Hydra&on)/)dehydra&on)transforma&on)mechanism) …...This document was presented at PPXRD -...

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Hydra&on)/)dehydra&on)transforma&on)mechanism)of)pharmaceu&cal)crystals)revealed)by)SDPD)method)

Hidehiro(Uekusa,)Kotaro)Fujii)Department)of)Chemistry)and)materials)Science)

Tokyo)Ins&tute)of)Technology,)JAPAN)�

XRPD(Techniques/Rietveld(Refinement�

Real%Time%“in#situ”%Reac,on%Chemistry%

May)23,)Beijing�

This document was presented at PPXRD -Pharmaceutical Powder X-ray Diffraction Symposium

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About)this)talk�

1. Hydra&on)/)dehydra&on)phenomena)and)powder)structure)analysis)

–  Dehydra&on)and)Hydra&on)phenomena)

–  Structure)Determina&on)from)Powder)Diffrac&on)data)

–  Pharmaceu&cal)applica&on:)Dehydra&on)of)Acrinol)

2. Isomorphic)desolvates))(dehydrate,)but)same)structure))

–  Cefalexin,)Cefaclor)

–  Erythromycin)A)

Collabora&on)with)Pharmaceu&cal)groups.)Prof.)Katsuhide)Terada)(Toho)univ.))Prof.)Etsuo)Yonemochi)(Hoshi)univ.))

Funding:))Japan)Science)and)Technology)Agency)(JST))(“CREST((Core(Research(

for(EvoluBonal(Science(&(

Technology)(program.”�

In)dehydra&on)&)hydra&on)�

•  Crystal)structure)changes)with)solvent)(water))molecular)leaving)out)or)coming)in)

•  When)we)analyze)the)both)crystal)structures)before)and)aXer)phase)transi&on,)we)can)deduce)the)process)of)dehydra&on)/)hydra&on)

•  For)example)…)

hydrate�

Pseudo)polymorphic)phase)transi&on)between)hydrate)and)anhydrous)phases

!  For)Pharmaceu&cals,)de/hydra&on)is)a)big)problem�

!  Structural)study)is)essen&al)to)understand)and)control)such)dynamic(aspects(of(molecular(crystals.�

hydra,on�

Hydration/dehydration changes(physicochemical(property:(

(Solubility,(soluBon(rate,(stability,(bioavailability…(

dehydra,on�

!  It)may)occur)in)manufacturing,)processing,)and)storage)

Structural,change,makes,powder,crystals!�However,�

Anhydrate�

Powder)structure)analysis)of))dehydra&on)process�

Single,crystal� Powder,crystal,

Structure)Determina&on)from)Powder)Data))technique)resolves)such)problems�

��X�� X��

ab(iniBo)Structure)analysis)from)powder)data)(XRD)�

•  Structure)Determina&on)from)Powder)Diffrac&on)Data)(SDPD))–)determinaBon(&(Rietveld(refinement(

Structure%solu,on%

Direct%space%method:)simula&on)of)crystal)structure)which)reproduce)PXRD�

Structure%refinement%

Rietveld)method:)refine)atomic)and)profile)parameters)to)fit)XRD)pa`ern)by)leastasquare)method.�

What is SDPD?�

Indexing)a)labce)parameters)Extrac,on)a)diffrac&on)intensi&es�

How)to)solve)the)structure)from)XRD)pa`ern)?)))))))Direct(space(method(

"  We)can)Build)a)crystal)structure)model)(simula&on))and)calculate)XRD)pa`ern(blue))to)compare)with)observed)XRD(red))and)then)see)the)difference!))(central)violet)plot)to)become)flat))

"  Bond)lengths)and)angles)are)fixed,)but)torsion)angles)are)free)to)rotate.)Molecular)posi&on,)orienta&on,)and)torsions)are)free.)

Correct!��

Our)previous)works�Twin%Crystal� Phase%Transi,on%

of%Pharmaceu,cals�

Int.(J.(Pharm.,)2009,)369,)12)�

Photoreac,on%in%Crystalline%State�

Mechanochemical%reac,on%(MOF)�

Chem.Comm.,2010,46,)7572�

CrystEngComm,2011,(13,(3197�

Vapor%Induced%%Transforma,ons%

Angew.Chem.Int.Ed.,2006,45,6013�

Chem.Comm,2010,)46,)4264�Cryst.Growth&Des.,2009,)9,)1201�

Dehydra,on%Phase%Transi,on%of%Pharmaceu,cals�

Cryst.Growth&Des.,2012,12,)6165�

J.Phys.Chem(C.,2010,114,580�

All,structures,were,analyzed,by,SDPD,technique�

Cryst.Growth&Des.,2010,10,3176�

Acrinol)(An&sep&cs))

Ethacridine)

Lac&c)acid)

Acrinol)(crystal)structure)and)cRH)�

2H2O�

anhydrous%phase%A

anhydrousphase%B

Anhydrous)A)and)B)have)different)hydra&on)characters)A:)easily)hydrates)around)R.H.)5%)B:)stable)up)to)R.H.)75%�

