 1:2 drugrasin ratio. As the crosslinking ratio and
particlesizeincreased,thedrugloadingandreleaseratedecreased
duetothereducedeffectivediffusioncoefficientandsurface area17,
18.Whentheresinishighlycrosslinked,fewerfunctionalgroupsare
availableinsidetheparticle,resultinginlowionexchangecapacity.

Sedimentationvolume(F)isaratioofthefinalorultimatevolumeof
sediment (Vu) to the original volume of sediment (VO) before
settling.Itcanbecalculatedbyfollowingequation.
F=Vu/VO(1)
Where,Vu=finalorultimatevolumeofsediment
VO=originalvolumeofsuspensionbeforesettling.
g)Acceleratedstabilitystudy
MNZ suspensions were packed in 60 ml glass bottle. The packed
bottleswereplacedinstabilitychambermaintainedat40+2 oCand
75+5%RHfor3month.Sampleswerecollectedatdays0,5,15,30,
60 and 90. 14, 15 The analyses comprised chemical testing of
quantifiable parameters, which could possibly change during
storage,suchasviscosity,pH,drugcontents,sedimentationvolume,
redispersibility,tasteandanykindofmicrobialorfungalgrowth.

DissolutionprofileofoptimizedformulationM6

RESULTSANDDISCUSSION

InvitroreleaseStudywascarriedoutin0.1NHCLusingUSPpaddle
apparatusat50rpm.Morethan80%ofdrugwasreleasedwithin 30
minfromM6formulation.Ingeneral,strongacidtyperesinsshowed
greater sustained release than weak acid type resins in in vitro
dissolution tests 19. Some drug molecules released accumulated
around the surface of the resinates to form an aqueous boundary
layer. Stirring can be introduced to diminish this layer. However,
highercrosslinkedresinsdisplayamoresustainedreleaseeffectthan
lowercrosslinkedresins.Slightdistinctionbetweenreleaseprofileof
formulationsmaybeduetovariouscrosslinkingratioofresins.

Formulation M1 was prepared without resin, which may provide

clear distinction between actual taste of drug before masking and
taste after masking by making complex with various resins in
different ratios. Formulation M2, M3 andM4 wereprepared using
kyron T114 at different drug: polymer ration 1:1, 1:2 and 1:3
respectively. Prepared suspensions showed satisfactory physical
properties.DrugloadingforM2,M3andM4were34.45,44.41and
42.78% respectively[table 2]. Formulation M3 showed somelevel
of acceptance but it was not sufficient to prepare pediatric
formulation. Formulation M5, M6 and M7 were prepared using
kyron T134 at different drug: polymer ration 1:1, 1:2 and 1:3
respectively. Prepared suspensions showed satisfactory physical
properties. All showed superior drug loading [table 2]. Taste
evaluation by panel method showed palatable taste in M6 and M7
[table3].FormulationM7,M8andM9werepreparedusingIndion
234 at different drug: polymer ration 1:1, 1:2 and 1:3 respectively.

Accelerated stability study of M6 is shown in [Table 4]. Study

revealedthatpreparedformulation can be remain intactfor along
period of time without major changes in assay, viscosity and
sedimentation volume20. It was found that formulation was
remainedpalatablewithoutany appearance of microbialgrowthin
agarplates.

Table1:FormulationofMNZsuspensionwithdifferentresins
Ingredients
Complexpreparation
MNZ(mg)
KyronT114
KyronT134
Indion234
Purifiedwater(ml)
Syruppreparation
Sucrose(gm)
Glycerine(ml)
Xanthangum(mg)
Methylparaben(mg)
Propylparaben(mg)
Aspartame(mg)
Mangocandyflavor(ml)
Quinolineyellowcolor(mg)
Purifiedwateruoto(ml)

