DTIC ADA541017: Rheological Study Of The Mixture Of Acetaminophen And Polyethylene Oxide For Hot-Melt Extrusion Application (PREPRINT)

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4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER
Rheological Study Of The Mixture Of Acetaminophen And Polyethylene
5b. GRANT NUMBER
Oxide For Hot-Melt Extrusion Application
5c. PROGRAM ELEMENT NUMBER
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US Army, ARDEC, RDAR-MEE-W,Propulsion Technology & Direct REPORT NUMBER
Fire Branch,Picatinny Arsenal,NJ,07806
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14. ABSTRACT
There is a growing interest of extrusion drug and polymer together to manufacture various solid dosages.
In those cases, the drug?s release profiles are greatly affected by the miscibility of two materials. The goal
of this study is to test the drug?s solubility in molten polymer and obtain the mixture?s rheological
properties for the purpose of optimizing the extrusion process. The dynamic and steady viscosities of
APAP?PEO mixture were determined using oscillatory and capillary rheometers. The curves of viscosity
vs. drug loading generally have a ??V?? shape, and the minimal point gives the APAP?s solubility in PEO.
The test results suggest that different dynamic methods lead to essentially the same solubility data. At high
shear rates, the mixtures show shear thinning behavior and the viscosity becomes less sensitive to the drug
loading. In other words, it is desirable to use a low shear rate in order to deduce the drug?s solubility in
polymer from the viscosity data. On the other hand, viscosity data at high shear rates are more
representative of the materials? rheological properties during extrusion
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EuropeanJournalofPharmaceuticsandBiopharmaceuticsxxx(2011)xxx–xxx
ContentslistsavailableatScienceDirect
European Journal of Pharmaceutics and Biopharmaceutics
journal homepage: www.elsevier.com/locate/ejpb
Research paper
Rheological study of the mixture of acetaminophen and polyethylene oxide
for hot-melt extrusion application
Herman Suwardiea,⇑, Peng Wangb,c, David B. Todda, Viral Panchale, Min Yangd, Costas G. Gogosa,d
aPolymerProcessingInstitute,Newark,UnitedStates
bDepartmentofChemicalEngineering,UniversityofRhodeIsland,RI,USA
cDepartmentofBiomedicalandPharmaceuticalSciences,UniversityofRhodeIsland,RI,USA
dOttoYorkDepartmentofChemical,BiologicalandPharmaceuticalEngineering,NewJerseyInstituteofTechnology,Newark,USA
ePropulsionTechnology&DirectFireBranch,USArmy,ARDEC,RDAR-MEE-W,PicatinnyArsenal,USA
a r t i c l e i n f o a b s t r a c t
Articlehistory: Thereisagrowinginterestofextrusiondrugandpolymertogethertomanufacturevarioussoliddosages.
Received9November2010 Inthosecases,thedrug’sreleaseprofilesaregreatlyaffectedbythemiscibilityoftwomaterials.Thegoal
Acceptedinrevisedform16March2011 ofthisstudyistotestthedrug’ssolubilityinmoltenpolymerandobtainthemixture’srheologicalprop-
Availableonlinexxxx
ertiesforthepurposeofoptimizingtheextrusionprocess.ThedynamicandsteadyviscositiesofAPAP–
PEOmixtureweredeterminedusingoscillatoryandcapillaryrheometers.Thecurvesofviscosityvs.drug
Keywords: loadinggenerallyhavea‘‘V’’shape,andtheminimalpointgivestheAPAP’ssolubilityinPEO.Thetest
Hot-meltextrusion
resultssuggestthatdifferentdynamicmethodsleadtoessentiallythesamesolubilitydata.Athighshear
Rheology
rates,themixturesshowshearthinningbehaviorandtheviscositybecomeslesssensitivetothedrug
Viscosity
loading.Inotherwords,itisdesirabletousealowshearrateinordertodeducethedrug’ssolubility
Viscoelasticity
Solubility inpolymerfromtheviscositydata.Ontheotherhand,viscositydataathighshearratesaremorerepre-
Rheometer sentativeofthematerials’rheologicalpropertiesduringextrusion.
(cid:2)2011ElsevierB.V.Allrightsreserved.