Crystal)structure)difference?))))SDPD!)�

Dihydrate� Anhydrate)A� Anhydrate)B�Dehydra&on@400K�

Thermal)transi&on)@470K�

Dynamic(Vapor(SorpBon�

J.Phys.Chem(C.,2010,114,580�

Difficult)to)hydrate�

Crystal)structure)and)hydra&on)property�

dehydra&on�

reahydra&on�

Easy)and)smooth�

hydrate anhydrous%phase%A

anhydrous%phase%B

Crystal)structure)similarity)and)difference)explain)the)dehydra&on)/)hydra&on)property�

Erythromycin)A)–)Isomorphic(Desolvates(–�

#  Macrolide)class)of)an&bio&cs)#  C37H67NO13,)m.w.)733.93)g/mol)#  dihydrate)form)is)marketed�

Crystal Growth & Design, 2013, 13 (5), pp 2060–2066�

Erythromycin)A)dihydrate)/)TGaDTA�

dehydra&on�

melt�

crystallize�

melt�

Dihydrate� Anhydrous%Phase%I�

Anhydrous%Phase%II�

DTA�

303))))))323)))))))343)))))))363)))))))383))))))))403)))))))423)))))))443)))))))463)))))))483)))))))))))))))))))))))))))))))))))))))))Temperature)(K)�

Dihydrate� Anhydrate)I� Anhydrate)II�Dehydra&on@360K�

Thermal)transi&on)@430K�

Erythromycin)A))/)XRDaDSC�DSC�XRD�

Two)anhydrous)phases)are)crystalline)states�

Dihydrate�

Anhydrous%Phase%I�

483)473)463)453)443)433)423)413)403)393)383)373)363)353)343)333)323)313)303)298)

rature)(K

Erythromycin)A))/)Dynamic)vapor)sorp&on�

DVS%plot%of%anhydrous%phase%I� DVS%plot%of%anhydrous%phase%II�

Dihydrate�

Anhydrous%Phase%I�

Anhydrous%Phase%I� Dihydrate�

>)RH)5%�

<)RH)5%�

New%hydrate�

Humidity�

nonstoichiometric%hydra,on�

One)water)2.4%�

stoichiometric%hydra,on�

SDPD%for%anhydrous%phases%I%and%II%to%reveal%structural%change�

New%%hydrate�

SDPD)of)Erythromycin)A)/)phase)I)and)II�

[SoXware])DICVOL04,)DASH,)GSAS)

a/Å� 9.5162(3)�

b/Å� 9.5449(3)�

c/Å� 46.255(1)�

V/Å3� 4201.4(3)�

Z(Z’)� 4(1)�

Rwp� 0.0374�

space)group)P212121)

PF%4B2%

SPringR8%BL02B2%

Anhydrous%Phase%I%@%100��

Anhydrous%Phase%II%@%RH%3%�

a/Å� 32.5162(9)�

b/Å� 23.8539(7)�

c/Å� 10.7657(2)�

V/Å3� 8350.3(5)�

Z(Z’)� 8(2)�Rwp� 0.0528�

space)group)P21212)

26%parameters%in%direct%space%method�

Voids)observed)in)the)anhydrous)phase)I�Dihydrate� AnhydrousPhase%I�

#  Anhydrous)phase)I)has)voids)(Isolated))#  Void)posi&ons)are)same)as)water)posi&ons)in)dihydrate)

Anhydrous)phase)I)easily)hydrates)stoichiometrically))�

b�O�

Side)View�Side)View�

a�O�

Voids)observed)in)the)anhydrous)phase)II�

c�O�

Side%View�

a�O�

Large)hydrophobic)voids)(111Å3))exist)between)HB)tetramer)units�

nonstoichiometric)hydra&on)may)occur)in)these)voids�

Anhydrous)II)–)nonstoichiometric)hydra&on�

DVS%plot%of%anhydrous%phase%II�

New%hydrate�

Humidity�

nonstoichiometric)hydra&on�

Isomorphic)de/hydra&on.))Powder)structure)analysis)(SDPD)!�

New%%hydrate�

Li`le)PXR

D)change)!�

isomorphic)desolvates)summary�

In)textbook,))the)idea))is)linked)up)with)“water)channel)or)water)sheet”)structure.�

Now,)we)suggest)“spongealike”)structure)with)voids)can)also)be)“isomorphic)desolvates”,)which)is)only)revealed)by)SDPD)analysis.�

…and,)they)open)and)close)dynamically.�

H� A�

Summary�

Pharmaceu,cal%PseudoRpolymorphic%phase%transi,on%%%%%%%%%%%%%%%%%%%%%%%%%R%hydra,on%/%dehydra,on%structural%change%

Acrinol)–)two)anhydrous)phases,)different)hydra&on)property)Cefalexin)–)channel)water,)block)subastructure)slides)Cefaclor,)Erythromycin)A(II))–)void(structure,(nonstoichiometric((

))))))))))))))))))))))))))))))))))))))))))))))))–)Isomorphic)Desolvates)–)%�

SDPD)is)powerful)technique)in)characteriza&on)of)pharmaceu&cal)crystals)and)in)revealing)dynamic)phenomena)observed)in)them.)

Hydra&on)/)dehydra&on)transforma&on)mechanism) …...This document was presented at PPXRD -...

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