Polymorphs 多晶体Word格式文档下载.docx
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Polymorphs 多晶体Word格式文档下载.docx
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Ifthepolymorpharedifferent→theshape,sizeanddensityofpolymorpharedifferent.Itwillbedifficulttoseparate.
2.Drying
Ifthereremainalargeamountofsolvent,itishardtoachieveuniformproduct.Itwillalsolengthenthetimeneedtodrywhichiswasteofenergy.
3.ActivityandStability
Polymorphhasdifferentsolubility.Itcan’tbeheatingtodissolvebecausesomewillbecharredonthesideofvessel→Intermediatewilldissolveslowerwhichaffectitsreactivity→toomuchsolventwillbeabsorbed→hardtoagitate.
Itisnecessarytoinvestigatethepolymorphofcrystalatregularintervalsbeforepharmaceuticalprocess.Althoughthecertainformhavebeenmanufacturedformanyyears,itispossibletoformanothermorestablemorph.Itisneededtodeterminetheirphysicalandchemicalproperties,thermodynamicstabilityandkineticsofinterconversiontoidentifythereproducibilityandvariabilityofdrugs.Thereareseveralwaystocheckthepolymorph,likeobservation,meltingpointundermicroscope,suspension/heating,solventofcrystallizationchanges,DSC,IR,X-ray,NMR,TGA.
2.Objective:
1.Tofindtheeffectsofimpuritiesoncrystalnucleationandgrowth.
2.Toidentifytheparametersthataffectsthecrystalphysicalproperties.
3.Discussion
3.1Paracetamol:
Figure1.Thestructureofparacetamol,metacetamol,acetanilide.Metacetamolandacetanilideactasimpurities.
Table1.Thecontentofimpurities:
Paracetamolwithmetacetamol
0.008g/0.192g=4%
Paracetamolwithacetanilide
0.007g/0.192g=4%
3.1.1Microscopyanalysis:
TheMicroscopygraphscomefromA1,A6,A2respectively.
Figure.2Thecrystalpossessamonocliniclattice.Itmeansthatwithoutanyimpurities,paracetamoltendtobeorthorhombicstructure.
Figure.3Itisremainthemonoclinicshapeofcrystal.Butitisobviousthatthesizeofparacetamolwith4%metacetamolismuchsmallerthanthepureparacetamol.Metacetamolhaseffectsonthesizeofcrystalbutlitteeffectontheshapeofcrystal.
Figure.4Thecrystalpossessaorthorhombiclatticewhilethesizeislargerthanthepureparacetamol.Theimpurityacetanilideishaseffectonthesizeofcrystal.
3.1.2MeltingPointAnalysis
Table2.Standardmeltingpoint:
Compound
Meltingpoint(℃)
Paracetamol
169-172
Metacetamol
145-148
Acetanilide
113-115
Thefactorsthataffectthemeltingpoint.:
1.Themeltingpointismainlydecidedbythelatticeenergy.Therearethreefactorsthataffectthelatticeenergywhichistheintermolecularforce(vandervaalsforce),thestructureofmoleculeandthetypeoflattice.
2.Thestructureofparacetamolismoresymmetry→Itisgoodfororderlymoleculearrangement.→Themeltingpointishigher.Themetacetamolislesssymmetryandhaslowermeltingpoint.
3.Ifhydrogenbondsexist,themeltingpointwillincrease.Aprimaryfeatureoftheparacetamolcrystalishydrogenbondingwhichaccountfor30%ofthetotallatticeenergy,whichaffectsthemeltingpointlargely.AcetanilidethatisnoOHGroupdoesn’tofferaprotontotheexistinghydrogenbonding.→lowmeltingpoint.MetacetamolhasanOHgroup,allowthehydrogen-bondingnetworktobepreserved.→lessmeltingpointdecrease.[1]
Theresultsseemthatmanyofthemhaddeviations,whichmaycomefrom:
1.Misoperationofthermometer:
Thermometerdidn’tputontherightplace(notclosetothesamplebutclosetotheheatingsource).Asaresult,Meltingpointsofsomegroupweretoohighortoolow.