1.Introduction the drying step and can produce large volume of units in a rela-
tivelyshorttimeperiod.Itismoreenergyefficientthanhigh-shear
Hot-meltextrusion(HME)hasbeenwidelyusedintheplastic granulation. Furthermore, the intensive mixing, a result of the
and rubber industry to manufacture a broad variety of products. characteristicsoftheequipmentandelevatedprocessingtempera-
Theprocessinvolvesmixingdifferentmaterialsusingascrewex- ture,leadstoauniformdispersion.
truder at an elevated temperature and pumping the mixture Inthisstudy,therheologicalpropertiesofa mixtureofmodel
throughadietoformaproductofdesiredshape.Recently,thepro- drug and a polymer excipient are systematically studied using
cess has caught a great deal of interest from the pharmaceutical oscillatory and capillary rheometers. Thus, obtained rheological
industry[1–5,13,14].Ithasbeenappliedtoextrudecombinations data not only can be used to optimize the extrusion process but
ofdrugs,polymersandplasticizersintovarioussoliddosageforms also indirectly provide the drug’s solubility in polymer excipient,
suchastablets,transdermalpatches,granules,capsulesandsoon. aselaboratedinthefollowingpartofthispaper.Generallyspeak-
Muchofthepreviousresearchinteresthasbeenfocusedonuti- ing,ifapolymerandadrugformonephaseattheprocessingtem-
lizingHMEtoimprovethedrug’sbioavailabilitythroughincreasing perature,notonlyamoreuniformproductcanbeobtained,itmay
theactivepharmaceuticalingredient’s(API’s)dissolutionrateinan alsoleadtootherdesirableproductpropertiessuchasfasterdrug
aqueous solution [2–5]. A large percentage of newly developed dissolutionrate.Havingthesolubilitydatacanminimizethetime
chemical entities are poorly soluble, and HME is believed to be for trial-and-error experimentsand help to understand evolution
oneofthemostpromisingmethodstoimprovethebioavailability ofthedrug’sphysicalstateduringtheHMEprocessandthestorage
ofthoseAPIs.Inaddition,HMEoffersanumberofotheradvantages period.Despitetheobviousbenefitandgreatinterestofknowing
comparedtothesolventmethodssuchasspraydrying:nosolvents thedrug’ssolubilityinpolymericexcipient,veryfewpreviouspa-
are required and fewerprocessing steps are needed comparedto pershavediscussedhowtoexperimentallydeterminethesebasic
thetraditionalprocessessuchaswetgranulation.HMEeliminates data.Differentialscanningcalorimetry(DSC)method[1]requires
heatingamixturesamplefromroomtemperaturetothetempera-
⇑ tureofinterestatanextremelyslowratesothatthekineticsdoes
Correspondingauthor.PolymerProcessingInstitute,Newark,NJ07102,USA.
Tel.:[phone]. not affect the solubility data obtained. As a result, a long testing
E-mailaddress:[email protected](H.Suwardie). period is required, which may cause the thermal degradation of
0939-6411/$-seefrontmatter(cid:2)2011ElsevierB.V.Allrightsreserved.
doi:10.1016/j.ejpb.2011.03.013
Pleasecitethisarticleinpressas:H.Suwardieetal.,Rheologicalstudyofthemixtureofacetaminophenandpolyethyleneoxideforhot-meltextrusion
application,Eur.J.Pharm.Biopharm.(2011),doi:10.1016/j.ejpb.2011.03.013
2 H.Suwardieetal./EuropeanJournalofPharmaceuticsandBiopharmaceuticsxxx(2011)xxx–xxx
thesample.Inthisstudy,wewilldeducethesolubilitydatafrom Two materials are stable at the testing temperature range.
the mixture’s viscosity at different drug loadings, which only re- Thermal stability data can be found in one of our recently
quiresrelativelyconvenientandfasttestonviscosity. publishedpapers[15].
