Polymer-plasticizer compatibility during coating formulation: A multi-scale investigation

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Polymer-plasticizer compatibility during coating

formulation: A multi-scale investigation

Ahmed Jarray, Vincent Gerbaud, Mehrdji Hemati

To cite this version:

Ahmed Jarray, Vincent Gerbaud, Mehrdji Hemati. Polymer-plasticizer compatibility during coating

formulation: A multi-scale investigation. Progress in Organic Coatings, Elsevier, 2016, vol. 101, pp.

195-206. �10.1016/j.porgcoat.2016.08.008�. �hal-01406764�

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Eprints ID : 16025

To link to this article : DOI : 10.1016/j.porgcoat.2016.08.008

URL :

http://dx.doi.org/10.1016/j.porgcoat.2016.08.008

To cite this version :

Jarray, Ahmed and Gerbaud, Vincent and

Hemati, Mehrdji Polymer-plasticizer compatibility during coating

formulation: A multi-scale investigation. (2016) Progress in Organic

Coatings, vol. 101. pp. 195-206. ISSN 0300-9440

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Polymer-plasticizer

compatibility

during

coating

formulation:

A

multi-scale

investigation

A.

Jarray

_,

_V.

_Gerbaud

_,

_M.

_Hemati

a_{UniversitédeToulouse,INP,UPS,LGC(LaboratoiredeGénieChimique),4alléeEmileMonso,F-31432ToulouseCedex04,France} b_{LGC,INP,ENSIACET,4AlléeEmileMonso,31432Toulouse,France}

Keyword: Plasticizer Miscibility Pharmaceuticalproducts Coating Moleculardynamics

a

b

s

t

r

a

c

t

Duringtheformulationofsoliddosageformscoating,plasticizersareaddedtothefilmformingpolymer toimprovethemechanicalpropertiesofthecoatingshellofthedrugproduct.Forthecoatingformulation tobesuccessfulandinordertoproduceflexiblecontinuousfilm,theplasticizershouldbecompatible withthefilmformingpolymer(i.e.highplasticizer-polymermiscibilityinsoliddispersion)(McGinity andFelton,2008).Thispaperproposesandcomparesdifferentmulti-scalemethodstopredictthe com-patibilitybetweenplasticizersandfilmformers.Themethodsarebasedon,i)Moleculechargedensity usingCOSMO,ii)SolubilityparametercalculationusingMoleculardynamics,iii)Mesoscalesimulation usingDPD,whereweproposeacoarse-grainmodel,andiv)experimentalDSCanalysisforvalidation. ThemethodsaretestedforvariousblendsincludingHPMC-PEG,MCC-PEGandPVP-PEG.Thedifferent methodsshowedsimilarresults;PEGplasticizerdiffusesinsideHPMCandPVPpolymerchains,thereby extendingandsofteningthecompositepolymer.However,MCCsurroundsPEGmoleculeswithout diffus-inginitsnetwork,indicatinglowPEG-MCCcompatibility.WealsofoundthatDPDsimulationsoffermore detailsthantheothermethodsonthemiscibilitybetweenthecompoundsinaqueoussoliddispersion, andcanpredicttheamountofplasticizerthatdiffuseinthefilmformingpolymernetwork.

1. Introduction

Polymeric film coatings are widely used for oral-controlled orsustaineddrugrelease.Theygenerallyconsistof mixturesof various materials that are added to confer or enhance specific propertiestothefinalproduct.Typically,acoatingdispersionis composedofwater,film-formingpolymer,plasticizerand other additivessuchasfillersandstabilizers.

Today,importantdifficultiesinpolymericcoatingformulation are; a)theassessment ofpolymer-plasticizerinteraction,b)the selectionofasuitableplasticizercompatiblewiththefilm-forming polymer,andc)understandingthemechanismbywhich plasticiz-ersimprovetheflexibilityofcoatingfilmsatthemolecularand mesoscales.

Variousstudieshavebeenreportedintheliterature, investigat-ingtheeffectofplasticizersonthepropertiesofthefinalpolymeric

∗ Correspondingauthorat:UniversitédeToulouse,INP,UPS,LGC(Laboratoirede GénieChimique),4alléeEmileMonso,F-31432ToulouseCedex04,France.

E-mailaddresses:ahmed.jarray@ensiacet.fr(A.Jarray),

vincent.gerbaud@ensiacet.fr(V.Gerbaud),mehrdji.hemati@ensiacet.fr

(M.Hemati).

coating.Laboulfieetal.[1]studiedtheeffectofplasticizeronthe mechanicalresistanceandthermalbehaviorofcompositecoating films.Theyfoundthatadditionofaplasticizer(polyethyleneglycol (PEG))enhancedtheplasticbehavioroftheHPMC-basedcoating filmsandimproveditsmechanicalproperties.Jarrayetal.[2]also studiedtheaffinitybetweenpolymersandcoatingadditivesindry andaqueoussystems.Saettoneetal.[3]foundthatthedrugrelease isinfluencedbythetypeandamountoftheplasticizer.

In this work, we propose and compare four multi-scale approachesallowingtochoosetheadequateplasticizerandto for-mulate therightaqueous polymericcoating; thefirstapproach is based on the generation of s-profiles of the materials. s-profilespresentamap ofthechargedensityoverthesurfaceof the moleculeand provideinformation aboutthe moleculeand an understandingof themutualsolubilitiesof solvents[4]. The secondapproachisamolecularscaleapproach,basedonthe sol-ubility parameterı (i.e.thesquare rootofthecohesiveenergy density).Thisparameterdescribestheintramolecularand inter-molecularforcesofa substance.Itisa measureofthetendency of a moleculeto interactwith thesurrounding molecules. The solubilityparameterisusedinthecoatingindustryforselecting compatiblesolventsforcoatingsmaterials,andinsurface charac-terizationoffillers(e.g.calculationofinterfacialenergyassociated http://dx.doi.org/10.1016/j.porgcoat.2016.08.008

Fig.1. Schematicrepresentationofatypicalfilmformationmechanismandplasticizereffectondrugrelease.

with stearic acid/water interface) [5]. The third approach is a mesoscaleapproach, wheredissipative particledynamics(DPD) simulationisusedtoinvestigatethestructureofpolymeric coat-ingdispersion,wherewefollowthesameDPDparameterization used by Jarrayet al. [6]. The last approach is an experimental thermalanalysisusingdifferentialscanningcalorimetry(DSC).The developedapproaches aretested forvarioussystems composed of polyvinylpyrrolidone (PVP), microcrystalline cellulose (MCC), hydroxypropyl-methylcellulose(HPMC),polyethyleneglycol(PEG) andwater.

