Cölfen, Helmut
0000-0002-1148-0308 Berufsbeschreibung
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Non-stoichiometric hydrated magnesium-doped calcium carbonate precipitation in ethanol
The effect of Mg2+ on the precipitation pathway of CaCO3 in absolute ethanol has been studied to investigate the role of ion solvation in the crystallization process. Our data reveal that high concentrations of Mg2+ promote the precipitation of an amorphous transient phase together with non-stoichometric hydrated phases of calcium carbonate.
Flüssige metastabile Vorstufen von Ibuprofen als Zwischenprodukt der Nukleation in wässriger Lösung
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.
Stabilization of Mineral Precursors by Intrinsically Disordered Proteins
Biogenic nucleation and crystallization occur in confined spaces with defined interfacial properties. However, the regulatory functions of organic players in the stabilization and transport of inorganic precursors such as ion clusters, liquid‐condensed phases, and amorphous particles are unclear. Given the prevalence of unstructured proteins in biogenic materials, the present study investigates the effects of biomineral‐associated, intrinsically disordered protein domains with simple and repetitive amino acid compositions on mineral nucleation and their capability to form distinct supramolecular assemblies. The quantitative assessment and structural evaluation of the nucleation process reveal that disordered regions confine hydrated mineral precursors within vesicles, transiently suppressing mineral precipitation. Stabilization of the amorphous mineral is attributed to protein self‐association and restructuration toward β‐configurations, triggered by specific bioinorganic interactions. In consequence, the conditioned macromolecules localize at phase boundaries formed upon liquid–liquid demixing of mineral precursors and stabilize the fluidic mineral precursors against crystallization. Thus, the conformational plasticity and self‐association of intrinsically disordered sequences in response to crystallization environments mediates the selection of functional macromolecular subensembles dedicated to biomaterial growth.
Hydration dynamics in CaCO3 nucleation by THz spectroscopy
In CaCO3 nucleation, the role of water remains enigmatic. Changes in THz absorption during the early stages of CaCO3 nucleation evidence altered coupled motions of hydrated calcium and carbonate ions. By high precision THz absorption measurements we were able to follow the changes in the hydration bond dynamics during nucleation. Our THz data strongly suggest that amorphous CaCO3 forms through solidification of initially liquid precursors. Polycarboxylates, which stabilize CaCO3 liquid precursors, significantly enhance the kinetic stability of the metastable liquid-liquid state. The importance of water network dynamics in phase separation mechanisms as tested by THz absorption measurements using a p-Ge spectrometer is likely to be more general for aqueous systems.
Liquid Metastable Precursors of Ibuprofen as Aqueous Nucleation Intermediates
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.
On classical and non-classical views on nucleation
Classical nucleation theory (CNT) is based on the notion of critical nuclei serving as transition states between supersaturated solutions and growing particles. Their excess standard free energy depends on supersaturation, and determines the height of the barrier for phase separation. However, predictions of CNT nucleation rates can deviate from experimental observations by many orders of magnitude. We argue that this is due to oversimplifications within CNT, rendering the critical nucleus essentially a conceptual notion, rather than a truly existing physical entity. Still, given adequate parametrization, CNT is useful for predicting and explaining nucleation phenomena, since it is currently the only quantitative framework at hand. In the recent years, we have been introducing an alternative theory, the so-called pre-nucleation cluster (PNC) pathway. The truly “non-classical” aspect of the PNC pathway is the realization that critical nuclei, as defined within CNT, are not the key to nucleation, but that the transition state relevant for phase separation is based on a change in dynamics of PNCs rather than their size. We provide a summary of CNT and the PNC pathway, thereby highlighting this major difference. The discussion of recent works claiming to provide scientific evidence against the existence of PNCs reveals that such claims are indeed void. Moreover, we illustrate that an erroneous interpretation of the concentration dependence of the free energy has led to a postulated rationalization of the standard free energy of ion pairs and stable ion associates within CNT, which is not sustainable. In fact, stable ion associates are stuck in a free energy trap from the viewpoint of CNT and cannot be considered in a straightforward manner. On the other hand, the notions of the PNC pathway, by dismissing the idea of the CNT-type critical nucleus as a required transition state, overcome this issue. While a quantitative theory of the PNC pathway is eagerly anticipated, the rationalization of experimental observations that are inconsistent with CNT proves its qualitative explanatory power, underpinning great promise towards a better understanding of, for instance, polymorph selection and crystallization control by additives.