To understand why the drug’s solubility in polymer can be
derived from the mixture’s viscosity, let us consider a series of
API–polymermixtureswithdifferentdrugloadingsequilibratedat 3.Experimental
atemperaturelowerthanthedrug’smeltingpoint,buthigherthan
thepolymer’smelting/softeningpoint.Ifthedrugandthepolymer 3.1.Oscillatoryrheometer
formasolution,theviscosityofthemixturedecreaseswiththedrug
loading because the dissolved small drug molecules increase the RheometricMechanicalSpectrometerRMS-800fromRheometric
mobilityofthepolymerchainandthefreevolumeamongpolymer Scientific (now TA Instruments) was used to determine the
molecules.Abovethesolubilitylimit,themixtureconsistsofsolid dynamic properties such as G0 (elastic modulus), G00 (viscous
drugparticlesandadrug–polymersolution.Inthetwo-phasere- modulus)andg⁄(dynamicviscosity)ofPEOanditsmixturewith
gion,thedependenceofthemixture’sviscosityonthedrugloading Acetaminophen.RMS-800isastrain-controlledandSMT(Separate
can be explained by the Einstein’s theory [6]. Assuming the Motor Transducer) rheometer. Samples were compounded in
dispersedsolidparticlesaresingle-sizedspheres,thereducedvis- Brabendermixerand thenmoldedat120(cid:3)Cintodisks.A sample
cosityg/g ofthemixtureincreaseswithvolumefractionvofthe disk of 25mm in diameter and 1mm in thickness was loaded
o
dispersedphase,asdescribedbythefollowingequation. betweentwoparallelplatesforeachtest.
Dynamic frequency sweeps were conducted at constant tem-
g=g ¼1þ2:5v ð1Þ peratures(80,100,120and140(cid:3)C).Astrainof10%,withinthelin-
o
earviscoelasticregionofthematerials,wasappliedtoallsamples,
Herein,gistheviscosityofthemixtureandg istheviscosityofthe except 5% strain for 50% APAP. The sample was subjected to a
o
puresolventormoltenpolymerinourstudy.Eq.(1)suggeststhat strainwithfrequencyvaryingfrom100to0.1rad/s.
the viscosity of the mixture will increase with the amount of the Dynamic time sweep was conducted at a constant frequency
drugparticleswhenthesolubilitylimitispassed.Theslopeofthe of1Hz(6.28rad/s).Astrainof10%,withinthelinearviscoelastic
curveofg/g vs.visdependentonfactorssuchastheshapeofpar- region of the material, is applied to all samples except 5% strain
o
ticlesandthepotentialparticle–particleandparticle–solventphys- for 50% APAP. Each sample was subjected to 1800s time
icalinteractions.Inotherwords,theslopemayvaryfrom2.5given sweep.
here. Dynamic temperature ramp was conducted at a constant fre-
Insummary,iftheviscosityofadrug–polymermixtureisplot- quencyof1Hz(6.28rad/s).Astrainof10%,withinthelinearvisco-
tedagainstthedrugconcentration,theslopeisexpectedtobeneg- elastic region of the materials, was applied to all samples. The
ativebelowthesolubilitylimitandchangestopositivebeyondthe samplewascooleddownfrom140(cid:3)Ctothelowestpossibletem-
limit.Thecriticalpointonthecurvegivesthedrug’ssolubilityin perature with 2(cid:3)C/min cooling rate. Herein, the lowest tempera-
the polymeric excipient. The similar phenomenon has been ob- tureisdecidedbythetorquelimitoftherheometer.
servedinblowingagent-polymersystems[7]. For all the aforementioned tests, the sample was loaded at a
Acetaminophen(APAP)andpolyethyleneoxide(PEO)werecho- constanttemperatureof 140(cid:3)C and then quicklycooled downto
senasthemodeldrugandpolymer,respectively.Theviscositiesat thetestingtemperatures.PurePEOandvariousconcentrationsof
different APAP concentrations and various temperatures were Acetaminophen in PEO were tested during the experiments (10,
determined by a series of dynamic and steady rheological tests. 20,25,30,35,40and50wt.%).
ThereducedviscositywasplottedasafunctionofAPAPconcentra- Steadyratesweepwasconductedfrom0.01to101/swith5s
tionandtemperature.Foreachtemperature, thecriticalpointon delay and 5s measurement times. PEO with 10, 20, 30, 40 and
thecurveofviscosityvs.drugloadinggivesthesolubilityofAPAP 50wt.%wasselectedforthetests.
atthattemperature.
3.2.Capillaryrheometer
2.Materials
The steady viscosities of PEO and mixtures of three different
Acetaminophen,withacommercialnameofparacetamol,was APAP concentrations, 10, 20 and 30wt.%, were determined at
suppliedbySpectrumQualityProducts,Inc.(Gardena,CA90428). 100, 120 and 140(cid:3)C using an Instron capillary rheometer. The
It has a formula of C H O with the molecular weight of 156.17. other two concentrations, 40 and 50%, were determined at 120
8 9 2
Its density at 25(cid:3)C is 1.293g/cc, and it has a melting point of and140(cid:3)C.Thebarreldiameteris9.5mm.Thestainlesssteeldie
168(cid:3)C. The molecular structure of Acetaminophen is shown in has a length of 30mm and a diameter of 1mm. The crosshead
Fig.1. speedfrom0.5to500mm/minwasappliedtocovermoderateto
Poly(ethyleneoxide)wassuppliedbyDowChemicalCompany. high shear rates. The drug was mixed with the polymer in the
Theglasstransitionis(cid:2)67(cid:3)C,andthemeltingpointis65(cid:3)C.The Brabender Torque Rheometer at 120(cid:3)C and 45rpm for 10min.