2. Filmformersandplasticizer

2.1. Filmformers

Ingeneral,filmformersareorgano-chemical macromolecule-formingsubstancesthat undergoapolymerizationreactionand formcrystallineoramorphouscontinuousstructureasthe coat-ingdries.Theroleofthefilmformeristoformacohesivecoating filmonagivensubstrateand–whererelevant–toholdtogether thecomponentsofthecoating[7].Filmformationistheresultof theincreaseinpolymerconcentrationinthecolloidaldispersion, leadingtotheformationofathree-dimensionalnetwork.

Theformationofapolymericfilmarisesfromthe‘coalescence’, i.e. deformation, cohesion and polymer chain interdiffusion, of theindividualcolloidalparticlesnormallyheldapartby stabiliz-ingforces [8].Evaporationof theinterstitial waterupon drying leadstothedeformationoftheparticlesofpolymeruntilcomplete coalescence(Fig.1).Thismechanismrequiressufficientcolloidal stabilitytoformclosepackinguponcoalescence;otherwise,poor filmqualitymaybeobtained.Filmformationprocessalsorequires thespreadingof thesolutionintoa thin-layer.Keddieetal.[9]

demonstratedthatvoidscouldremaininthefilmduringfilm for-mationevenafterwaterevaporation.

Theobtainedfilmmustbesmoothanduniform.However, typ-ically,filmcoatingpreparedfrompurepolymertendstobebrittle andcrackupondrying.Toovercomethisproblem,onewayisto addaplasticizertothecoatingdispersion.

2.2. Plasticizersincoatingformulations

Forpolymerswithlimitedfilm-formationability,aplasticizer may be added to ease the deformation and to favor colloidal particlescoalescence.Theplasticizerpartiallyeliminatesthe inter-actions responsible for the mechanical cohesion between the chains,andthereforeincreasestheirmobility.Asaconsequence,

therigidmaterialis transformedintosoft and flexiblematerial

[10].PlasticizersreducetheglasstransitiontemperatureTgand theminimumpolymerfilmformingtemperature(MFT)atlevels thatdependonthecoatingprocess.Plasticizersalsocreate chan-nelsthroughwhichdrugdiffusesforpelletscoatedwithinsoluble films[11](Fig.1).

Agoodchoiceofaplasticizerdependsonitscompatibilitywith thepolymerandonthepermanenceoftheplasticizerinthefilm during coating. Compatibility between a polymer and a plasti-cizerproducesstableand homogeneouscoating film.Itis often characterizedby a highmiscibility betweentheplasticizer and thepolymerblend.Polymer-plasticizerincompatibilityinfluences notonlythemechanicalpropertiesbutalsodrugrelease[12,13]. Permanenceofaplasticizermeansitstendencytoremaininthe plasticizedmaterial;i.e.longtermcompatibility.Itdependsonthe sizeofthemoleculeandonitsrateofdiffusion.

Bodmeier and Paeratakul [14,15] studiedthe distributionof plasticizersbetweentheaqueousphaseand colloidalpolymeric dispersions.Theyalsostudiedthefactorsinfluencingtherateof diffusionofplasticizerthroughthepolymer.Duringsoliddosage formscoatingpreparation,foroptimalmixingbetweenthe plas-ticizer and the polymeric dispersion, Bodmeier and Paeratakul recommendedtheintroductionofwater-insoluble plasticizerto theaqueouspolymerdispersionbeforedilutionofthelatter.They alsorecommendedalongerplasticizationtimeforwater-insoluble plasticizersthanforwater-solubleplasticizers.Inhisworkonthe coating of large Alumina particles, Ould-chikh [16] found that addingaplasticizer(PolyvinylAlcohol(PVA))inaqueouspolymeric suspensionreducesdramaticallythesegmentationorthecracking ofthecoatingfilmsupondrying.

3. Materialsandmethods

3.1. Materials

Ourexperimentalstudyiselaboratedwithdifferentmaterials widelyusedinfoodandpharmaceuticalindustries.Thepolymers are;PVP:polyvinylpyrrolidone(K10),MCC:microcrystalline cel-lulose(AvicelPH-101)andHPMC:hydroxypropyl-methylcellulose (E19).ThechosenplasticizerisPEG400:polyethyleneglycol400. AllthecompoundsarepurchasedfromSigma–Aldrich.

Polyvinylpyrrolidoneorpovidone(PVP)occursasafine,whiteto creamy-whitecolored,describedasasyntheticpolymerconsisting essentiallyoflinear1-vinyl-2-pyrrolidinonegroups[17].Although PVPisusedinavarietyofpharmaceuticalformulations,itis primar-ilyusedinsolid-dosageforms.PVPsolutionsareusedasbindersin

Table1

Compositionofthedifferentformulationstudiedthroughoutthispaper. Formulationname Binder/coatingcomposition(w/w)

Polymer Plasticizer Solvent PEG10% – 10%PEG 90%water HPMC-PEG10%–10% 10%HPMC 10%PEG 80%water PVP-PEG10%–10% 10%PVP 10%PEG 80%water MCC-PEG10%–10% 10%MCC 10%PEG 80%water HPMC:hydroxypropyl-methylcellulose,PVP:polyvinylpyrrolidone,MCC: micro-crystalline.

cellulose,PEG:polyethyleneglycol.

wet-granulationprocesses[18,19]andasasolubilizerinoraland parenteralformulations.

Microcrystalline cellulose (MCC)is purified cellulose, practi-callyinsolubleinwaterandinmostorganicsolvents,producedby convertingfibrous-cellulosetoaredispersiblegeloraggregateof crystallinecelluloseusingacidhydrolysis[20].MCCishighly cohe-sivecellulose[21].Itiswidelyusedinpharmaceuticals,primarily asabinder/diluentinoraltabletandcapsuleformulationswhereit isusedinbothwet-granulationanddirect-compressionprocesses

[22].

