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

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

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

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

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

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

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

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

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

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

Polymorphism and Thermotropic Properties of Nanocrystals Experimental Results 2004 Anthranilic Acid (AA) Pore diameter sizes 7.5, 24, and 55 nm Form III 55 nm (thermodynamically stable phase) Form II and III 24nm Form II 7.5 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

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

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)

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

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

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

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

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

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