Solvates and Hydrates Desolvation Mechanisms a Survey

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Solvates and HydratesDesolvation Mechanismsa
Survey
Gérard. Coquerel Unité de Croissance Cristalline
et de Modélisation Moléculaire UPRES EA
3233 gerard.coquerel_at_univ-rouen.fr Erice June
2004
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Outlines
Few words about the context !!! A too short
visit to thermodynamicland Models
available Some illustrative examples Concluding
remarks and bonus (if time available)
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Some Figures !
220 different cocrystallized organic solvent
molecules appear in the organic and
metalloorganic structures. 15 solvents
methanol, dichloromethane, benzene, ethanol,
chloroform, acetonitrile, acetone, toluene, THF,
ethyl acetate, diethyl ether, dioxane, DMSO, DMF,
n-hexane, represent more than 82 of the total
number of solvates. The number of hydrates
exceeds the total number of solvates of organic
structures. Proportion of heterosolvates
(containing up to five different solvent
molecules !) is sharply increasing over the
years. The larger the solute the greater the
probability to crystallize as a solvate or a
heterosolvate. For molecules larger than 1200 Å3
the probability exceeds 40 !
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Visit to Thermodynamicland !
Examples of heterogeneous equilibria involving
more than two phases
H2O
Acétate de sodium
Dehydration of Na2SO4.10H2O and sodium acetate
trihydrate in water
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Nature of the system
ltARSkH2Ogt ? Saturated solution ltASgt ltARgt
Hygroscopicity yes or not ?
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Exchanges of solvents
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The different models of desolvation
Rouen 96 model Concept of transmission of
structural information S. Petit and G. Coquerel,
Chem. Mater., 1996, 8, pp 2247-2258
Galweys Classification Macroscopic mechanisms
and kinetics of the dehydration A.K. Galwey,
Therm. Acta., 355, (2000), pp 181-238
Morriss Classification Environment of the water
molecule K. R. Morris, Polymorphism in
pharmaceutical solids (ed. H G. Brittain),
Marcel Dekker Inc., New York 1999, p.125
Mimuras Classification Classification of
pharmaceutical clathrates Mimura et al.,
Colloids and Surface B Biointerfaces 26 (2002),
pp 397-406
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The Rouen 96 model
C1 channels or layers large enough to allow the
release of the solvent molecules
C2 desolvation energy close to the lattice energy
Cooperative release of solvent molecules
C4 sufficient cristallinity of the resulting
phase
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A case study trehalose dihydrateresults
predicted by the Rouen 96 model
Influence of the experimental conditions of
dehydration
Close to thermodynamic equilibrium
(I-C-C) Dehydration far from equilibrium
amorphous solute (I-C-D)
J. F. Willart et al. J. of Phys. Chem. B 2002
106(13) 3365-3370
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Data ignored in the Rouen 96 model
- the kinetics of desolvation -Formation or not
of an interface -Evolution of the physical
characteristics of the material upon successive
desolvation resolvation cycles - Exchange of
solvents
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Galweys classification Macroscopic mechanisms
and kinetics of the dehydration
Classification according to how water molecule
are released ? 6 different classes are defined
WET (Water Evolution Type)
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Schematic representation of the different classes
WET1 The structure is not affected by the
dehydration
WET4a formation of a waterproof superficial layer
WET 4b the amorphous material recrystallizes
WET2 continuous mode No formation of cracks
WET 4 c The amorphous Material does not
recrystallize
WET3 continuous mode Contraction of the crystal
Lattice induces apparition of cracks.
WET5 and WET6 fusion
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Data ignored
Criteria taken into account
Existence or not of an interface
kinetics Behaviour of the material at a µ scale
Molecular structure of the mother phase and the
daughter phase Influence of the dehydration mode
(e.g. heating rate) Crystallinity of the daughter
phase
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Morris Classification
The initial structures are classified according
to the environment of the water molecules 3
Classes are defined -Class I the water
molecules are encapsulated within the
structure. Destructive mechanism -Class II The
water molecules are located in channels or
between layers The release of the water molecules
occurs at T lt Tboiling(Water) . -Class III
Water molecules (or hydroxyl groups) are strongly
bonded to cations The release of the water
molecules occurs at T gt Tboiling(Water) .
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Data ignored
Data taken into account
The thermal behaviour The structure of the
initial phase
Kinetics and possible reversibility Nature of
the resulting particles size and
crystallinity Possible structural filiations
between mother phase and daughter phase
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Mimuras classification Pharmaceutical
clathrates classification Class A The
dehydration leads to amorphous materials. Water
molecules play an important role in crystal
structure cohesion (no reconstructive step of
the daughter phase) Class B The phase obtained
after dehydration is different from the starting
phase (reconstructive step of the daughter
phase) Class C The dehydration leads only to
variations of cell parameters Class D No
change of the crystal lattice occurs after
dehydration (topotactic only) isomorphous
desolvate
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Data ignored
Data taken into account
- initial structure - final structure

