Polymorphs 多晶体.docx

Polymorphs 多晶体.docx

《Polymorphs 多晶体.docx》由会员分享，可在线阅读，更多相关《Polymorphs 多晶体.docx（11页珍藏版）》请在冰点文库上搜索。

Polymorphs多晶体

Title：

PolymorphsPractical

1.Introduction：

Crystallizationisformationofcrystalfromsaturatedsolutionincludingtwosteps，nucleationandgrowthofcrystal.，.Itiscommonlyusedtoseparatesolidsfromliquid.Duringtheprocess，notallthecrystalhavethesamesizeandshape.Oncethesolutionisnotsupersaturatedanymore，thecrystallizationiscompleted.Crystalwillbeformedasanunstablemorphologyfirstandthentransfersintothestablemorphology.

Theatomandmoleculeistendtoformthemoststablestageofbyarrangementwhichmeansthatunderdifferentconditionssuchastemperature,thecrystalmaybeformedindifferentmorphologieswhichiscalledpolymorph.Polymorphismistheexistenceofdifferentmorphologiesofcrystalthathassamecompoundbutdifferentarrangementofmoleculeduringthecrystallizationprocess.Italsoincludessolvatesandamorphs.Differentpolymorphhasdifferentphysicalandchemicalpropertieslikemeltingpoint,chemicalreactivity,apparentsolubility,dissolutionrate,opticalandelectricalproperties,vapourpressureanddensity.

Thecrystalhabitdeterminestheexternalshape（needle，platesorprism）.Manyfactorsaffectthecrystalhabitsuchastemperature，levelofsupersaturation，rateofcooling/agitation,solventpolarity,natureofimpurities,concentration,viscosity.

Duringtheprocess,therearemanythingsneedtobeconsidered:

1.Nucleationandtherateofgrowth

2.Controlofprocessparameter→thekindofproductpolymorph.

3.Thelevelofsupersaturation→mostdifficulttocontrol.

4.Thetemperature.Sometimestheoptimumtemperaturefornucleationisdifferentwiththetemperatureforgrowthofcrystal.

TheAPIs（activepharmaceuticalingredients）ofdrugsaremainlycrystal.Thephysicalpropertiesofcrystalaremainlydeterminedbythemoleculeinternalarrangement.Theinteractionforceandinternalarrangementofthemoleculedirectlyaffectsthesolids.Therearemanyfactorsthatcaninfluenceonthecrystalsuchassize，productionprocess，reactivity，toxicity，bioavailability.Whenthecrystalhaspolymorph，itisnecessarytohavearesearchonthevariabilityandreproducibility.

Duringthepharmaceuticalprocess，somepropertiesofPolymorphismcandirectlyaffectthequalityandprocessabilityofdruglikestability，dissolution，andbioavailability.Anychangesofprocessconditionswillaffectthecrystalhabit，suchassynthesisconditionandstoragecondition.Itisessentialtocontrolthesizeandpurityofproductsbytheminimumcostthoughtheallproductionprocess.ContinuousCrystallizerandBatchCrystallizerhavebeenused.

Polymorphismhaseffectsonthepharmaceuticalpropertiesinseveralwayssuchasbioavailability,stability（bothchemicalandphysical）,processfactors（Hygroscopicity,bulk,mechanicalandrheologicalproperties,easeofisolation,filtrationanddrying）,

Inchemicalproduction,therearethreeaspectneedtobeputattention.

1.Solidhandling

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.

Group

Paracetamol（℃）

DeviationofP+A

DeviationofP+M

B1

170-174

-1/0

-5/-4

B4

160-170

0/-3

-20/-10

B6

163-169

-6/-9

-6/-6

B7

174-177

-8/-3

B8

162-172

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

2H

C4,C8

D

9.1385

1.0018

1H

C6

E

9.6485

1.0000

1H

-NH

PeakBCDbelongstoaromatichydrogenofParacetamol.ThehydrogenconnectedtoC5,C7isorthotoOH，sotheyareupfield.[2]Thestructureoftheparacetamolissymmetrythatexplainthatonly5Hpeaks.

Table.6.theH-NMRanalysisofMetacetamol:

Peak

Ppm

Area

Numberofhydrogen

Position

F

2.0184

3.0622

3H

C1’

G

6.4205

1.0068

1H（triple）

C6’

H

6.9143

1.0148

1H（double）

C8’

I

7.0493

1.0295

1H（triple）

C7’

J

7.1856

1.0000

1H

C4’

K

9.3344

1.0350

1H

C5’,-OH

L

9.7832

1.0198

1H

-NH

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