Crystallization Caught in the Act with Terahertz Spectroscopy : Non-Classical Pathway for L-(+)-Tartaric Acid
Crystal formation is a highly debated problem. This report shows that the crystallization of l-(+)-tartaric acid from water follows a non-classical path involving intermediate hydrated states. Analytical ultracentrifugation indicates solution clusters of the initial stages aggregate to form an early intermediate. Terahertz spectroscopy performed during water evaporation highlights a transient increase in the absorption during nucleation; this indicates the recurrence of water molecules that are expelled from the intermediate phase. Besides, a transient resonance at 750 GHz, which can be assigned to a natural vibration of large hydrated aggregates, vanishes after the final crystal has formed. Furthermore, THz data reveal the vibration of nanosized clusters in the dilute solution indicated by analytical ultracentrifugation. Infrared spectroscopy and wide-angle X-ray scattering highlight that the intermediate is not a crystalline hydrate. These results demonstrate that nanoscopic intermediate units assemble to form the first solvent-free crystalline nuclei upon dehydration.
On Biomineralization : Enzymes Switch on Mesocrystal Assembly
Cellular machineries guide the bottom-up pathways toward crystal superstructures based on the transport of inorganic precursors and their precise integration with organic frameworks. The biosynthesis of mesocrystalline spines entails concerted interactions between biomolecules and inorganic precursors; however, the bioinorganic interactions and interfaces that regulate material form and growth as well as the selective emergence of structural complexity in the form of nanostructured crystals are not clear. By investigating mineral nucleation under the regulation of recombinant proteins, we show that SpSM50, a matrix protein of the sea urchin spine, stabilizes mineral precursors via vesicle-confinement, a function conferred by a low-complexity, disordered region. Site-specific proteolysis of this domain by a collagenase initiates phase transformation of the confined mineral phase. The residual C-type lectin domain molds the fluidic mineral precursor into hierarchical mesocrystals identical to structural crystal modules constituting the biogenic mineral. Thus, the regulatory functions of proteolytic enzymes can guide biomacromolecular domain constitutions and interfaces, in turn determining inorganic phase transformations toward hybrid materials as well as integrating organic and inorganic components across hierarchical length scales. Bearing striking resemblance to biogenic mineralization, these hybrid materials recruit bioinorganic interactions which elegantly intertwine nucleation and crystallization phenomena with biomolecular structural dynamics, hence elucidating a long-sought key of how nature can orchestrate complex biomineralization processes.
Mineral Nucleation : Stabilization of Mineral Precursors by Intrinsically Disordered Proteins
Biogenic crystallization reactions produce hybrid nanostructured materials under physiological conditions. In article 1802063, Helmut Cölfen and co‐workers identify the disorder to order transitions of biomacromolecules as a regulatory feature of additive‐controlled mineralization. This molecular conditioning generates conformational sub‐ensembles and supramolecular assemblies adept at controlling the pathways of nucleation and crystallization.
Modulating Nucleation by Kosmotropes and Chaotropes : Testing the Waters
Water is a fundamental solvent sustaining life, key to the conformations and equilibria associated with solute species. Emerging studies on nucleation and crystallization phenomena reveal that the dynamics of hydration associated with mineral precursors are critical in determining material formation and growth. With certain small molecules affecting the hydration and conformational stability of co-solutes, this study systematically explores the effects of these chaotropes and kosmotropes as well as certain sugar enantiomers on the early stages of calcium carbonate formation. These small molecules appear to modulate mineral nucleation in a class-dependent manner. The observed effects are finite in comparison to the established, strong interactions between charged polymers and intermediate mineral forms. Thus, perturbations to hydration dynamics of ion clusters by co-solute species can affect nucleation phenomena in a discernable manner.