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1ElectronicSupplementaryInformationIonizedFormofAcetaminophenwithImprovedCompactionPropertiesSathyanarayanaReddyPerumalla,LiminShi,andDepartmentofPharmaceutics,CollegeofPharmacy,UniversityofMinnesota,9-127BWeaver-DensfordHall,ChangquanCalvinSun*308HarvardStreetS.
E.
,Minneapolis,MN55455.
Fax:612-626-2125;Tel:612-624-3722;Email:sunx0053@umn.
eduS1.
Syntheticprocedurefor1.
FigureS1.
X-RaydifferenceFouriermapintheregionoftheatomsO(7)andO(100)inthecrystalstructureof1.
FigureS2.
ORTEPdiagramofasymmetricunitof2.
S2.
MechanicalpropertiesdeterminedbynanoindentationFigureS3.
Nanoindentationload-unloadcurvesofACMFormIand1.
S3.
PowdercompactionS4.
PowderX-raydiffractometryFigureS4.
CalculatedandmeasuredPXRDpatternsof1forbulkpowder.
S5.
X-RaycrystallographicdatacollectionstrategyandrefinementTableS1.
X-Raycrystaldataandstructurerefinementfor1.
TableS2.
X-Raycrystaldataandstructurerefinementfor2.
References2S1.
Synthesisof1:Acetaminophen(ACM,302mg)wasdissolvedinCon.
HCl(1.
6mL)withslightheatingthencooledtoroomtemperature.
Singlecrystalsof1suitableforstructuredeterminationbyX-raydiffractionmethodwereformedwithin30min.
AnX-raydifferenceFouriermaprevealsthatthesiteofprotonationistheamideoxygen,O(7)(FigureS1),whichisconsistentwiththeobservationmadeinliterature(Refs4and7inthepaper).
FigureS1.
X-RaydifferenceFouriermapintheregionoftheatomsO(7)andO(100)inthecrystalstructureof1.
Thesinglemaximumof0.
63e-3neartheatomO7correspondstoprotonatedhydrogen;itsdistancefromO(7)is0.
89,anditsdistancefromO(100)is1.
61.
Wepreparedbulkpowdersof1byeitherlinearlyscalinguptheabove-mentionedreactionorbysuspendingACM(15g)inCon.
HCl(75mL)atroomtemperaturefor12hours.
Ifprolongedheatingisapplied,crystalsof2areproduced(FigureS2).
3FigureS2.
ORTEPdiagramofasymmetricunitof2.
S2.
MechanicalpropertiesdeterminedbynanoindentationCrystalhardness,H,weredeterminedusingananoindenter(TriboIndenterTI-900,HysitronInc.
,MN,USA)withaBerkovichdiamondindentertip.
Beforenanoindentationtesting,thetipareafunctionwasderivedfromaseriesofindentationsonafusedquartzstandard.
Thenanoindentationexperimentswereperformedunderthedisplacementcontrolmode.
Theratesofloadingandunloadingwereboth100nm/sanda10sholdingwasappliedatthemaximumindentationdepthof500nm.
Nanoindentationdatawereanalyzedfollowingthestandardprocedure.
S1RepresentativenanoindentationdataforACMFormIand1areshowninFigureS3.
40100200300400500012341Load(mN)Displacement(nm)FormIFigureS3.
Nanoindentationload-unloadcurvesofACMFormIand1.
Amuchlowerforceisrequiredtomakeanindentofthesamesizeon1thanonACM.
S3.
PowdercompactionAmaterialtestingmachine(model1485,Zwick/Roell,Kennesaw,GA)wasusedtoperformcompactionstudyofbulkpowderof1ataloadingrateof1mm/s.
Powderwasgrindedinamortarusingapestletoreduceparticlesizebeforecompactionstudiesatpressuresrangingfrom25to350MPa,whereadie(round,8mmdiameter)andflat-facedpuncheslubricatedwithmagnesiumstearatewereemployed.
Tabletswererelaxedunderambientenvironmentfor24hbeforemeasuringdiametricalbreakingforceusingatextureanalyzer(TA-XT2i,TextureTechnologiesCorp.
,Scarsdale,NY).
Tablettensilestrengthwascalculatedfromthebreakingforceandtabletdimensionsfollowingstandardprocedure.
S25S4.
PowderX-raydiffractometryX-Raypowderdiffractogramwasobtainedonawide-anglediffractometer(D5005,BruckerAXS).
