Organic Nucleation: Water Rearrangement Reveals the Pathway of Ibuprofen.

The organic nucleation of the pharmaceutical ibuprofen is investigated, as triggered by the protonation of ibuprofen sodium salt at elevated pH. The growth and aggregation of nanoscale solution species by Analytical Ultracentrifugation and Molecular Dynamics (MD) simulations is tracked. Both approaches reveal solvated molecules, oligomers, and prenucleation clusters, their size as well as their hydration at different reaction stages. By combining surface-specific vibrational spectroscopy and MD simulations, water interacting with ibuprofen at the air-water interface during nucleation is probed. The results show the structure of water changes upon ibuprofen protonation in response to the charge neutralization. Remarkably, the water structure continues to evolve despite the saturation of protonated ibuprofen at the hydrophobic interface. This further water rearrangement is associated with the formation of larger aggregates of ibuprofen molecules at a late prenucleation stage. The nucleation of ibuprofen involves ibuprofen protonation and their hydrophobic assembly. The results highlight that these processes are accompanied by substantial water reorganization. The critical role of water is possibly relevant for organic nucleation in aqueous environments in general.

Phase separation of binary mixtures induced by soft centrifugal fields.

We use the model system ethanol-dodecane to demonstrate that giant critical fluctuations induced by easily accessible weak centrifugal fields as low as 2000g can be observed above the miscibility gap of a binary liquid mixture. Moreover, several degrees above the phase transition, i.e. in the one-phase region, strong gradients of ethanol concentration occur upon centrifugation. In this case, the standard interpretation of sedimentation equilibrium in the analytical ultracentrifuge (AUC) yields an apparent molar mass of ethanol three orders of magnitude higher than the real value. Notably, these composition gradients have no influence on the distribution gradient of solutes such as dyes like Nile red. The thick opaque interphase formed upon centrifugation does not appear as the commonly observed sharp meniscus, but as a turbidity zone, similar to critical opalescence. This layer is a few millimeters thick and separates two fluids with low compositional gradients. All these effects can be qualitatively understood and explained using the Flory-Huggins solution model coupled to classical density functional theory (DFT). In this domain hetero-phase fluctuations can be triggered by gravity even far from the critical point. Taking into account Jean Perrin's approach to external fields in colloids, a self-consistent definition of the Flory effective volume and an explicit calculation of the total free energy per unit volume is possible.

Nonclassical Recrystallization.

Applications in the fields of materials science and nanotechnology increasingly demand monodisperse nanoparticles in size and shape. Up to now, no general purification procedure exists to thoroughly narrow the size and shape distributions of nanoparticles. Here, we show by analytical ultracentrifugation (AUC) as an absolute and quantitative high-resolution method that multiple recrystallizations of nanocrystals to mesocrystals is a very efficient tool to generate nanocrystals with an excellent and so-far unsurpassed size-distribution (PDIc =1.0001) and shape. Similar to the crystallization of molecular building blocks, nonclassical recrystallization removes "colloidal" impurities (i.e., nanoparticles, which are different in shape and size from the majority) by assembling them into a mesocrystal. In the case of nanocrystals, this assembly can be size- and shape-selective, since mesocrystals show both long-range packing ordering and preferable crystallographic orientation of nanocrystals. Besides the generation of highly monodisperse nanoparticles, these findings provide highly relevant insights into the crystallization of mesocrystals.

Two Types of Liquid Phase Separation Induced by Soft Centrifugation in Aqueous Ethyl Acetate Using Ethanol as Cosolvent.

Water/ethyl acetate/ethanol is widely used as a "green" extractant system. We show that 2 different types of phase separation can be induced upon centrifugation in this ternary system using ethanol as a cosolvent of water and ethyl acetate: centrifuge-induced criticality and centrifuge-induced emulsification. The expected composition profiles of samples after centrifugation can be represented by bent lines in a ternary phase diagram when gravitational energy is added to the free energy of mixing. The experimental equilibrium composition profiles behave qualitatively as expected and can be predicted using a phenomenological theory of mixing. The concentration gradients are small except near the critical point, as expected for small molecules. Nevertheless, they are usable when accompanied by temperature cycles. These findings open new possibilities of centrifugal separation, even if control is delicate during temperature cycles. These schemes are accessible even at relatively low centrifugation speed for molecules that float and sediment with apparent molar masses several hundred times larger than the molecular mass.

Thermostable protein-stabilized gold nanoclusters as a peroxidase mimic.