• -other types of crystalline compounds
• -mechanism of dehydration
• -kinetics of dehydration
• -possible formation of a transformation interface

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Characteristics in common of the different models
Class III
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Experimental Results TGA analysis of SR xxx
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TR-XRPD of SR-xxx-1H2O
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Reversibility of the glass transition
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b-cyclodextrin
Cell parameters continuously change as a function
of relative humidity
This type of behaviour corresponds to II-T WET
4b Class II (Morris) Class C (Mimura)
T.Steiner et al., J. Am. Chem. Soc., 1994, 116,
pp 5122-5128
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Cortisone acetate (IICR)
Monohydrate
Form II
translation of slices (002) of steroids
Structural filiation between mother and daughter
phases
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Dexamethasone acetate
Dexamethasone acetate monohydrate gives form II
upon dehydration
60C
initial
Onset of dehydration 57C
Projection along z
Progression of a transformation interface, with
probably a destructive / reconstructive
mechanism (WET 3, I-D-R or I-C-R)
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Dehydration of ?-lactose monitored by microscopy




15 days

EtOH








Faces 0
-
11 (
49)



15 days

EtOH










Faces (hk0) (
49)


Morphology did not evolve during dehydration Only
fractures appeared on (hk0) faces
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Dehydration of a-lactose monohydrate
Dehydration in dry methanol soft dehydration
Determination of cell parameters of phase ?S
Dicvol 91
Cell  triclinic P1 M(20) 41.5 a 19.862Å a
111.19 F(20) 121.5 b 7.88Å b
88.03 Volume  720.04Å3 c 4.986Å g 98.24
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Structure obtained

