Phase Behavior and Polymorphism of Organic Crystals Confined within Nanoscale Chambers

Abstract

Controlling polymorphism, the ability of a compound to adopt more than one solid-state structure, often relies on empirical manipulations of conditions such as solvent, temperature, and mode of crystallization. Despite a growing interest in nanocrystalline formulations, however, the influence of crystal size on polymorph formation and stability is largely unexplored. Nanocrystals of pimelic acid, HO 2 C(CH 2 ) n-2 CO 2 H (n = 7), glutaric acid (n = 5), suberic acid (n = 8), and coumarin (1,2-benzopyrone) in nanometer-scale pores of controlled pore glass (CPG) beads and hexagonally ordered cylindrical pores of poly(cyclohexylethylene) (p-PCHE) monoliths exhibit size-dependent polymorphism and thermotropic behavior because of the physical constraints imposed by the dimensions of the pores. Pimelic acid, suberic acid, and coumarin also exhibit heretofore unknown polymorphs, denoted δ-pimelic acid, β-suberic acid, and β-coumarin, in CPG with pore sizes <23 nm and p-PCHE with pore diameters <40 nm. The melting points of the confined crystals decrease monotonically with decreasing pore size, and the enantiotropic phase behavior of bulk glutaric acid and suberic acid switches to monotropic when confined within the nanoscale pores of CPG and p-PCHE. Collectively, these results reveal that nanometer-scale size confinement can alter crystallization outcomes and affect polymorph stability compared with bulk crystallization. Moreover, crystallization in very small pores can lead to the discovery of new polymorphs that otherwise would not be detected using conventional screening methods.

One-dimensional self-confinement promotes polymorph selection in large-area organic semiconductor thin films

“…This is analogous, we believe, to the crystallization of organic compounds in nanoporous media. Crystallization of pharmaceutical compounds in nanoscale pores has been shown to enable selective crystallization of different polymorphs 38,41 .…”

“…Careful selection of molar volume of the solvent and surface tension also show unprecedented control of polymorphism, and this effect is explored with the help of molecular simulations. The 1D self-confinement process we report here is analogous to three dimensional (3D) nanoscale confinement in porous media used by the pharmaceutical industry to select polymorphism by using the size-dependent polymorphism of organic crystals 37,38 . The solution-shearing method has the added advantage of producing selected polymorphs over large areas, potentially in a roll-to-roll manner, without the requirement of a porous medium.…”

Guest–host interactions of a rigid organic molecule in porous silica frameworks

“…For example α-glutaric acid, once confined in controlled pore glass, can persist at room temperature for months without detectable phase transformation to its stable bulk phase β-glutaric acid (48). This is a special case of size-induced polymorphism resulting from differences in surface energies or interface energies, discussed in a number of recent papers for unconfined nanocrystals which cannot coarsen at low temperatures (49)(50)(51)(52).…”

Two-Stage Crystallizer Design for High Loading of Poorly Water-Soluble Pharmaceuticals in Porous Silica Matrices

“…www.mdpi.com/journal/crystals mesoporous silica with and without surface modifications and grain size control [23][24][25][26][27][28][29], controlled pore glass [30][31][32][33][34], and fumed silica [35] due to the high degree of control over pore size and inert nature leading to nucleation control and polymorph stabilization [36][37][38][39]. While many studies have used porous silica matrices with extremely small pores (<10 nm) to confine high loadings of the amorphous forms of poorly water-soluble drugs to the effect of dramatically enhanced dissolution profiles [40][41][42][43][44], this study aimed to retain crystallinity of the drug loaded in porous matrices due to the long-term stability requirements for formulated pharmaceuticals [10,45].…”