Table.3.Afterassessthealldata,thereliablemeltingpointresultsare:
Group
M.PofParacetamol(℃)
M.P.ofParacetamolwithAcetanilide(℃)
M.P.ofParacetamolwithMeacetamol(℃)
B1
170-174
169-174
165-170
B4
160-170
160-167
140-160
B6
163-169
157-160
157-163
B7
174-177
166-174
B8
162-172
162-167
155-158
Table.4.Crystalwithimpuritiescancausethe-reductionofmeltingpoint.
Paracetamol(℃)
DeviationofP+A
DeviationofP+M
-1/0
-5/-4
0/-3
-20/-10
-6/-9
-6/-6
-8/-3
0/-5
-7/-14
AcetonitrileisabletocauselessmeltingpointdecreasethanMetacetamol.
3.1.3IRanalysis:
TheIRspectraofpureparacetamol,paracetamol-metacetamolandparacetamol-acetanilidearefromGroup5,Group4,Group4respectivelylastyear.
Fromthespectra,ItisobviousthatthechemicalshiftisclosesoIRcan’tdistinguishtheparacetamol,paracetamo-metacetamol,paracetamol-acetanilide.
Theoretically,paracetamolandmetacetamolhavethesamefunctiongroupsandsimilarstructurewhenacetanilideislackof–OH.Itishardtodistinguishthemixtureofthem.
3.1.4NMRanalysis
Figure.5.thesturcureofParacetamol(theleft),andmetacetamol
Table.5.theH-NMRanalysisofParacetamol
Peak
Ppm
Area
Numberofhydrogen
Position
A
1.9859
2.9988
3H
C1
B
6.6886
2.0350
2H
C5,C7
C
7.3504
2.0034
C4,C8
D
9.1385
1.0018
1H
C6
E
9.6485
1.0000
-NH
PeakBCDbelongstoaromatichydrogenofParacetamol.ThehydrogenconnectedtoC5,C7isorthotoOH,sotheyareupfield.[2]Thestructureoftheparacetamolissymmetrythatexplainthatonly5Hpeaks.
Table.6.theH-NMRanalysisofMetacetamol:
F
2.0184
3.0622
C1’
G
6.4205
1.0068
1H(triple)
C6’
H
6.9143
1.0148
1H(double)
C8’
I
7.0493
1.0295
C7’
J
7.1856
C4’
K
9.3344
1.0350
C5’,-OH
L
9.7832
1.0198
PeakGHIJKbelongstoaromatichydrogen.
FromthetwoH-NMRs,ItisobviousthatH-NMRcaneasilydistinguishtheisomerofparacetamol.
3.2Metronidazole
Figure.6.Thestructureofmetronidazole,C6H9N3M.W.=171.16
3.2.1Meltingpointanalysis:
Somegroupsdidn’tgetcrystalmaybecausetoomuchsolvent.
Theobjectiveoftheexperimentistofindtheeffectofdifferentsolventsandthedissolvedtemperatureonthemeltingpointofcrystalatdifferenttemperature.
AccordingtothemeltingpointofgroupsfromMoodle.
Polarity[3]:
Water(10.2)>HCl(0.1N)>Ethanol(5.2)>Methanol(5.1)>Dioxane(4.8)>Ethylacetate(4.4)>2-Propanol(4)=THF(4)>Butanol(4)>DCM(3.1)=Dichloromethane(3.1)>Isopropylacetate
Someresultsmaybeunreliable;
likethatthemeltingpointofB9DCMisdifferentfromitofB1DCM.
Comparedthemeltingpointof2-propanole,methanol,ethanol:
Name
2-propanole
methanol
Ethanol
Sturcture
M.P℃at25℃
160-165
142-151
150-154
ItseemsthatCH3,CH2groupwillaffectthehydrogenbonding→thehighmeltingpoint
Fromthetable,itindicatesthat
1.Thedissolvedtemperaturehasslighteffectonthemeltingpoint.
2.Thepolarityhasslighteffectonthemeltingpoint.Thehigherthepolarity,the
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