• Soft dehydration II-C.R model

structural filiations
Type WET 2 Morris Class II or III
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Comparison of the unit-cells
-H2O
Structural filiations between mother and daughter
phases
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Grinding of lactose
DSC analysis and X-ray powder diffraction
Earlier dehydration phenomenon is explained by
the formation of small particles with
strains Diffusion phenomena are minimised and
then a lower dehydration temperature is observed.
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Rehydration of lactose
Sample dehydrated at 130C and submitted to
ambient humidity during 3 days
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Desolvation of cortisone acetate (aceco) solvates
180C
DMSO Solvate
WET 4a mechanism formation of an impermeable
layer which prevents the solvent molecule
departure. Formation of vacuoles of saturated
solution.
DMF Solvate
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Structures of DMSO and DMF aceco solvates
DMSO Solvate
DMF Solvate
Steroid molecules are located in layers
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Desolvation of Dexamethasone acetate (acedex)
solvates
Case of DMF solvate
The desolvation proceeds through an interface
Destructive reconstructive process. WET 3, I-D-C
or I-C-C
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Structure of DMSO and DMF solvates
DMSO solvate
DMF Solvate
Steroid molecules are located along a 21 screw
axis
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Rulid monohydrate
Starting temperature of dehydration 40C The
structure of the initial phase is kept invariant
throughout the heating Checked by XRPD at
different temperatures
Model Rouen 96 this compound belongs to type
II-T Initial packing is kept Complete structural
filiation Model from Galwey type WET I Model
from Morris Class II Model from Mimura class
D
Several cycles of dehydration rehydration on
single crystals (0,2m²/g initially) under RH
100 and 75 lead to stabilisation around de 0,35
et 0,3 m²/g respectively.
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Desolvation of Rulid acetonitrile solvate
DSC analysis shows a broad endothermic event due
to continuous desolvation from room temperature
to 83C
T20C
T83C
Single crystal exhibits no change in
morphology after desolvation by heating
Desolvation of type II-T, WET 1, Class II
(Morris) , Class D (Mimura)
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Structure of solvate acetonitrile
Structure isomorphous to that of the monohydrate
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Solvent exchange via the gas phase case of Rulid
Two days RH100
Acetonitrile solvate
monohydrate
The exchange between acetonitrile and water
molecule is reversible
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Recrystallisation of amorphous Rulid
Amorphous formation - Fast evaporation of
solvents such as chloroform and dimethyl
carbonate -Fusion of the compound
Evolution of the amorphous material left under
various atmospheres
amorphous
acetonitrile saturated atmosphere
RH100
water/acetonitrile Azeotrope (12 / 88) atmosphere
acetonitrile solvate
monohydrate
mixed solvate water/acetonitirile 35 / 65
-gt Access to solid solution Rulid-H2Ox-acetonitr
ile(1-x)
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Solvent exchange with cortisone acetate
Crystals of THF solvate immersed in water turn
into dihydrate
Hypothetical destructive / reconstructive
mechanism which leads to opaque crystals Overall
shape of the initial particle is preserved
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Formation of whiskers
Case of DMSO and DMF solvates of dexamethasone
acetate (ACEDEX)
Case of ACEDEX -DMSO solvate
Whiskers appear 30s the beginning of the
immersion
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Preferential sites for whisker appearance
-defaults on surface of the initial single
crystal -edges and corners of the single crystal
Artificially damaged area by using of a sharp
needle Preferential sites for
whisker formation
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Displacement of a transformation interface
Crystal of ACEDEX-DMSO solvate coated with
waterproof varnish and plunged into water
t30s
t15min
Formation of an interface which moves slowly
into the coated part of the crystal.
t3h
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SEM observation
Initial solvate
Edge of the crystal
Transformed area
Transformed area is composed of fibers of ACEDEX
sesquihydrate The non transformed part of the
ACEDEX DMSO solvate remains smooth
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Focusing on the whiskers lying on the surface
Two types of whiskers hollow type solid type
square section
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Whiskers at high magnification
Light of the channel
Light of the channel nearly closed
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Observation with an optical microscope
Inner part of whisker
X 400
X 500
It seems that whiskers lying on the surface are
like sealed tubes
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Optical microscopy observation of crystals
resulting from a static precipitation Between a
saturated solution in DMSO and pure water
Resultant crystals of a precipitation are
whiskers But they are not hollow
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Growth mechanisms
initial single crystal
water
Hollow whisker
Transformed part made of solid whiskers
F. Mallet, S. Petit, S. Lafont, P. Billot, D.
Lemarchand G. Coquerel, J. Therm. Anal.
Calor., 73, 2003, 459-71
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Influx of water
Defect created by the transformation
Saturated DMSO solution
Droplets of DMSO solution converging towards the
surface
Defect created by the transformation
Influx of water
Interfacial zone
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Hollow whisker growth
The DMSO saturated solution moves towards the
surface
Crystallization of the solute In a shape of a
chimney
convection movement due to the crystallization
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Sealed tube
The internal pressure is no more sufficient to
sustain the growth of the chimney. The pipe
is sealed.
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Experimental assembly designed to produce hollow
whiskers
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Overview of the population of particles
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Hollow whiskers produced by injection of a
concentrated solution through a porous membrane
in an antisolvent
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Observation with an optical microscope
Specific Surface area de 3,3m²/g
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Efflorescence of a TRIMEB n-pentane Solvate
2 phases are obtained with TRIMEB - n-pentane
solvate
non efflorescent
efflorescent
Hypothesis permethylated ? cyclodextrines
complexes are packed into two different ways
ou
Structures to be determined
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Observations on single crystal
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Kinetics
Reversibilty of the mechanism
Type
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Conclusion (1)
Each model sheds light on particular aspects of
the desolvation -mechanism at a molecular scale
(perfect crystal) (Rouen 96) -Kinetics
(Galwey) -environnement of the solvent molecule
(Morris) -nature of the resulting phase
(Mimura) Attempt to bridge these approaches
!..(Rouen 04)
Solvent exchanges are more easily studied in
extreme cases -close to thermodynamic
equilibrium (Rulid) -exchange kinetically driven
very far from equilibrium (Acedex) Intermediate
situations are more difficult to study Kinetics
and history of the material are important
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Conclusion (2)
Various pathways investigated to desolvate a
given phase ( non limitative list)
S-Ax-By
Atmosphere A-B
S-B ou S
liquid B
heating
Possible Formation of Whiskers
S
S-A
Atmosphere With low conc. in A
grinding
S
S
Initial and final structures are not suffisant
for determining -The reversibility of the
mechanism (? reversibility of the reaction). -
influence of the desolvation conditions on the
resulting phase
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Volumic fraction of the solvent molecule vs
mechanism of desolvation
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The quest for the molecular quasi crystals !!!
Do heterosolvates able to reproduce Penrose 3D
pavement i.e. access to quasi-crystal i.e.
Symmetries 5, 7, 8, 9, ? This is treasure
hunt !..
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Thanks are due to
Interreg III Network ESRF
Franck Mallet ( PhD Defence Q4 2004) Samuel
Petit Marie-Noëlle Petit Servane Coste
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