Miscibility of amorphous solid dispersions: A rheological and solid-state NMR spectroscopy study.

Miscibility is critical in the prediction of stability against crystallization of amorphous solid dispersions (ASDs) in the solid state. However, currently available approaches for its determination are limited by both theoretical and practical considerations. Recently, a rheological approach guided by the polymer overlap concentration (c*) has been proposed for miscibility quantification of ASDs [J.

Probing Molecular Packing of Amorphous Pharmaceutical Solids Using X-ray Atomic Pair Distribution Function and Solid-State NMR.

The structural investigation of amorphous pharmaceuticals is of paramount importance in comprehending their physicochemical stability. However, it has remained a relatively underexplored realm primarily due to the limited availability of high-resolution analytical tools. In this study, we utilized the combined power of X-ray pair distribution functions (PDFs) and solid-state nuclear magnetic resonance (ssNMR) techniques to probe the molecular packing of amorphous posaconazole and its amorphous solid dispersion at the molecular level.

Engineering the glass structure of a discotic liquid crystal by multiple kinetic arrests.

X-ray scattering has been used to characterize the columnar packing and the π stacking in a glass-forming discotic liquid crystal. In the equilibrium liquid state, the intensities of the scattering peaks for π stacking and columnar packing are proportional to each other, indicating concurrent development of the two orders. Upon cooling into the glassy state, the π-π distance shows a kinetic arrest with a change in the thermal expansion coefficient (TEC) from 321 to 109 ppm/K, while the intercolumnar spacing exhibits a constant TEC of 113 ppm/K.

Disrupting the phase separation of KAT8-IRF1 diminishes PD-L1 expression and promotes antitumor immunity.

Immunotherapies targeting the PD-1/PD-L1 axis have become first-line treatments in multiple cancers. However, only a limited subset of individuals achieves durable benefits because of the elusive mechanisms regulating PD-1/PD-L1. Here, we report that in cells exposed to interferon-γ (IFNγ), KAT8 undergoes phase separation with induced IRF1 and forms biomolecular condensates to upregulate PD-L1.

Ultrafast magic angle spinning NMR characterization of pharmaceutical solid polymorphism: A posaconazole example.

Protons represent the most NMR-sensitive nucleus in pharmaceutical compounds. Therefore, proton-detected solid-state NMR techniques under fast magic angle spinning are among the few solutions to overcome the challenge of low sensitivity to analyze natural abundant drug substances and products. In this study, we report the structural characterization of crystal polymorphs of a commercial drug molecule, posaconazole, with a relatively large molecular weight of 700.

Structures of glasses created by multiple kinetic arrests.

X-ray scattering has been used to characterize glassy itraconazole (ITZ) prepared by cooling at different rates. Faster cooling produces ITZ glasses with lower (or zero) smectic order with more sinusoidal density modulation, larger molecular spacing, and shorter lateral correlation between the rod-like molecules. We find that each glass is characterized by not one, but two fictive temperatures T (the temperature at which a chosen order parameter is frozen in the equilibrium liquid).

Structures of glass-forming liquids by x-ray scattering: Glycerol, xylitol, and D-sorbitol.

Synchrotron x-ray scattering has been used to investigate three liquid polyalcohols of different sizes (glycerol, xylitol, and D-sorbitol) from above the glass transition temperatures T to below. We focus on two structural orders: the association of the polar OH groups by hydrogen bonds (HBs) and the packing of the non-polar hydrocarbon groups. We find that the two structural orders evolve very differently, reflecting the different natures of bonding.

Prolific Polymorph Generator ROY in Its Liquid and Glass: Two Conformational Populations Mirroring the Crystalline-State Distribution.

5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, dubbed ROY for its numerous crystal polymorphs of red, orange, and yellow colors, has been studied in its liquid and glassy state by infrared spectroscopy. Two populations of conformers are observed, whose equilibrium is characterized by Δ = 2.4 kJ/mol and Δ = 8.

Amorphous Drug-Polymer Salt with High Stability under Tropical Conditions and Fast Dissolution: The Challenging Case of Lumefantrine-PAA.

Lumefantrine (LMF), a high-mobility and easy-to-crystallize WHO drug for treating malaria, can form an amorphous salt with poly(acrylic acid) (PAA) that is remarkably stable against crystallization at high humidity and temperature and has fast dissolution rate. The amorphous salt up to 75% drug loading was synthesized under a mild slurry condition easily implemented in basic facilities for global health. Salt formation was confirmed by IR spectroscopy and the much elevated glass transition temperature.

Using Deposition Rate and Substrate Temperature to Manipulate Liquid Crystal-Like Order in a Vapor-Deposited Hexagonal Columnar Glass.

We investigate vapor-deposited glasses of a phenanthroperylene ester, known to form an equilibrium hexagonal columnar phase, and show that liquid crystal-like order can be manipulated by the choice of deposition rate and substrate temperature during deposition. We find that rate-temperature superposition (RTS)-the equivalence of lowering the deposition rate and increasing the substrate temperature-can be used to predict and control the molecular orientation in vapor-deposited glasses over a wide range of substrate temperatures (0.75-1.

Organic glasses with tunable liquid-crystalline order through kinetic arrest of end-over-end rotation: the case of saperconazole.

Liquid crystals (LCs) undergo fast phase transitions, almost without hysteresis, leading to the notion that it is difficult to bypass LC transitions. However, recent work on itraconazole has shown that a nematic-to-smectic phase transition can be frustrated or avoided at moderate cooling rates. At each cooling rate, the highest smectic order obtained is determined by the kinetic arrest of the end-over-end molecular rotation.

Improving Stability and Dissolution of Amorphous Clofazimine by Polymer Nano-Coating.

Purpose: To inhibit the surface crystallization and enhance the dissolution of the basic amorphous drug clofazimine by polymer nano-coating.

Methods: The free surface of amorphous clofazimine was coated by dip coating in an alginate solution at pH 7. The stability of the coated amorphous drug against crystallization was evaluated by X-ray diffraction and light microscopy.

Polymer Nanocoating of Amorphous Drugs for Improving Stability, Dissolution, Powder Flow, and Tabletability: The Case of Chitosan-Coated Indomethacin.

As a result of its higher molecular mobility, the surface of an amorphous drug can grow crystals much more rapidly than the bulk, causing poor stability and slow dissolution of drug products. We show that a nanocoating of chitosan (a pharmaceutically acceptable polymer) can be deposited on the surface of amorphous indomethacin by electrostatic deposition, leading to significant improvement of physical stability, wetting by aqueous media, dissolution rate, powder flow, and tabletability. The coating condition was chosen so that the positively charged polymer deposits on the negatively charged drug.

Effect of molecular size and hydrogen bonding on three surface-facilitated processes in molecular glasses: Surface diffusion, surface crystal growth, and formation of stable glasses by vapor deposition.

Recent work has shown that diffusion and crystal growth can be much faster on the surface of molecular glasses than in the interior and that the enhancement effect varies with molecular size and intermolecular hydrogen bonds (HBs). In a related phenomenon, some molecules form highly stable glasses when vapor-deposited, while others (notably those forming extensive HBs) do not. Here we examine all available data on these phenomena for quantitative structure-property relations.

Crystal nucleation rates in glass-forming molecular liquids: D-sorbitol, D-arabitol, D-xylitol, and glycerol.

The rate of crystal nucleation has been measured in four glass-forming molecular liquids: D-sorbitol, D-arabitol, D-xylitol, and glycerol. These polyalcohols have similar rates of crystal growth when compared at the same temperature relative to T (the glass transition temperature), peaking near 1.4 T, while the nucleation rates J are vastly different.