Hydroxypropyl-methylcelluloseorHypromellose(HPMC)isa whiteorcreamy-whitefibrousorgranularpowder.It’savailablein severalgradesthatvaryinviscosityandextentofsubstitution[17]. It’ssolubleincoldwater,formingaviscouscolloidalsolution; prac-ticallyinsolubleinhotwater.Dependingupontheviscositygrade, concentrationsof2–20%(w/w)areusedforfilm-formingsolutions tofilm-coattablets.Lowerviscositygradesareusedin aqueous film-coatingsolutions.ComparedwithMethylcellulose,HPMC pro-ducesaqueoussolutionsofgreaterclarity,withfewerundissolved fiberspresent,andisthereforepreferredinformulationsfor oph-thalmicuse[17].

Polyethyleneglycols(PEG’s)ormacrogolsareproducedby poly-merizationofethyleneoxideinthepresenceofwater.PEGsare widelyusedinavarietyofpharmaceuticalformulationsandcan beusedtoenhancetheaqueoussolubilityordissolution charac-teristicsofpoorlysolublecompounds[23].Theyarealsousefulas plasticizersinmicroencapsulatedproductstoavoidruptureofthe coatingfilmwhenthemicrocapsulesarecompressedintotablets. WhenaddedtomixturesofHPMC,PEGimprovesthemechanical propertiesofthefinalcoatingproduct[1,24,25].

3.2. Preparationprotocolofthesamples

Polymer-plasticizer-watersamples(PVP-PEG,HPMC-PEGand MCC-PEG in water) were prepared by adding the polymer in deionizedwaterpreviouslyheatedto80◦_{C.Themixturewasthen}

homogenizedbymoderateagitationfor30–60minusinga rotor-statorhomogenizer(UltraturraxT25,JankeandKunkel,Germany) at85◦_{C.Theplasticizerwasthenprogressivelyaddedunder}

agi-tationuntilitwasevenlydispersed.Themixturewasthencooled usinganicebathunderagitationfor30min.Solutionswere there-afterdegassedat50mbarfor2h.Toattainmaximumstabilization, thereadilypreparedsolutionswerestoredimmediatelyat5◦_Cfor

atleast24h.

Thesampleswereafterward spread onaglass plateusinga CAMAG handcoater(Manufactured by CAMAG, Switzerland) to produceathinfilmof5mm.Theliquidfilmsarethenplacedfor 24hatambienttemperatures.Table1presentsthedifferent for-mulationsusedthroughoutthisstudy.Typically,thepercentageof plasticizerinthecoatingdispersionislessthan10%(w/w).The rea-sonwechoseahighpercentageofPEGequaltothepercentageof thedifferentpolymersisdouble;i)Tobeabletoseethemixingof

PEGwiththepolymersintheDPDsimulations,andii)Toclearlysee theeffectofaddingPEGinthecoatingwhenusingDSCanalysis.

3.3. Methods

3.3.1. MethodA:sigmaprofile

COSMO(Conductor-likeScreeningModel)[26]isapredictive modelforthethermodynamicpropertiesoffluidsandsolutions thatcombinesquantumchemistryandstatisticalthermodynamics. Inthismodel,thesolventisregardedasahomogeneous conduct-ing medium but affected by a finite dielectric constant arising fromalargenumberofelectrostaticchargesenvelopingthe sur-faceofthesolutemolecule.Thesurfaceofthismoleculebearsa polarizationchargedensity.Todeterminethis density,quantum mechanicscalculationbasedonthedensityfunctionaltheory(DFT) arelaunchedinordertooptimizethegeometryofthemoleculeand toestablishitselectronicstructure.Then,calculationsbasedonthe COSMOmodelareusedtoconstructthechargedensitycurvecalled sigma-profile.Thisprofileistheprobabilityp()offindingsurface segmentwiththechargedensity[4]:

p()=Ai()/Ai (1)

withAi()thesurfaceareawithachargedensityofvalueand

Aithetotalsurfaceofthemateriali.COSMOemploysmolecular shapedcavitiesthatrepresenttheelectrostaticpotentialby par-tial atomic charges.The resultsdepend mainlyon thevan der Waalsradiiusedtoevaluatethecavitysurface.Thecavitysurface isobtainedasasuperimpositionofspherescenteredattheatoms, discardingallpartslyingontheinteriorpartofthesurface[26]. MoredetailsaboutCOSMOcanbefoundinRef.[26].

Conductor-like Screening Model (COSMO) implemented in Dmol3moduleasapartofMaterialStudio7.0packageof Accel-rys was used to generate the sigma-profiles of the molecules. Wateris chosen asthe solventenvironment (relativedielectric constant=78.54).Aglobalorbitalcutoffradiusof3.7Åwasused throughoutthecalculations.Wehaveusedthegradient-corrected functionals(GGA)ofPerdewandBecke[27,28]forthegeometry optimization and the COSMO calculations. It has been demon-stratedbyPerdewandWangthatthistechniqueproducesmore reliablepredictionsthantheVosko-Wilk-Nusair(VWN)technique

[29].Forbestaccuracy,weusedthetriple-numericalpolarization (TNP)basisset[30].InDmol3-CSOMO[31],theradiiofthespheres thatmakeupthecavitysurfacearedeterminedasthesumofthe vanderWaalsradiioftheatomsofthemoleculeandoftheprobe radius.First,geometryoptimizationwasperformedtobringthe energytoobtainthemoststableconformationandtoadjustthe coordinatesoftheatoms.Thesigmaprofileswerethereafter gener-ated.Complementarysigmaprofilesofapolymerandaplasticizer indicategoodmiscibilitybetweenthem[4].

Fig.2showsthesigmaprofileofwateraswellasitsCOSMO surface.WatercanacteitherasH-bonddonororH-bond accep-tor.The s-profile ofwater spansintherange of±0.02eÅ−2.It isdominatedbytwomajorpeaksarisingfromthestronglypolar regions;thepositiveregion(H-bondacceptorregion)isduetothe polaroxygenandthenegativeone(H-bonddonorregion)isdue tothepolarhydrogenatoms.Thenegativelychargedsurfacesof thewatermoleculesappearblueandthepositivelychargedones appearred.Non-polarpartsofthesurfaceofthemoleculearegreen. Thepeakarisingfromthepositivelypolarhydrogensislocatedon theleftside,atabout−0.015eÅ−2_{.Mostpartsofthesurfaceof}

water moleculesareabletoformmoreorlessstronghydrogen bond.Hydrogenbondingisconsideredasweakupto±0.01eÅ−2_.

