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)�
1)
XRPD(Techniques/Rietveld(Refinement�
Real%Time%“in#situ”%Reac,on%Chemistry%
May)23,)Beijing�
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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)
2
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)…)
3
hydrate�
Pseudo)polymorphic)phase)transi&on)between)hydrate)and)anhydrous)phases
4)
! 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�
5
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)�
hv�
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
9
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�
A�
B�
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�
TG�
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�
Anhydrous%Phase%II�
483)473)463)453)443)433)423)413)403)393)383)373)363)353)343)333)323)313)303)298)
Tempe
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%II�
Anhydrous%Phase%I� Dihydrate�
>)RH)5%�
<)RH)5%�
New%hydrate�
Anhydrous%Phase%II�
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/� 9.5162(3)�
b/� 9.5449(3)�
c/� 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/� 32.5162(9)�
b/� 23.8539(7)�
c/� 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))�
c�
b�O�
Side)View�Side)View�
c�
a�O�
Voids)observed)in)the)anhydrous)phase)II�
a�
c�O�
Side%View�
b�
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�
Anhydrous%Phase%II�
New%hydrate�
Anhydrous%Phase%II�
Humidity�
nonstoichiometric)hydra&on�
Isomorphic)de/hydra&on.))Powder)structure)analysis)(SDPD)!�
New%%hydrate�
Li`le)PXR
D)change)!�
isomorphic)desolvates)summary�
19
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�
20)
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.)