average molecular weight is about 100,000g/gmol. Its density is Themixturewasthencompressedforapproximately8mintoform
1.113g/ccat25(cid:3)C,andtheviscosityof5%solutioninwaterisin athinsheetviacompressionmoldingat120(cid:3)C.Thesheetwascut
the range of 12–50 cP at 25(cid:3)C. The molecular structure is given intosmallpiecestobefedintothebarrel.
inFig.1.
3.3.Differentialscanningcalorimetry
ThermalanalysisofPEO–APAPsystemwasconductedwithDSC
Q-100 from TA Instrument. Three to five milligrams sample of
PEO–APAPmixturewasfromthesamemixturespreparedforrhe-
ological characterization. The sample underwent heat–cool cycle
Fig. 1. The molecular structure of acetaminophen (left) and polyethylene oxide
(right). from0to100(cid:3)Cwith10(cid:3)C/minheatingandcoolingrate.
Pleasecitethisarticleinpressas:H.Suwardieetal.,Rheologicalstudyofthemixtureofacetaminophenandpolyethyleneoxideforhot-meltextrusion
application,Eur.J.Pharm.Biopharm.(2011),doi:10.1016/j.ejpb.2011.03.013
H.Suwardieetal./EuropeanJournalofPharmaceuticsandBiopharmaceuticsxxx(2011)xxx–xxx 3
4.Resultsanddiscussion Table1
G0/G00crossoverofPEO–APAPmixtures.
4.1.Viscoelasticproperties wt.%ofAPAP Crossoverfrequency(rad/s)atvarioustemperatures((cid:3)C)
140 120 100 80
Dynamicfrequencysweepiscommonlyusedtodeterminethe
0 N.A. 82.2 47.4 25.6
viscoelasticpropertiesofthematerials.Fig.2showsthedatafrom
10 N.A. N.A. 86.0 44.8
dynamic frequency sweep of PEO at 140(cid:3)C. The Fig. clearly dis- 20 N.A. N.A. 91.8 47.5
plays that G00 (viscous modulus) is always higher than G0 (elastic 30 N.A. N.A. 93.0 45.1
modulus) at all frequencies investigated, indicating that PEO 40 N.A. N.A. N.A. 44.2
50 N.A. N.A. 88.6 49.0
behaves and flows like a viscous material at this particular
temperature.
Fig.3depictstheviscoelasticbehaviorofPEOat80(cid:3)C.G0andG00
crossoveratfrequencyof25.6rad/s,abovewhichthematerialbe- Forthemixturesattemperaturesof100(cid:3)Cand80(cid:3)C,theaddi-
havesmorelikeasolid. tionofAPAPincreasestheG0/G00 crossoverfrequencyuptocertain
Table 1 lists the G0/G00 crossover points for pure PEO and the criticalvalue,afterwhichthecrossoverfrequencydecreaseswith
mixturesatdifferenttemperaturesandconcentrations.Thecross- theincreasingdrugloading.Thecriticaldrugloadingisthedrug’s
over frequency of pure PEO decreases as the temperature de- solubility in polymer. As explained in the introduction part, the
creases. Unlike the pure PEO, the mixture samples do not show physical state of the drug changes beyond the solubility limit,
crossoverpointsat140(cid:3)Cand120(cid:3)Cwithinthetestedfrequency. whichleadstodifferentimpactofthedrugloadingontheviscos-
ThephenomenasuggestthattheadditionofAPAPtransformsthe ity. Moredetailed illustrationcan be foundin thesections under
mixtureintoamoreliquid-likematerial,as alsoindicatedbythe thetitleofsolubilitycalculation.