Outside this limit, moleculescan beregarded asstrongly polar

Fig.2.s-profileofwater.(Forinterpretationofthereferencestocolourinthetext,thereaderisreferredtothewebversionofthisarticle.)

3.3.2. MethodB:solubilityparameterviamolecularsimulations 3.3.2.1. Solubility parameter. Thesolubilityparameter,ı (i.e.the square root of the cohesive energy density), describes the intramolecularandintermolecularforcesofasubstance.Itisa mea-sureofthetendencyofamoleculetointeractwiththesurrounding molecules.Solubilityparameterhasbeenprovedusefulforseveral pharmaceuticalapplicationsandhasbeencorrelatedtoavarietyof properties[32]suchasthesurfacetension,refractiveindex,workof adhesionandtensilestrength.Solubilityparameterwasalsousedin thecoatingindustryforselectingcompatiblesolventsforcoatings materialsandalso,insurfacecharacterizationoffillers[5].

Inmolecularsimulation,theHildebrandsolubilityparameter canbecalculatedfromthepairpotentialbysummingthepairwise interactions[33].Thecohesiveenergydensityisequaltominus theintermolecularenergy,i.e.theintramolecularenergyminusthe totalenergy: ı2_k= < n

X

Avogadronumber,k=1,2,arethevanderWaalsenergy (disper-sion)andthecoulombianenergy(polar)respectively. ¨<> ¨denotes atimeaverageoverthedurationofthedynamicsinthe canoni-calensembleNVT,Vcellthecellvolume,theindex“i”referstothe

intramolecularenergyofthemoleculei,andtheindex“c” repre-sentsthetotalenergyofthecell.

AsshownintheworkofHildebrandandScott[34],the compat-ibilitybetweenaplasticizerandapolymercanbedeterminedby themiscibilitybasedonthesolubilityparameter.Theenthalpyof thepolymer(1)−plasticizer(2)mixturecanbedeterminedby:
H=

v

v

v

v

where

v

volumesofthepolymerandtheplasticizerrespectively,
E1and

E2aremolarenergiesofvaporization,x1andx2arevolume

frac-tions.

Aplasticizer(1)andapolymer(2)aremiscibleinallproportion whenı1=ı2[35],whichgivesapositivevalueoftheenthalpyofthe

mixture.ThisassumesthattheGibbsfreeenergyofmixing
Gis negative(
G=
H-T
S)toallowsolutionformation.Inthiscase, alltheinteractionsbetweenthemoleculesoftheplasticizerand thepolymerareofthesameorderofmagnitude.Thedegreeof miscibilitybetweenaplasticizer(1)andapolymer(2)increases asthesquareofthedifferencebetweenthesolubilityparameters
ı=(ı1-ı2)2decreases.

AsimilarapproachwasadoptedbyPrice[36]topredictthe com-patibilitybetweenpolymersandplasticizers, butheusedgroup contribution methodto calculate the solubilityparameter, and foundthattheobtainedvalues areunderestimated.Inthis arti-cle,we willusemolecularsimulationtocalculatethesolubility parameterratherthangroupcontributionmethods.Jarrayetal.[2]

andBenali[37]usedmolecularsimulationstocalculatethe solu-bilityparameterandfoundgoodagreementwiththeexperimental solubilityparametervalues.

3.3.2.2. Computationofthesolubilityparameter. Forthe computa-tionofthesolubilityparameters,werunmolecularsimulationsin thecanonicalensembleNVTwiththeForcite®_moduleofthe

Mate-rialStudioSuiterelease7[31].Simulationsarerunover500pswith atimestepof1fs.ThetemperatureissetatT=298Kandcontrolled byaNoseHooverthermostatwithaQratioequalto0.01.Energy andpressurestabilitywaschecked.Thelast50psareusedfor aver-agingpotentialenergycomponents.Theaveragecohesiveenergy iscomputedtoderivethesolubilityparameterbyusingequation

(2).Thestandarddeviationmethodcanbeevaluatedbytheblock averagesmethod[38].FollowingtheworkofJarrayetal.[2],we estimatedtheaveragestandarddeviationastentimesthestandard errorgivenbyForcite[31].

COMPASSII(Condensed-phaseOptimizedMolecularPotentials forAtomisticSimulationStudiesII)[39]forcefieldwasusedwith itspredefinedatomtype parameters.VanderWaalsinteraction

Fig.3.“Coarse-grained”compounds;moleculesandmonomerconversionintoequallysizedbeads.

was truncated by a spline function after 15.5 angströms. For theCoulombianinteraction,partialchargeswereassignedbythe predefinedforcefieldequilibrationmethod,whiletheEwald sum-mationwasusedtoaccountforthelong-rangeinteractions.

3.3.3. MethodC:DPDmethod

3.3.3.1. Overview of the DPD method.The dissipative particle dynamics method (DPD) is a particle mesoscopic simulation methodwhichcanbeusedforthesimulationofsystemsinvolving colloidalsuspensions, emulsions, polymersolutions, Newtonian fluidsand polymermelts.Thismethodenablesaccessinglarger spatiotemporalscalesthanthoseinthemoleculardynamics.

Recently,anumberofworkershaveusedtheDPDmethodfor thesimulationofpolymersystemsincludingSchulzetal.[40,41], Schlijperetal.[42],TomasiniandTomassone[43],Jarrayetal.[6]

and Caoetal. [44].Also, GamaGoicochea[45] usedit tostudy polymeradsorption.

IntheDPDmethod,thecompoundsarecomposedofmolecules described as a setof soft beads that interact dynamically in a continuousspaceandmovealongtheNewtonmomentum equa-tion.Theseinteractionsbetweenthesoftbeadsgoverntheaffinity betweenthecompoundsandtherefore,controlthefinalstructure builtbythebeadsintheDPDsimulation.

AnimportantparameterintheDPDmethodistheterm ¯aijof

theconservativeforce,whichrepresentsthemaximumrepulsion betweentwounlikebeads;itencompassesallthephysical infor-mationofthesystem.Itcanbedeterminedaccordingtoalinear relationshipwiththeFlory-Hugginsparameterij:

¯aij(¯=3)=¯aii+

ij

0.286 (4)

The number density ¯ is equal to 3 DPD units, for which therepulsionparameter/Flory-Hugginsparameterrelationshiphas beendefined[46].TheFlory-Hugginsvaluescanbecalculatedfrom theHildebrandsolubilityparameter[34]usingtheformula: ij=

(ıi-ıj)2(Vi+Vj)

2kBT (5)

withVthevolumeofthebeads,ıjandıiarethesolubility

param-etersofbeadsiandjrespectively.