CuKαradiationwasused.
Thevoltageandcurrentappliedwere45kVand40mArespectively.
Themeasurementwasperformedwithastepsizeof0.
02ofrom5oto35o681012141618202224262830323402040608010012014016018020068101214161820222426283032340204060801001201401601802001recordedRelativeintensityDiffractionangle2θ1calculatedtwothetaandadwelltimeof1s.
PXRDdatawereanalyzedusingacommercialsoftware(JADE,MaterialsDataInc.
,Livermore,CA).
Asidefromthedifferentpeakintensities,whichisattributedtothephenomenonofpreferredorientation,experimentalPXRDpatternofthebulkpowderusedforcompactionmatcheswellwiththecalculatedPXRDpattern(FigureS4).
FigureS4.
CalculatedandmeasuredPXRDpatternsof1forbulkpowder.
6S5.
X-RaycrystallographicdatacollectionstrategyandrefinementSuitablesinglecrystalwasplacedontothetipofa0.
1mmdiameterglassfiberandmountedonaBrukerApexIICCDareadetectordiffractometerfordatacollectionat173(2)KusingMoKαradiation(graphitemonochromator).
S3DataprocessingwasaccomplishedwiththeSAINTprocessingprogram.
ThestructurewassolvedusingBrukerSHELXTLandrefinedusingBrukerSHELXTL.
S4Adirect-methodssolutionwascalculated,whichprovidedmostnon-hydrogenatomsfromtheE-map.
Full-matrixleastsquares/differenceFouriercycleswereperformed,whichlocatedtheremainingnon-hydrogenatoms.
Allnon-hydrogenatomswererefinedwithanisotropicdisplacementparameters.
AllhydrogenatomswerelocatedfromthedifferenceFouriermapandallowedtorideontheirparentatomsintherefinementcycles.
KeycrystaldataanddatacollectionparametersaresummarizedinTableS1andS2for1and2respectively.
DatacollectionandstructuresolutionwereconductedattheX-RayCrystallographicLaboratory,S146KolthoffHall,DepartmentofChemistry,UniversityofMinnesota.
7TableS1.
X-Raycrystaldataandstructurerefinementfor1.
EmpiricalformulaC8H12ClNO3Formulaweight205.
64Temperature173(2)KWavelength0.
71073CrystalsystemMonoclinicSpacegroupP2(1)/cUnitcelldimensionsa=6.
2761(6)α=90°.
b=22.
345(2)β=97.
2570(10)°.
c=6.
8833(7)γ=90°.
Volume957.
56(16)3Z4Density(calculated)1.
426Mg/m3Absorptioncoefficient0.
374mm-1F(000)432Crystalsize0.
36x0.
26x0.
16mm3Thetarangefordatacollection1.
82to26.
84°.
Indexranges-72sigma(I)]R1=0.
0272,wR2=0.
0734Rindices(alldata)R1=0.
0306,wR2=0.
0760Largestdiff.
peakandhole0.
193and-0.
243e.
-38TableS2.
Crystaldataandstructurerefinementfor2.
EmpiricalformulaC6H8ClNOFormulaweight145.
58Temperature173(2)KWavelength0.
71073CrystalsystemMonoclinicSpacegroupP2(1)/cUnitcelldimensionsa=6.
4919(6)α=90°.
b=6.
1159(6)β=90.
0320(10)°.
c=16.
8700(16)γ=90°.
Volume669.
80(11)3Z4Density(calculated)1.
444Mg/m3Absorptioncoefficient0.
480mm-1F(000)304Crystalsize0.
19x0.
16x0.
15mm3Thetarangefordatacollection2.
41to27.
56°.
Indexranges-82sigma(I)]R1=0.
0226,wR2=0.
0658Rindices(alldata)R1=0.
0228,wR2=0.
0660Extinctioncoefficient0.
017(3)Largestdiff.
peakandhole0.
271and-0.
207e.
-39References:(S1)W.
C.
Oliver,G.
M.
Pharr,J.
Mater.
Res.
1992,7,1564-1583(S2)J.
T.
Fell,J.
M.
Newton,J.
Pharm.
Sci.
1970,59,688-691.
(S3)Bruker(2007).
APEX2,SADABSandSAINT.
BrukerAXSInc.
,Madison,Wisconsin,USA.
(S4)G.
M.
Sheldrick,ActaCrystallogr.
2008,A64,112–122.