lowervaluesofthedynamicviscosity.Thetablealsoindicatesthat
thebestprocessingtemperaturesforanyPEO–APAPmixturesare 4.2.Coolingexperiment
between 120 and 140(cid:3)C because G00 is always higher than G0 in
the temperature range, suggesting the viscous behavior of the Fig.4showstherheologicaldataofPEOobtainedfromthecool-
mixture. ing experiment, i.e., dynamic temperature sweep. This cooling
experiment is analogous to the cooling scan in the differential
scanningcalorimeterasshowninFig.5.InFig.4,G00isalwayshigh-
105 105 erthanG0 atthestartingtemperature,140(cid:3)C.However,G0 grows
faster with the drop of the temperature and the two equals at
the crossover point. Further, lowering the temperature makes G00
lessthanG0,andthematerialbehavesmorelikeasolid.Theexper-
) 104 104 imenthastoceaseoncetheinstrumentreachesthemaximumtor-
G" ([Pa] [PEta qpuroecelismsiintgotfe2m0p0e0ragtcumre.aTnhdetchreosvsaolvueerspaoreinftouginvdesaltwheaymsicnloimseutmo
G' ()[Pa] 103 103 a-s])* ( tahseshPoEwOncrinysTtaalblilzeat2i.onThteemrepseurlattaulrseodsuetgegremstisnetdhaftrothmeDmSiCnimteustms,
processing temperature for pure PEO is close to 100(cid:3)C, as con-
cludedinthepreviouswork[3].Itisverycommontochoosethe
processing temperature to be 50(cid:3)C or more than the transition
point,inthiscasethecrystallizationtemperatureofthePEO.
102 102
10-1 100 101 102
Freq [rad/s] 4.3.Solubilitycalculation:dynamictimesweep
Fig.2. ViscoelasticpropertiesofPEOat140(cid:3)C.
Fig.6showstheoverlayofdynamicviscosityofPEOatdifferent
temperatures. As expected, the viscosity at 140(cid:3)C is the lowest,
105 105
106 105
G' / G" Crossover Point:(25.6,4.7x104)
)
G' ()G" ([Pa][Pa] 104 104[Pa-s])Eta* ( )G" ()[Pa] 105 G'/G" Crossover: 43.6 [°C] 104[Pa-s]Eta* (
G' ([Pa] 104 )
103 103
10-1 100 101 102
Freq [rad/s] 103 103
40.0 60.0 80.0 100.0 120.0 140.0
Fig.3. ViscoelasticpropertiesofPEOat80(cid:3)C.(Forinterpretationofthereferences Temp [°C]
to color in this figure legend, the reader is referred to the web version of this
article.) Fig.4. G0,G00andtheviscosityofpurePEOobtainedfromthecoolingexperiment.
Pleasecitethisarticleinpressas:H.Suwardieetal.,Rheologicalstudyofthemixtureofacetaminophenandpolyethyleneoxideforhot-meltextrusion
application,Eur.J.Pharm.Biopharm.(2011),doi:10.1016/j.ejpb.2011.03.013
4 H.Suwardieetal./EuropeanJournalofPharmaceuticsandBiopharmaceuticsxxx(2011)xxx–xxx
15 3.0
46.96°C
80°C
10
W/g) 2.0
w ( ) 100°C
Heat Flo 5 n/no ([ ]
120°C
49.06°C
0 149.4J/g 1.0
140°C
-5
20 30 40 50 60
Exo Up Temperature (°C) Universal V4.0C TA Instruments 0.0
0.0 10.0 20.0 30.0 40.0 50.0
Fig.5. CrystallizationpeakofPEOduringthecoolingscaninDSC.(Forinterpre- APAP Concentration [%]
tationofthereferencestocolorinthisfigurelegend,thereaderisreferredtothe
webversionofthisarticle.)
Fig.7. Overlayofreducedviscositydataandthefittingcurves.
Table2 Table3
CrystallizationtemperaturedeterminedfromDSCandrheologicaltests. SolubilityofAPAPinmoltenPEOatdifferenttemperatures(datafromdynamictime
sweep).
wt.%ofAPAP Crystallizationtemperature((cid:3)C)
CoolinginDSC Coolinginrheometer Temperature((cid:3)C) Solubility(wt.%)
0 47.0 43.8 80 23.0
10 41.0 43.8 100 30.0
20 38.6 40.0 120 36.3
30 36.9 39.3 140 39.3
40 41.5 43.0
50 – 42.6
sweep. It is interesting to find out whether the data from the
104 dynamicfrequencysweepcanalsobeusedtocalculatethesolubil-
ity.Forthatend,thezeroshearviscosityofPEO–APAPmixturewas
calculatedfromthedataobtainedfromdynamicfrequencysweep
80 C ofthemixture.Thedynamicviscosityofthemixturesatdifferent
) frequency was fittedwith the following Cross’constitutiveequa-
y ( 100 C tion[8]:
sit g
cos] g¼ o ð2Þ
VisPa- 120 C 1þðc2xÞð1(cid:2)c3Þ
c [
mi 140 C wherec isassociatedwithrelaxationtimeandc withthepower
2 3
a
n law index. Fig. 8 shows the data obtained from the dynamic fre-
y
D quencysweepof PEOat 140(cid:3)C andthe fittingparameters. Asthe
figureindicates,theequationfitsthecurveperfectly.