Forpolymers,thenumberofbeadsthatcomposesonepolymer chaincanbeestimatedwiththenumberofDPDnDPD:

nDPD= Mw

MmCn

(6)

Mw is themolecular weightof thepolymer,Mm themolecular

weightofthemonomerandCnthecharacteristicratioofthe

poly-mer.AdetaileddescriptionoftheDPDmethodisbeyondthescope ofthisarticlebuthasbeendescribedinourpreviouswork[6]and intheworkofGrootandWarren[46].

3.3.3.2. DPDsimulation parameters. In ourDPD simulations,we usedthesameapproachproposedbyJarrayetal.[6].Polymerand plasticizersmoleculeswerecoarse-grainedintobeads(seeFig.3); A waterbeadrepresents6water molecules(volumeofawater molecule≈30Å3),whichroughlycorrespondstoasinglemonomer ofPVP, andtoahalfmonomerofMCC. PEG400iscomposedof threesimilarbeads;eachonecontainsthesamefragmentwhich wecalledPEG1.Inthesameway,HPMCrepeatingunitis coarse-grainedinto4beads(oneHL,twoHOandoneHC)(Fig.3).

ThenumberofbeadsusedtodescribetheHPMCpolymerin theDPDsimulationsisdeterminedbytheDPDnumbernDPDwhich

wascalculatedusingEq.(6).Theratiocharacteristicwascomputed usingMaterialStudio’s[31]Synthiamodule[47].Wefoundthatthe HPMCpolymerchainiscomposedof10repetitions(nDPD=10),and

theMCCpolymeriscomposedof44beads(nDPD=44).The

conser-vativeforceparametersaijbetweeneverycoupleofbeadsisthen calculatedusingtherelationship(4).Theresultsaresummarized inTable2.

AllDPDsimulationswereperformedwithinMaterialsStudio7 softwarepackage[31].A30×30×30rc3(i.e.24.4×24.4×24.4nm) simulationcellboxwasadoptedwhereperiodicboundary condi-tionswereappliedinallthreedirections.Initially,thebeadswere randomlydispersedinthesimulationcell.EachDPDsimulationran for1000DPDunits(i.e.5374.17ps)whichwassufficienttogeta steadyphase.Theintegrationtimewastakenast=0.02DPDunits (i.e.107.48fs).DPDsimulationswereruninthecanonical ther-modynamicNVTensembleatatemperatureofT=298K.TheDPD parametersaresummarizedinTable3.

Fig.4.s-profileofwater,PVP,HPMC,MCCandPEG400.

Table2

Theconservativeforceparameters ¯aij.

¯aij PVP MCC HL HO HC PEG1 Water

PVP 157.00 MCC 170.85 157.00 HPMC HL 157.00 170.5 157.00 HO 161.14 159.85 161.12 157.00 HC 159.09 179.56 158.82 167.56 157.00 PEG1 157.38 167.64 157.43 159.26 161.33 157.00 Water 256.78 198.64 252.37 222.05 260.48 253.79 157.00 PVP:polyvinylpyrrolidone,MCC:microcrystallinecellulose,HPMC:hydroxypropyl-methylcellulose,PEG:polyethyleneglycol.

Table3

ListofparametersusedinDPDsimulations.

Numberofmoleculesofwaterinonebead 6

Simulationboxsize 24.4×24.4×24.4nm Cut-offradiusrc 8.314Å

Dissipationparameter 4.5DPDunits(i.e. 0.09043gmol−1_fs−1₎ DPDsimulationtime 1000DPDunits(i.e.

5374.17ps) Integrationtime 0.02DPDunits(i.e.

107.483fs) TemperatureT 298K

3.3.4. MethodD:differentialscanningcalorimetry(DSC)

Differential scanning calorimetry (DSC) performs measure-mentsofheatflowbyvaryingthethermalenergysuppliedtothe sample.Thistechniqueisparticularlyusefulfordeterminingthe glasstransitiontemperatureTgandthemeltingtemperatureTm.

Meltingisaphasetransition,characterizedbythemelting tem-peratureTm,thatoccurswhenthepolymerchainsfalloutoftheir crystalstructuresandbecomeadisorderedliquid.

Inthiswork,theDSCtestswerecarriedoutwithadifferential scanningcalorimetryanalyzerDSCQ2000.Thesoftwareusedfor analysisofDSCdatawasUniversalAnalysis2000softwareanalysis. IntheDSCinstrument, thesamplesweresealedinDSC alu-minumpanandscannedbetween25–300◦_{Cwithaheatingrate}

of20◦_Cmn−1_{.Anemptyaluminumpanservedasreference.Each}

panisincontactwithathermocoupleconnectedtoacomputer. Theregistrationofasignalproportionaltothedifferenceinthe

heatflowbetweenthesetwopansisusedtodeterminethemelting temperatureTmandthemeltingenthalpy
H.Thepeak tempera-tureofthemeltingendothermintheDSCcurveswastakentobe themeltingtemperatureTmofthepolymer.
Hwascalculatedby integratingthemeltingpeak’sareaforeachsample.

InourDSCanalysis,westudiedmorepreciselythecrystalline meltingpointsofthefilmsassociatedwiththeappearanceofan endothermicpeakintheDSCcurves.Thismeltingpeakprovides accesstothemeltingtemperatureTm,andtotheenergyrequired

formeltingdifferentmorphologiescrystals.

