1. Manipulating Crystal Growth and Polymorphism by Confinement in Nanoscale Crystallization Chambers
Gabby Riek

2. Contents Concepts Introduction Nucleation: Classical Models
Thermotropic Properties of Ultrasmall Crystals in Nanoporous Silaceous Materials
New Explorations Using Engineered Nanoporous Matrices
Polymorphism and Thermotropic Properties of Nanocrystals
Nanocrystal Orientation
Outlook

3. Concepts
Classic nucleation theory: balance between unfavorable surface free energy and stabilizing volume free energy
Size constraint large ratios of surface area to volume
Confinement of nanoscale pores can influence crystallization pathways
Can control polymorphism

4. Concepts cont.
This account reviews studies of polymorphic and thermotropic properties of crystalline materials in nanometer-scale pores of porous glass powders and porous block-polymer-derived plastic monoliths
Size confinement allows measurement of thermotropic properties

5. Introduction
Difference between bulk and nanoscale is most apparent with respect to melting point depression
Balance between energy just like the Classical nucleation theory
It is suggested that thermodynamic stability of embedded phases and nucleation (a kinetic effect) are linked
Size dependent behaviors in the pores
Selective formation and stabilization of metastable amorphous and crystalline phases
Shift of thermotropic relationships
Discovery of unknown polymorphs

6. Nucleation: Classical Models
Nuclei smaller than rcrit spontaneously dissolve whereas nuclei larger than rcrit spontaneously grow
Energetic profiles determine crystallization outcome
Can be manipulated through changes in solvent and temperature
Are there any other environmental factors that we can change?
Additives can stabilize or arrest growth

7. Polymorphism can be controlled by intervening at the nano-meter scale
Pores serve to confine crystallization at length scales
Gibbs-Thomson Equation
Predicts linear relationship between change in melting point and inverse particle size

8. Theta is assumed to be 180° Used even when wetting is expected
Can we find a more accurate relationship for wetting?
Best relationship because phase transitions are subject to defects, impurities, molecular diffusion, and conformational rearrangements

9. Thermotropic Properties of Ultrasmall Crystals in Nanoporous Silaceous Materials
Size dependence of ∆Hfus should produce a nonlinear relationship between ∆Tm and 1/r.
Disordered liquid layer smaller nuclei are more liquid-like when surrounded by a amorphous shell with fixed thickness
Experiment Results
Benzene and Carbon tetrachloride showed melting point depressions and elevations
Rault et al. found that no crystallization occurred below 1.5nm shell thickness suggesting a critical size for nucleation
Jackson and McKenna found that crystallization of amorphous phases was suppressed in pores with diameters both greater than and less than 2rcrit

11. New Explorations Using Engineered Nanoporous Matrices
Controlled pore glass (CPG)
Permits measurements of parameters from Gibbs- Thomson
Contain random pores with large size distributions
Created by shear alignment of block polymers consisting of at least 2 immiscible segments that can form a structure consisting of nanometer-scale cylindrical domains
From: polyactide (PS-PLA) and poly(cyclohexylethylene)-polylactide (PCHE-PLA) as well as polystyrene-poly(dimethylacrylamide)-polyactide (PS-PDMA-PLA

12. Polymorphism and Thermotropic Properties of Nanocrystals
Experimental Results
2004 Anthranilic Acid (AA)
Pore diameter sizes 7.5, 24, and 55 nm
Form III nm (thermodynamically stable phase)
Form II and III nm
Form II nm
Form III had a larger critical size and form II had a lower free energy
Reflects size dependent polymorph stability
Crystallization of ROY (5-methyl-2-[(2- nitrophenyl)-amino]-3-thio- phenecarbonitrile
20 and 30nm pores
Y form was present in 30nm pores
Y and R suppressed in 20nm pores
What happened when the crystals were heated above the melting temperature and then cooled?
Recrystallization of R form with (111) planes parallel to the pore direction

13. Melting behaviors of R-methyl adipic acid (RMAA) and 2,2,3,3,4,4-hexafluoropentane- 1,6-diol (HFPD)
Melting temperature dependence was as expected from Gibbs- Thomson
Slope differed for HFPD in CPG and p-PS
Suggests dependence on porous matrix (theta is not 180°)
Therefore theta cannot be ignored in Gibbs-Thomson

14. Melting point depression showed a linear dependence while ∆Hfus was also decreasing linearly with increasing 1/r
Still linear because of a decrease in ln(ynl)

15. Acetaminophen Melting point depression consistent with Gibbs-Thomson
4.6nm diameter pore, crystallization suppressed for amorphous phase
Due to critical size effects or kinetic stabilization of amorphous phase
22-60nm pores – metastable form III of acetaminophen
103 nm pores – forms II and III
Upon heating, form III melting point depression could induce melting prior to a III to II transition (like in the bulk material)
Rapidly quenching molten acetaminophen caused an amorphous phase that recrystallized slowly over time

16. Could be used to study the effect of confinement on crystallization
CPG monoliths
Easy handling and cleaning
Polymer softens and pores collapse when melting points are higher than Tg
Could be used to study the effect of confinement on crystallization
Glycine
ß-glycine formed exclusively
55 nm pores slowly transformed to alpha- glycine
Provided estimate of Tm value –cannot be measured due to instability
Initial stage of glycine crystallization forms ß nuclei

17. Pimelic acid, glutaric acid, suberic acid, and coumarin
Exhibited unknown polymorphs with smaller pore sizes
Melting points decreased monotonically
Nanoscale confinement can alter crystallization outcomes and affect polymorph stability

18. Nanocrystal Orientation
ROY nanocrystals – preferentially aligned with (111) crystal planes
Parallel to pore direction
Flufenamic acid, and coumarin
Preferential orientation
n-hexane crystals
Parallel to pore direction, consistent with bulk
Preferred orientation is attributed to a continuous and reversible nucleation and growth
Fast-growth direction parallel can surpass a critical length
Darwinistic competition

20. ß-glycine Chiral and so it has two enantiomorphs
Blocks fast-growth because of enantioselective binding
Change of crystal habit from needles to plates
Enantiopure auxiliary binds selectively –inhibits growth of only one enantiomorphs
Shows that specific binding works at the same length scale as critical nuclei formation
Faces have high surface energies

21. Outlook Polymorph screening and control – crucial to drug development
Small nanoscale pores show unreported polymorphs
Dependence on Gibbs-Thomson might be a new way to manipulate polymorphism and thermotropic properties
New, tunable glass nanopores have enabled investigations of nanocrystal orientation
Preferred orientations argue against heterogeneous nucleation, it is a consequence of critical size effects and surface energy considerations
Confinement favors critical size