103
0.0 300.0 600.0 900.0 1200.0 1500.0 1800.0 105 105
time [s]
Fig.6. OverlayofdynamicviscosityofPEOatdifferenttemperatures.
ofoflltohweetdimbeys1w20e,e1p0i0sannodrm80al(cid:3)iCze.dThweimthixtthuerep’usrveisPcEoOsi’tsyvgisactotshiteyegnod. G" ()[Pa] 104 104[PEta
wTanhadescrfieotdntuceecdendtursavitniisogcno5swtithyasdocefagPlrcEeuOela–ptAeoPdlAyanPnogdm/sgiaholo,awtannddiifnfeaFreimgn.itn7ti.meEmaucpmhercpautourivnreet G' ()[Pa] 103 103a-s]* ()
Data: Eta*(Freq) [1..16] (16 pts)
wasobtainedforeachcurve.Asexplainedintheintroductionpart, Note: Predefined Fit
theminimalviscositypointgivesthedrug’ssolubilityinpolymer. MEqond:e l:c 1C/(r1o+ss(c M2xo)(d1e-cl3 ))
Table3displaysthesolubilityofAPAPinmoltenpolymeratfour Fit Error: 0.9997
3 Coefficients:
differenttemperatures. 102 1.525x104 3.4966 0.5337 102
10-1 100 101 102
4.4.Solubilitycalculation:zeroshearviscosity Freq [rad/s]
Fig. 8. Dynamic frequency sweep of PEO at 140(cid:3)C. (For interpretation of the
Theabovesectionexplainshowthedrug’ssolubilitycanbeob-
referencestocolorinthisfigurelegend,thereaderisreferredtothewebversionof
tained using the dynamic viscosity data from the dynamic time thisarticle.)
Pleasecitethisarticleinpressas:H.Suwardieetal.,Rheologicalstudyofthemixtureofacetaminophenandpolyethyleneoxideforhot-meltextrusion
application,Eur.J.Pharm.Biopharm.(2011),doi:10.1016/j.ejpb.2011.03.013
H.Suwardieetal./EuropeanJournalofPharmaceuticsandBiopharmaceuticsxxx(2011)xxx–xxx 5
Table4givesthevaluesofCross’parametersforPEOatvarious Theshearratefortheoscillatoryrheometerislimitedbythetorque
temperatures.Thereducedviscosityisdefinedastheratioofzero andedgeeffect.Theedgeeffectbecomesmoresevereastheshear
shearviscosityofPEO–APAPtothatofPEOatthesametempera- rateincreases[9].Themaximumtorquefortheoscillatoryrheom-
ture.Thereducedviscositywasplottedagainstwt.%ofAPAPatdif- eterusedinthisstudyis1500gcm,whiletheedgeeffectisoften
ferenttemperature,andthecurveateachtemperaturewasfitted manifestedbythesuddendropofthetorque.
with5thdegreepolynomial,asthecasewithdynamictimesweep. TheviscosityinacapillaryflowiscalculatedusingfollowingEq.
Table5showsthevaluesofsolubilityatdifferenttemperature [10]:
obtainedbyzeroshearviscositymethod.Fig.9comparesthesolu- s ¼gc_ ð3Þ
bility data obtained by two different methods (reduced viscosity w w
from the dynamic time sweep and reduced zero shear viscosity and
fromdynamicfrequencysweep).Theresultssuggestthatsolubility
D DP RDP F=A
dataobtainedfromtwomethodsonlyhaveveryminordifferences, s ¼ c ¼ ¼ barrel ð4Þ
w 4L 2L 4L=D
withthedynamictimemethodgivingslightlyandyetconsistently c
lower solubility. This slight difference may be a result of the Eq. (4) does not take into consideration of Bagley’s correction
frequency difference: the dynamic time sweep is conducted at a [11]. L/D, the ratio of the die length to the diameter, used in all
frequency of 1Hz, while the zero shear viscosity essentially is experiments was 30. The values of s , shear stress at the wall,
w
theviscosityatextremelysmallfrequency. calculatedwithoutBagley’scorrectiontypicallyhavelessthan2%
error.Twoorthreedieswithsimilardiameteranddifferentlength
4.5.Steadyviscositymeasurement areusuallyemployedforBagley’scorrection.Fistheforcerequired
ateachshearrate,andAistheareaofthebarrel.