Toestimatetheinteractionbetweenthematerialsintheblend, weusedtheFlory-Hugginstheory[48].TheFlory-Hugginstheory hasprovidedagoodempiricaldescriptionofthemixingbehaviorof polymer-diluentsystemsandpolymer–polymersystems[49,50]. Caoetal.[51] andMarsacetal.[52,53]usedtheFlory-Huggins theoryfortheestimationofpolymer-solventinteractionusingthe meltingpointdepression dataobtainedfromDSCthermograms. Meltingpointdepressionisthereductionofthemeltingpointofa polymerwhenmixedwithanothermaterialandoccurswhenthe twocomponentsaremiscibleorpartiallymiscible[53].Also,Nishi andWang[54]usedtheFlory-Hugginstheoryfordrug–polymer interaction.For theestimation of theFlory-Huggins interaction parameter  between the plasticizer and a polymer, we have decidedtousethesameconceptandwecalculatedusingthe followingequation: 1 Tm -1 Tm0 =- R
Hm(lnxplast+ (1-1 mr)(1-xplast) +(1-xplast)2) (7)

Fig.5.Dmol3-COSMOsurfacesofHPMC,PVP,MCCandPEG400.

where
Hmisthemeltingheatofthepureplasticizer,TmandT0m

arethemeltingtemperaturesoftheplasticizerinthe plasticizer-polymermixturesandinthepureplasticizerrespectively,Risthe gasconstant,xplastisthevolumefractionoftheplasticizerandmr

istheratioofthevolumeofthepolymerrepeatingunittothatof thepureplasticizer.

A negative  means that the attraction between a polymer–plasticizer pair is stronger than the aver-age attraction between a polymer–polymer pair and a plasticizer–plasticizer pair (i.e., plasticizer–polymer attraction >½(plasticizer–plasticizer+polymer–polymer)attraction).Inthis case,plasticizermoleculesprefertobein contactwithpolymer segmentsthanwiththeplasticizermolecules.Themorenegative thevalueof,thestrongertheattractionbetweentheplasticizer and the polymer, the higher the miscibility, and vice versa; a positive value of  indicates that the polymer and plasticizer moleculestendtobeincontactwiththeirownkind,leadingto repulsionbetweentheplasticizerandthepolymer[55,56].

Fig.6.MiscibilityofHPMC,PVPandMCCwithPEG400predictedfromthesolubility parametercalculations.

Table4

Solubilityparameterscalculatedbymoleculardynamicsandexperiments. Solubilityparameterı(Jcm−3₎1/2

Moleculardynamics Exp.

PVP 21.12±0.16 –

MCC 29.98±0.24 29.3[57]

HPMC 20.68±0.13 22.8[58] PEG400 22.88±0.24 – Water 47.78±0.59 47.9[32] PVP:polyvinylpyrrolidone,MCC:microcrystallinecellulose

.HPMC:hydroxypropyl-methylcellulose,PEG:polyethyleneglycol400.

4. Resultsanddiscussions

4.1. MethodA:-profiles

Fig.4showsthes-profileofPVP,HPMCandPEG400,and com-paresthemtothatofawatermolecule.Fig.5showstheCOSMO surfaceofMCC,PVP,HPMCandPEG400.

HPMChasanasymmetricprofile.Anasymmetricprofilemeans thatthematerialdoesnotfeelcomfortableinitspurestate[4],i.e. thereisanamountofelectrostaticmisfit.HPMChasadominant peak inthenon-polarregionat−0.0029eÅ−2 _{andasmallpeak}

around0.011eÅ−2_{arisinginthepositivepolarregion,andanother}

smallershoulderextendingfrom−0.01toabout0.015eÅ−2

corre-spondingtothepositivelychargedatoms.ThissuggeststhatHPMC moleculesprefertobeincontactwithasolventshowinghydrogen bonddonorcharacteristicsuchaswater.

PVPs-profile,showninFig.4,isalsoasymmetric,ithasamajor non-polarpeakat−0.0028eÅ−2_{andasmallerpeakinthepositive}

regionofs-profile,meaningthatPVPcanonlyactasH-bond accep-torandislookingforaH-bonddonor.ThepolaroxygeninPVPdoes notfindapartnerwithareasonablynegatives;hence,when mix-ingwithwater,thismisfitcanbeadjusted,andthepolaroxygen maypairupwiththepolarhydrogenofwater.PEGhasavery simi-larcurveshapetoHPMC,suggestingsolubilityinwater.FromFig.4, wealsonoticethatHPMC,PVPandPEGhavesimilars-profile,this indicatesasimilarbehaviorinwaterand,consideringthattheyare alllookingforaH-bonddonor,maysuggestthattheyaremiscible witheachotherifweconsidertheoldchemicalaphorism“similia similibussolvuntur”or“likedissolveslike”.MCCmoleculeispolar and hastwo pronouncedpeaksat−0.005eÅ−2 _and0.009eÅ−2_.

Fig.7. ImagesofDPDsimulationofPVP-PEG400,HPMC-PEG400andMCC-PEG40010%–10%(w/w)inwateratthefinalsimulationstep.

Fig.8.Distributionofpolymerbeads(PVP,HPMCandMCC)aroundandthroughPEG.

Inthenegatives-profileregion,thepositionoftheMCCpeakis clearlyshiftedtothenon-polars-profilerangeandbothpeaksare strongerthanthoseexhibitedbythewatermolecules.BothMCC andwaterhaveasimilarsymmetricals-profile,whichmeansthey feelcomfortableintheirpurestate.

The conclusionsobtained fromCOSMO aremostly interpre-tationsbased oncharge distributions, and theydo not provide a quantitativeor a substantialqualitative methodfor assessing polymer-plasticizercompatibility.Nevertheless,theresultscanbe comparedtotheremainingmethodsofthisarticle.

4.2. MethodB:solubilityparameterı

Table 4 compares experimental solubility parameters with thosecalculatedbymolecularsimulations.Wefollowedthesame calculationmethoddescribedaboveandproposedbyJarrayetal.

[2].Theaveragevalueofthecohesiveenergydensityisobtained forallcompoundsfromthelast50picoseconds(ps)ofthe500ps dynamicsimulation,spanning500000timesteps.

Table4showsthatexperimentalHildbrandsolubility param-etersvaluesareclosetothemolecularsimulationresults.Jarray etal.[2]calculatedthesolubilityparameterfordifferentmaterials andalsofoundthatmolecularsimulationgivessolubilityparameter valuesclosetotheexperimentalones.

Calculation of 1ı for PVP, MCC and HPMC with a plas-ticizer (PEG400) indicates the likelihood of miscibility between them (Fig. 6). PEG400 gives 1ı (PEG400-PVP)=10.7<1ı (PEG400-HPMC)=17.5<1ı (PEG400-MCC)=22.4Jcm−3, showing that

the miscibility decreases in the following order:

PEG400-PVP>PEG400-HPMC>PEG400-MCC. This suggests that PVP andHPMCaremorecompatiblewithPEG400asaplasticizerthan MCC.