M1

M2

M3

M4

M5

M6

M7

M8

M9

M10

200

2.5

200
200

2.5

200
400

2.5

200
600

2.5

200

200

2.5

200

400

2.5

200

600

2.5

200

200
2.5

200

400
2.5

200

600
2.5

2.25
0.5
20
10
4
15
0.13
0.1
5

2.25
0.5
20
10
4
15
0.13
0.1
5

2.25
0.5
20
10
4
15
0.13
0.1
5

2.25
0.5
20
10
4
15
0.13
0.1
5

2.25
0.5
20
10
4
15
0.13
0.1
5

2.25
0.5
20
10
4
15
0.13
0.1
5

2.25
0.5
20
10
4
15
0.13
0.1
5

2.25
0.5
20
10
4
15
0.13
0.1
5

2.25
0.5
20
10
4
15
0.13
0.1
5

2.25
0.5
20
10
4
15
0.13
0.1
5

(200mgmetronidazole=321.6mgmetronidazolebenzoate)

Table2:EvaluationparameterofMNZsuspensionwithdifferentresins
Parameters
Drugloadingofdry
resinates(%)
Color
Viscosity
(mPas)
pH
Sedimentatio
nvolume(F)
Redispersibility
Assay%

M1

M2
34.45

M3
44.41

M4
42.78

M5
39.42

M6
47.65

M7
44.86

M8
39.56

M9
41.37

M10
38.47

Pale
yellow
258.4

Pale
yellow
282.3

Pale
yellow
312.7

Pale
yellow
342.5

Pale
yellow
301.8

Pale
yellow
319.3

Pale
yellow
322.4

Pale
yellow
278.4

Pale
yellow
309.9

Pale
yellow
312.4

8
0.98

8
0.98

8.1
0.95

7.9
0.98

7.8
0.97

8
0.98

7.9
0.98

8
0.98

8
0.95

7.9
0.97

+++
101.3

+++
99.41

++
98.49

+++
97.17

+++
98.28

++
99.83

++
98.38

+++
99.55

+++
98.93

+++
99.27
17

Sutharetal.
IntJAppPharm,Vol3,Issue1,2011,1619
Table3:Evaluationoftasteofsuspension
Formulations
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10

1
3
2
1
0
2
0
0
2
2
2

2
4
3
0
1
3
0
1
3
2
1

3
4
3
0
0
3
1
2
3
2
0

4
4
2
0
1
2
0
0
2
3
2

5
3
3
0
1
3
0
1
3
2
3

Volunteers
6
4
2
1
0
2
1
1
2
2
1

7
4
3
0
0
3
0
1
3
3
3

8
4
3
0
0
3
0
0
3
2
2

9
3
2
1
0
2
0
2
2
2
3

10
3
2
0
1
2
0
0
2
3
2

0=Palatable,1=Normal,2=Slightlybitter,3=bitter,4=Extremelybitter

Table4:Acceleratedstabilitystudy
Parameters
Assay%
Viscosity(mPas)
Ph
Sedimentationvolume
Redispersibility
Taste

Timeperiods
initial(0Day)
99.83%
319.3
8
0.98
+++
Palatable

1month
99.7%
315.29
7.9
0.98
+++
Palatable

2month
99.56%
317.7
7.9
0.97
+++
Palatable

3month
99.4%
313.23
7.9
0.97
+++
Palatable

Fig.1:InvitrodissolutionprofileofM6

CONCLUSION

REFERENCES

Many parents are faced with the daily challenge of getting their
children to take a medicine. The unpleasant flavor of the medicine
canthwartthebenefitsofeventhemostpowerfuldrug,andfailure
to consume medication may do the child harm, and in some cases,
may be lifethreatening. Use of weak cation exchange resin offers
superior method for preaparing tastemasked substrates of MNZ.
Results obtained in this work shows that drugresin complexes
effectively masked bitter taste of MNZ. While liquid formulation
provide easier way to administer and getting the child to swallow.
Betterunderstandingofthescientificbasisfordistaste,and howto
ameliorateit,isapublichealthpriorityforadvancingavailabilityof
formulationsofdrugproductsthatwillbeacceptedbychildren.

1.

ACKNOWLEDGEMENT
Authors would like to thank Corel Pharma Chem for providing gift
sample of Kyron T114 and Kyron T134. We are also grateful to
Lincoln Pharmaceuticals Ltd for giving the gift sample of MNZ.
Authors would also like to thank Dr. M. M. Patel, Head of the
Department, for providing the necessary facilities to carry out this
researchwork.

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