Steadyexperimentswereconductedusingbothoscillatoryand Thecorrectedshearrateatthewall,c_w,canbecalculatedafter
capillaryrheometer.Oscillatoryrheometergivesthesteadyviscos- Rabinowitsch’s[12]correctionusingthefollowingequation:
ityatlowshearrates,usuallybetween0.01and101/sorless.In 1 (cid:2) dlogðCÞ(cid:3)
contrast, capillary rheometer gives the steady viscosity at higher c_w¼4C 3þdlogðs Þ ð5Þ
shearrates,intherangeof1–10,0001/s,whichcoverstheranges w
usually seen in extrusion and injection molding operations. and
4Q 4ðCHSÞðAÞ
C¼ ¼ barrel ð6Þ
Table4 pR3 pðDc=2Þ3
Cross’parametersforPEOatvarioustemperatures.
whereCisapparentshearrate,andCHSisthecrossheadspeedof
Temperature((cid:3)C) g0(Pas) c2 c3 theplungerintherheometer.Finally,thecorrectedshearviscosity
140 15,250 3.5 0.5337 canbecalculatedfromfollowingequation:
120 22,420 5.3 0.5232
100 32,500 7.7 0.5079 g¼sw=c_w ð7Þ
80 47,980 11.1 0.4905
The shear viscosity data from the oscillatory rheometer were
combined with the data obtained from the capillary rheometer.
ThecombineddataofshearviscosityofPEOat140(cid:3)Careshown
Table5
onFig.10.ThesteadyshearviscositywasfittedusingCross’consti-
Solubility of APAP in molten PEO at different temperatures, zero shear viscosity
method. tutiveequation.ThezeroshearviscosityofPEO–APAPmixturesat
differenttemperatureisgiveninTable6.
Temperature((cid:3)C) Solubility(wt.%)
Fig.11showsarepresentativeoverlayofsteadyshearviscosity
80 24.5 of PEO–APAP mixture at 100, 120 and 140(cid:3)C, respectively. The
100 33.0
graphscontainthesteadyshearviscosityobtainedfrombothoscil-
120 37.6
latoryandcapillaryrheometer.Itisworthwhiletopointoutthat
140 42.2
105
50.0 50.0 Data: Eta(Rate) [1..25] (25 pts)
Note: Predefined Fit
Model: Cross Model
Eqn: c1/(1+(c2x)(1-c3))
40.0 40.0 104 Fit Error: 0.9976
) E 3 Coefficients:
xp 6844.2 0.5623 0.4137
e
alculated Solubility ([%]2300..00 Zero Shear Viscosity Dynamic Time 2300..00[ ]rimental Solubility ( Eta ()[Pa-s] 110023 Oscillatory Rheometer
C )
10.0 10.0
Capillary Rheometer
0.0 0.0 101
25.0 50.0 75.0 100.0 125.0 150.0 10-3 10-2 10-1 100 101 102 103 104
Temp [°C]
Rate [s-1]
Fig. 9. Solubility of APAP in PEO determined from two different methods. (For
interpretationofthereferencestocolorinthisfigurelegend,thereaderisreferred Fig.10. SteadyviscosityofPEOat140(cid:3)C.(Forinterpretationofthereferencesto
tothewebversionofthisarticle.) colorinthisfigurelegend,thereaderisreferredtothewebversionofthisarticle.)
Pleasecitethisarticleinpressas:H.Suwardieetal.,Rheologicalstudyofthemixtureofacetaminophenandpolyethyleneoxideforhot-meltextrusion
application,Eur.J.Pharm.Biopharm.(2011),doi:10.1016/j.ejpb.2011.03.013
6 H.Suwardieetal./EuropeanJournalofPharmaceuticsandBiopharmaceuticsxxx(2011)xxx–xxx
Table6 1.2
ZeroshearviscosityofPEO–APAPmixtureatdifferenttemperature.
