Building solids inside nano-space: from confined amorphous through confined solvate to confined ‘metastable’ polymorph

Abstract

The nanocrystallisation of complex molecules inside mesoporous hosts and control over the resulting structure is a significant challenge. To date the largest organic molecule crystallised inside the nano-pores is a known pharmaceutical intermediate - ROY (259.3 g mol(-1)). In this work we demonstrate smart manipulation of the phase of a larger confined pharmaceutical - indomethacin (IMC, 357.8 g mol(-1)), a substance with known conformational flexibility and complex polymorphic behaviour. We show the detailed structural analysis and the control of solid state transformations of encapsulated molecules inside the pores of mesoscopic cellular foam (MCF, pore size ca. 29 nm) and controlled pore glass (CPG, pore size ca. 55 nm). Starting from confined amorphous IMC we drive crystallisation into a confined methanol solvate, which upon vacuum drying leads to the stabilised rare form V of IMC inside the MCF host. In contrast to the pure form, encapsulated form V does not transform into a more stable polymorph upon heating. The size of the constraining pores and the drug concentration within the pores determine whether the amorphous state of the drug is stabilised or it recrystallises into confined nanocrystals. The work presents, in a critical manner, an application of complementary techniques (DSC, PXRD, solid-state NMR, N2 adsorption) to confirm unambiguously the phase transitions under confinement and offers a comprehensive strategy towards the formation and control of nano-crystalline encapsulated organic solids.

Structure and Mobility of Lactose in Lactose/Sodium Montmorillonite Nanocomposites

“…62 It is known that nanoconfined/surface molecules demonstrate increased mobility that may lead to loss 23 of CP signal. 22,[63][64][65][66] Furthermore, the decreased signal intensity in the CP/MAS experiment can be related partially to the paramagnetic impurities present in the naturally sourced clay, that is, 2.9 wt% of the Fe(III) ions. 67 The substantial decrease in the longitudinal (T1) relaxation times due to contribution from electron-nuclear spin relaxation mechanism led to an overall decrease of the signal intensity.…”

“…Recently it has been demonstrated that increased stabilization of amorphous drug and excipients can be obtained by mixing these with inert clay or silicate particles, or by nanoconfinement within mesoporous silica. [22][23][24][25][26][27] The advanced studies of structure and dynamics in such materials at different lengths scales, that is, from molecular level to meso-and microstructure are needed to provide a more detailed insight into the origins of control of physical stability and compaction properties.…”

19F NMR Spectroscopy as a Highly Sensitive Method for the Direct Monitoring of Confined Crystallization within Nanoporous Materials

“…[2] Furthermore,the engineering of nanocrystals confined within nanosized chambers of controlled pore glasses yielded new crystalline structures,s tabilized metastable polymorphs,o r helped formulating amorphous drug-delivery systems. [3][4][5] Although the number of studies aimed at new applications of porous silica materials is rising, there is aconsiderable lack of molecular-level understanding of the phenomena that govern self-assembly in such systems.For example,ibuprofen, benzoic acid, and lauric acid confined within MCM-41 silica (pore diameter ca. 3-4 nm) have been found to be in ahighly mobile state,a sl iquid-like behavior was observed by solidstate NMR spectroscopy.…”

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization

“…The metastable α‐polymorph of indomethacin was also found to crystallize selectively on the layered cellulose nanocrystals generated by dip coating (Lu et al, ). A recently discovered form V of indomethacin was found to stabilize in nanoconfinement of the controlled porosity silica (Nartowski, Tedder, Braun, Fábián, & Khimyak, ). Metastable polymorphs of olanzapine (Warzecha et al, ), tolbutamide (Zhang et al, ) and mefenamic acid (Case et al, ) were also successfully crystallized using different heterosurfaces.…”