2021, Tsarfati, Yael, Biran, Idan, Wiedenbeck, Eduard, Houben, Lothar, Cölfen, Helmut, Rybtchinski, Boris

The crystallization mechanisms of organic molecules in solution are not well-understood. The mechanistic scenarios where crystalline order evolves directly from the molecularly dissolved state (“classical”) and from initially formed amorphous intermediates (“nonclassical”) are suggested and debated. Here, we studied crystallization mechanisms of two widely used analgesics, ibuprofen (IbuH) and etoricoxib (ETO), using direct cryogenic transmission electron microscopy (cryo-TEM) imaging. In the IbuH case, parallel crystallization pathways involved diverse phases of high and low density, in which the instantaneous formation of final crystalline order was observed. ETO crystallization started from well-defined round-shaped amorphous intermediates that gradually evolved into crystals. This mechanistic diversity is rationalized by introducing a continuum crystallization paradigm: order evolution depends on ordering in the initially formed intermediates and efficiency of molecular rearrangements within them, and there is a continuum of states related to the initial order and rearrangement rates. This model provides a unified view of crystallization mechanisms, encompassing classical and nonclassical pictures.

2019, Wiedenbeck, Eduard

2020-06, Lukić, Miodrag J., Wiedenbeck, Eduard, Reiner, Holger, Gebauer, Denis

Although Al(III) hydrolysis, condensation, and nucleation play pivotal roles in the synthesis of Al-based compounds and determine their chemical behavior, we still lack experimental evidence regarding the chemistry of nucleation from solution. Here, by combining advanced titration assays, high-resolution transmission electron microscopy (HR-TEM), and 27Al–nuclear magnetic resonance spectroscopy, we show that highly dynamic solute prenucleation clusters (PNCs) are fundamental precursors of nanosolid formation. Chemical changes from olation to oxolation bridging within PNCs rely on the formation of tetrahedral AlO4 in solution and trigger phase separation at low driving force (supersaturation). This does not include the formation of Keggin-Al13 ions, at least during the earliest stages. The PNC pathway of the formation of Al(III) (oxy)(hydr)oxides offers new possibilities toward the development of strategies for controlling the entire crystallization process.

2019, Wiedenbeck, Eduard, Kovermann, Michael, Gebauer, Denis, Cölfen, Helmut

Der Nukleationsmechanismus von Kristallen kleiner organischer Moleküle wurde durch Computersimulationen postuliert, doch bisher mangelt es an experimentellen Nachweisen. Hier wurde ein experimenteller Ansatz entwickelt, mit dem die frühen Stadien der Kristallisation von Ibuprofen als Modellsystem aufgezeigt werden. Ibuprofen vollzieht eine flüssig-flüssig Entmischung. Die binodalen und spinodalen Grenzen dieser Mischungslücke wurden analysiert und der flüssige Charakter der Phase wurde bestätigt. Ein Anstieg der Viskosität hält die kinetische Stabilität der dichten flüssigen Phase aufrecht, die intermolekularen Abstände entsprechen denen in den Kristallstrukturen. Die dichte flüssige Phase wurde als Vorläuferphase der Nukleation von Ibuprofen identifiziert, bei der zunächst eine Verdichtung stattfindet und sich erst später eine strukturelle Ordnung ausbildet. Diese Entdeckung verspricht die Möglichkeit, schwerlösliche Wirkstoffe in wässriger Lösung über klassische Löslichkeitsgrenzen hinaus zu befördern.

2019-09-26, Wiedenbeck, Eduard, Kovermann, Michael, Gebauer, Denis, Cölfen, Helmut

The nucleation mechanism of crystals of small organic molecules, postulated based on computer simulations, still lacks experimental evidence. In this study we designed an experimental approach to monitor the early stages of the crystallization of ibuprofen as pharmaceutically eminent molecule and a model system for small organic molecules. We found that ibuprofen undergoes liquid-liquid phase separation prior to nucleation. The binodal and spinodal limits of the corresponding liquid-liquid miscibility gap were localized by combining potentiometric titration with 1 H NMR spectroscopy and additional analyses. We confirmed the liquid character of this initially formed phase by applying PFG-STE self-diffusion experiments ( 1 H NMR) and found an increase in viscosity sustaining the kinetic stability of the dense liquid intermediate. Intermolecular distances of ibuprofen within the dense liquid phase were found to be similar to those in the crystal forms, according to 2D  1 H- 1 H NOESY measurements. Hence, this dense liquid phase is identified as a precursor phase within a nucleation pathway of ibuprofen, in which densification is followed by structural order generation. Fundamentally, this discovery bears the opportunity and promise to enrich poorly soluble pharmaceuticals beyond classical solubility limitations in aqueous environments.