Material wt.%ofAPAP Zeroshearviscosity(Pas) 1.0 100 1/s
100(cid:3)C 120(cid:3)C 140(cid:3)C
PEO 0 – 11,550 6844 0.8 10 1/s
PEO-10 10 12,160 9929 6218
)
PEO-20 20 10,590 7011 5092
PPEEOO--3400 3400 –7091 33576024 13675272 n/no ([ ] 0.6 32.43%2.9% 1 1/s
PEO-50 50 – 6571 2411
0.4
37.6%
0.2
0.0
10.0 20.0 30.0 40.0 50.0
% APAP [%]
Fig.13. OverlaysteadyviscosityofPEO–APAPat120(cid:3)Catvariousshearrates.
1.2
1.0 100 1/s
10 1/s
0.8
)
Fig.11. OverlayofsteadyviscosityofPEO-20at100,120and140(cid:3)C. no ([ ] 0.6 32.4% 1 1/s
n/ 32.9%
theshearratesofcommonprocessessuchasextrusionandinjec-
0.4
tionmoldingtypicallyfallinthetestrangeofthecapillaryrheom-
37.6%
eter.Thefigureclearlyindicatesthattheviscositydecreasesasthe
temperature increases. PEO–APAP mixtures exhibit Newtonian 0.2
behavior at low shear rates and shear thinning behavior at high
shear rates for all temperatures. Also, the temperature-induced 0.0
viscositydifferencebecomessmallerathighshearrates. 10.0 20.0 30.0 40.0 50.0
Fig.12showstheeffectoftheAPAPconcentrationonthesteady % APAP [%]
viscosity.At120(cid:3)C,theviscositydecreaseswiththeAPAPconcen-
Fig.14. OverlaysteadyviscosityofPEO–APAPat140(cid:3)Catvariousshearrates.
trationupto40%,indicatingtheplasticizereffectoftheAPAP.The
viscosityfor50%APAPishigherthanthatof40%APAP,indicating
thatthesystemhadreachedthesolubilityofAPAPatthattemper-
Figs.13and14showhowthereducedviscosityofthemixture
ature.Thedecreaseinviscosityisverypronouncedatlowershear
changeswiththedrugloadingat120(cid:3)Cand140(cid:3)C,respectively,at
rates up to 101/s and becomes insignificant at high shear rates.
threedifferentshearrates:1,10and1001/s.Thecriticaldrugload-
Thephenomenonsuggeststhatitisbettertouselowershearrate
ings are 37.6%, 32.9% and 32.4% for the shear rates of 1, 10 and
to obtain the drug’s solubility data as shown later in Figs. 13
1001/s, respectively. The critical drug loadings change to 44.1%,
and14.
44.4% and 45.4% for the same shear rates at 140(cid:3)C. The critical
pointforeachshearratewasobtainedbasedon5thdegreepolyno-
mialfitting,same as the dynamicmethod in previous paragraph.
Thecriticaldrug loadingdecreases withincreasingshearrates at
120(cid:3)C, while it is almost independent of the shear rates at
140(cid:3)C.Thisapparentdiscrepancyisprobablyduetothat5thde-
gree polynomial equation is not accurate enough to describe the
relationshipbetweentheviscosityandthedrugloading.
5.Conclusions
ThedynamicandsteadyviscositiesofAPAP–PEOmixturewere
determined using oscillatory and capillary rheometers. The com-
prehensiverheologicalstudyonthedrug–polymerbinarysystem
notonly helps to determinethe extrusionprocessing parameters
suchasthetemperaturebutalsoprovidesthedrug’ssolubilitydata
inpolymer.Thecurvesofviscosityvs.drugloadinggenerallyhave
a‘‘V’’shape,andtheminimalpointgivestheAPAP’ssolubilityin
Fig.12. OverlayofthesteadyviscosityofPEO–APAPat120(cid:3)C. PEO.
Pleasecitethisarticleinpressas:H.Suwardieetal.,Rheologicalstudyofthemixtureofacetaminophenandpolyethyleneoxideforhot-meltextrusion
application,Eur.J.Pharm.Biopharm.(2011),doi:10.1016/j.ejpb.2011.03.013
H.Suwardieetal./EuropeanJournalofPharmaceuticsandBiopharmaceuticsxxx(2011)xxx–xxx 7
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application,Eur.J.Pharm.Biopharm.(2011),doi:10.1016/j.ejpb.2011.03.013