MethodBbasedonthesolubilityparametercalculations can predictthecompatibilitybetweenthefilm-formingpolymerand theplasticizer;however,itdoesnotprovideinformationrelated tothestructureoftheblend,nordetailsregardingtheinteractions betweenthepolymerchainsandtheplasticizer(i.e.diffusionof plasticizerinthepolymerchains).Inthenextsubsections,wewill useDPDsimulationstovisualizethestructureoftheblendandwe willcomparetheresultstothoseobtainedbymethodB.

4.3. MethodC:DPDsimulations

Inthissection,weexaminethestructureofPVP,HPMCandMCC inthepresenceofaplasticizer(PEG400)usingDPDsimulations. Polymerandplasticizercontentineach mixtureisfixedto10% (w/w).

Foracompoundtobeeffectiveasaplasticizer,itmustbeable todiffuseintothepolymer.Theplasticizer willdiffuseintothe film-formingpolymerwiththerateandextentofdiffusionbeing dependentonitswatersolubilityandaffinityforthepolymerphase

[35].Plasticizersmoleculesactbyinsertingthemselvesbetween thepolymerchainstherebyextendingandsofteningthepolymer. Thiswillimprovethemechanicalpropertiesofthefinalfilm[35]. InFig.7(a)and(b),PVPandPEGaswellasHPMCandPEGarewell mixed,andPVP-PEGformsatubularstructure.InFig.7(c),MCCand PEGdonotmixandMCCsurroundsPEGbeads.

Fig.9.MiscibilityofHPMC,PVPandMCCwithPEG400predictedfromtheDPD simulationsbasedonthepercentageofpolymerthatdoesnotmixwithPEG400.

Fig.8showsthedistributionofpolymerbeads(PVP,HPMCand MCC)aroundandthroughPEGplasticizer.

Thepercentage ofbeadsofpolymerthat coverPEGnetwork Noutside

beads,polymercanbecalculatedbyusingthefollowingequation:

Noutside beads,polymer= 100 NBeads,polymer (NBeads,polymer−

X

Y

Where ri denotes the position vector of the ith polymer bead,

i=1...NBeads,polymer.NBeads,polymer isthetotal numberofpolymer

beads(HPMC,PVPorMCCinourcase),r_jdenotestheposition vec-torofthejthPEGbead,roisthepositionvectorofthebeadatthe

geometriccenteroftheblend,rwateristheradiusofawaterbead

whichisroughlyequaltotheradiusoftheotherbeads,and1is theDiracfunction.

Table5

Meltingtemperature(Tm)andmeltingenthalpy(1Hm).

Tm(◦_{C) 1Hm(Jg}−1₎

PEG 24.7 140.6

PEGinHPMC-PEG 6.3 32.5 PEGinMCC-PEG 16.8 38.1 PEGinPVP-PEG 9.61 37.2

InFig.8(a),PVPshowsthehighestpercentageofbeadsinside PEGnetwork(97%ofPVP),meaningthatPEGisasuitable plasti-cizerforPVP.PEGalsomixeswellwithHPMC(Fig.8(b))with82%of HPMCbeadsthatdiffusesthroughPEGand18%ofHPMCthat sur-roundPEGbeads.MCChowever,completelysurroundsPEGwith 89%ofMCCbeadsoutside PEG,formingathickerexternallayer comparedtothelayersformedinalltheothermixtures.This sug-geststhatMCCisnotcompatiblewithPEGasaplasticizer.Fig.9

summarizesthemiscibilityofthedifferentblendsbasedonthe amountofPEGthatdoesnotmixwiththepolymer.PVPismore compatiblewithPEGthanHPMC,andMCCshowstheleast com-patibility.DPDconclusionsare qualitativelysimilartosolubility parameterresults(obtainedusingMethodB).

4.4. MethodD:DSCresults

Fig.10showsphotographsoftheappearancesofthesamples usedinthisstudyandpreparedusingtheprotocoldescribedin theprevioussection.PEGissolubleinwaterandformsa homoge-noustransparentsolution(Fig.10(a)).HPMCisalsosolubleinwater andHPMC-PEGformsatransparentsolution(Fig.10(b)).MCC-PEG formsawhitesolution(Fig.10(c)).PVP-PEGformsatransparent yellowishmixture(Fig.10(d)).Inallthemixtures,nophase sepa-rationcanbeobservedbythenakedeye.

DSC thermogramsof thePEG400 and the films(HPMC-PEG, MCC-PEG, andPVP-PEG)wererecorded usingDifferential Scan-ningCalorimeterandarepresentedin Fig.11.Theminimumof theDSCmeltinggraphisthemeltingpointthatwedenotedearlier byTm.Table5presentsthemeltingtemperature(Tm)andmelting enthalpy(
Hm)obtainedfromtheDSCanalysis.

The thermal behavior of HPMC-PEG blend presents a low-temperature peak at 6.36◦_{C (enthalpy: 32.5Jg}−1_{). (Fig. 11).}

A decrease in the melting peak may indicate miscibility in

Table6

Resultssummarytable.

Mixture DSCanalysis Thedifferentmethods HPMC-PEG • HPMCformsmoreorderedcrystalstructure

withfewerimpuritiesthanMCC • PartialmiscibilitybetweenPEGandHPMC.

• PVP,HPMCandPEGhavesimilarbehaviorin water(i.e.possiblemiscibilitywitheach other)A_.

• HPMCandPVParemorecompatiblewith PEG400asaplasticizerthanMCCB • PartialmiscibilitybetweenPEGandHPMCC. PVP-PEG • PEGisagoodplasticizerforPVP(i.e.

miscibility).

• HighpercentageofPVPdiffusesinPEG networkC_.

• PVPmixeswithPEGinaqueoussystems BandC_.

MCC-PEG • MCCandPEGmoleculesshowrepulsion. • MCCislesscompatiblewithPEGthanPVP

andHPMC.

• MCCsurroundsPEGinaqueoussystemsC. • MCCisnotcompatiblewithPEGasa

plasticizerBandC_.

A:COSMO,B:SolubilityparameterandMD,C:DPDsimulation.

Fig.11.DSC curvesofPEG 10%(w/w), HPMC-PEG10%–10%(w/w), MCC-PEG 10%–10%(w/w)andPVP-PEG10%–10%(w/w).

drug–polymersystem.Severalresearcharticlesusedthisdecrease ofthemeltingtemperatureasanindicatorofsoliddosageforms polymermiscibility[59,60].MixingHPMCwithPEGreducedthe meltingtemperatureofPEGfrom24.7to6.3◦_{C(i.e.meltingpeak}

depression),indicatingasubstantialdegreeofmixingand misci-bility.AddingPEGtoHPMCenhancesthechainmobility inthe amorphousphaseofHPMC,andHPMC-PEGblendcrystallizeswith moreeaseatlowertemperatures.

MCC-PEG, ontheotherhand, presentsanenthalpy eventat 16.8◦_{C(enthalpy:38.1Jg}−1_{).ThemeltingpeaktemperatureofPEG}

generatedintheMCC-PEGblendishigherthantheonegenerated intheHPMC-PEGblend,suggesting betterinteractions between HPMCandPEGthanbetweenMCCandPEG.

PVP-PEGDSCcurveshowssimilartrendstotheHPMC-PEGcase witha slightlyhigher endothermicpeakat 9.61◦_{C and melting}

enthalpyequalto37.2Jg−1_{,suggestingmiscibilitybetweenPVP}

andPEGthatisslightlylowerthanthatofHPMC-PEG.However,as indicatedbyMengetal.[56],themeltingtemperaturedecreaseis notenoughtoclaimthataplasticizeriscompatiblewitha poly-mer.Intheremainingofthissection,wewillusetheFlory-Huggins theorytoevaluatethepolymer-plasticizermiscibilitywhichisthe sameapproachusedbyCaoetal.[51],Marsacetal.[52,53]and NishiandWang[54].

Themeltingtemperatureandtheenthalpyextractedfromthe DSCthermogramsareusedforthecalculationoftheFlory-Huggins

Fig.12. MiscibilityofHPMC,PVPandMCCwithPEG400predictedfromtheDSC resultsbasedontheFlory-hugginsparameter.

parameter.Asemphasizedintheprevioussection,a negative valueofindicatesthatthepolymerandtheplasticizerare mis-cibleinthemelt,andthepolymer–polymerinteractionbecomes strongerwiththedecreaseofthevalueof[55,56].Fig.12presents theFlory-Huggins interactionparameterofthedifferent blends calculatedusingEq.(7).

InthecaseofMCC-PEG,thepositivevalueof=1.07indicates repulsionbetweenPEGandMCCmolecules.Thisindicates immis-cibility(Fig.12)andthereforeMCCisnotcompatiblewithPEGand mayresultinalessflexiblefilm.Liewetal.[61]alsofoundthat MCCreducesthetensilestrengthandelasticityofthecoatingfilm containingPEG.Thenegativevalueof=−1.79intheHPMC-PEG blendindicatesattractionbetweenHPMCandPEGmolecules.An attractionindicatesmiscibilityandresultsinaflexiblecoatingfilm. ThisisinadequacywiththeexperimentalfindingofLaboulfieetal.

[1]whofoundthatmixingPEGplasticizerwithHPMCimproves themechanicalpropertiesofthecoatingfilm.Liewetal.[61]found thataddingPEGtoHPMCimprovestheelasticityoftheresulting coatingfilm.RegardingPVP-PEGblend,alargernegativevalueof =−3isobtainedsuggestinghighattractionbetweenPEGandPVP molecules,andconsequentlyhighmiscibility.Barmpalexisetal.

addi-tion,Liewetal.[61]foundthataddingPVPtoacompositecoating filmcontainingPEGincreasesbothtensilestrengthandelasticity. Similarly,Dana etal.[63]alsoshowedthattheadditionof PEG resultedinanincreaseinelasticityandadhesivenessofPVP-based hydrogels.

DSCresults(MethodD)aresimilartoDPD(MethodC)and solu-bilityparameterconclusions(MethodB)obtainedpreviously.DSC analysisshowedpartialmiscibilityofHPMCandPVPwithPEGin theblend,butPVPinteractsbetterwithPEGthanHPMC.Inaddition, thereisrepulsionbetweenMCCandPEGindicatinglow compat-ibility.Similarly,fromDPDsimulationsandsolubilityparameter calculation,weconcludedthatPVPismorecompatiblewithPEG thanHPMCandMCC.

5. Conclusion

Inthisstudy,differentmethodsfortheassessmentof polymer-plasticizerscompatibilitywereproposedandcompared.Wehave usedDmol3andCOSMOmodeltogenerates-profilesofthe com-pounds.We haveseenthats-profilesgivevaluableinformation regarding polarities,hb-donorsand hb-acceptors,wichallowto guessthesolubilityofcompounds.MCChasadifferents-profile shapethantheotherpolymer(HPMC,PVPandPEG)andthecurve suggestsalowsolubilityinwater.Butthes-profileresultswere notsufficienttopredictthecompatibilitybetweenPEGandthe dif-ferentpolymers.Weusedmolecularsimulationratherthangroup contributionmethodforthecalculationofthesolubilityparameter, andwefoundgoodagreementwiththeexperiments.Calculation ofsolubilityparameterıusingmolecularsimulationsshowedthat PVPandHPMCaremorecompatiblewithPEG400asaplasticizer thanMCC.

DPDsimulationsshowedthatPEGplasticizermixwellwithPVP indicatinggoodcompatibilitybetweenthem.Partialdiffusionof PEGthroughHPMCisobtainedshowingthatthereispartial mis-cibilitybetweenHPMCandPEG.However,PEGandMCCarenot miscible,andMCCtendstocoverPEGinwaterwithaspherical shell.TheexperimentalresultsobtainedbyDSCaresimilartothe DPDsimulationresults.Itshowedthatthereisabetter interac-tionbetweenHPMCandPEGthanbetweenMCCandPEG,andthat HPMCshowsahigherdegreeofmiscibilityandmoreattractionto PEGmoleculesthanMCC.Inaddition,PEGisagoodplasticizerfor PVP.

Each methodhasits own advantage compared tothe other methods;Forexample,theDPDmethodgivesinsightsonthe struc-tureoftheblendsand predictstheamountofpolymerdiffused insidetheplasticizer.COSMOmethodisfasterbutdoesnotpredict theextentofthecompatibility.TheDSCmethodistime-consuming andmoreexpensivethantheothermethods.

Table6summarizestheresultsobtainedbythedifferent sim-ulationmethodsandcomparesthemwiththeresultsobtainedby DSC.

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