Protein-stabilized gold nanoclusters (AuNCs) are fascinating nanostructures with exciting properties owing to their ultra-small sizes and functional shell. However, their applications under extreme conditions are still complicated, waiting for programmable solutions. Therefore, the design of a multi-functional protein stabilizer for specific purposes gains attention to improve the stability and functionality of AuNCs. Herein, we exploited the thermostability of genetically engineered KlenTaq DNA polymerase containing five cysteine residues (KTQ5C) to synthesize heat-stable AuNCs (AuNC@KTQ5C) and characterize optical, structural, and hydrodynamic properties. Besides their excellent photophysical properties, AuNC@KTQ5C also exhibit superior peroxidase-like (POD-like) catalytic activity following typical Michaelis-Menten kinetics together with a high affinity towards the POD substrate 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)-diammonium salt (ABTS). Moreover, FTIR and relative catalytic activity analysis of AuNC@KTQ5C reveal that KTQ5C is resistant to changes in protein secondary structure while the AuNCs conserve 70-80% of their catalytic performance after heat treatments up to more than 80 °C. Our findings show that stabilizing AuNCs with thermostable KTQ5C not only preserves the advantages of protein-stabilized AuNCs but can also promote the resistance of AuNCs against aggregation due to protein denaturation under extreme reaction temperatures, protecting their fluorescent emission or catalytic activity.

Highly hydrated paramagnetic amorphous calcium carbonate nanoclusters as an MRI contrast agent.

Amorphous calcium carbonate plays a key role as transient precursor in the early stages of biogenic calcium carbonate formation in nature. However, due to its instability in aqueous solution, there is still rare success to utilize amorphous calcium carbonate in biomedicine. Here, we report the mutual effect between paramagnetic gadolinium ions and amorphous calcium carbonate, resulting in ultrafine paramagnetic amorphous carbonate nanoclusters in the presence of both gadolinium occluded highly hydrated carbonate-like environment and poly(acrylic acid). Gadolinium is confirmed to enhance the water content in amorphous calcium carbonate, and the high water content of amorphous carbonate nanoclusters contributes to the much enhanced magnetic resonance imaging contrast efficiency compared with commercially available gadolinium-based contrast agents. Furthermore, the enhanced T1 weighted magnetic resonance imaging performance and biocompatibility of amorphous carbonate nanoclusters are further evaluated in various animals including rat, rabbit and beagle dog, in combination with promising safety in vivo. Overall, exceptionally facile mass-productive amorphous carbonate nanoclusters exhibit superb imaging performance and impressive stability, which provides a promising strategy to design magnetic resonance contrast agent.

Simple Determination of Gold Nanocrystal Dimensions by Analytical Ultracentrifugation via Surface Ligand-Solvent Density Matching.

Analytical ultracentrifugation (AUC) is a powerful technique to observe colloidal nanocrystals (NCs) directly in solution and obtain critical information about their physical-chemical properties. Nevertheless, a more comprehensive implementation of AUC for the characterisation of such a class of crystalline colloids has been traditionally impaired by the requirement of having a priori knowledge of the complex, multilayered structure formed by NC in solution. This includes the nature (density and mass) of the surface ligands (SLs) that provide NC colloidal stability and the shell of solvent molecules formed on it. Herein, we propose a methodology to determine the NCs size by using SLs with a density equal to that of the solvent. Thereby, the buoyancy force of the SL shell is neutral, and the density of the NCs is sufficient a priori knowledge to calculate their related mass and size distributions. The simplicity and reliability of the method are evaluated with cetyltrimethylammonium bromide (CTAB) stabilized spherical gold NCs (AuNCs) of dimensions ranging from 1 to 17 nm. The proposed method has great potential to be transferred to any non-crystalline and crystalline colloids of different nature and composition, which have a density that is equal to the bulk and can be stabilized by SLs having a density that matches that of the solvent.

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.

Morphogenesis of anisotropic nanoparticles: self-templating via non-classical, fibrillar Cd2Se intermediates.

A fibrillar, polymeric intermediate (Cd2Se)n was isolated from the synthesis of CdSe nanorods, which suggests that the reactants themselves can template anisotropic growth. It is shown that high monomer concentration is the principal factor favouring this reaction pathway. The intermediate is distinct from crystalline semiconductor or small clusters and is surprisingly temperature-stable below 250 °C.

Synthesis of calcium carbonate in trace water environments.

Calcium carbonate (CaCO3) was synthesized from diverse water-free alcohol solutions, resulting in the formation of vaterite and calcite precipitates, or stable particle suspensions, with the dimensions and morphologies depending upon the conditions used. The obtained results shed light on the importance of solvation during crystallization of CaCO3 and open a novel synthetic route for its precipitation in organic solvents.

Growth of organic crystals via attachment and transformation of nanoscopic precursors.

A key requirement for the understanding of crystal growth is to detect how new layers form and grow at the nanoscale. Multistage crystallization pathways involving liquid-like, amorphous or metastable crystalline precursors have been predicted by theoretical work and have been observed experimentally. Nevertheless, there is no clear evidence that any of these precursors can also be relevant for the growth of crystals of organic compounds. Herein, we present a new growth mode for crystals of DL-glutamic acid monohydrate that proceeds through the attachment of preformed nanoscopic species from solution, their subsequent decrease in height at the surface and final transformation into crystalline 2D nuclei that eventually build new molecular layers by further monomer incorporation. This alternative mechanism provides a direct proof for the existence of multistage pathways in the crystallization of molecular compounds and the relevance of precursor units larger than the monomeric constituents in the actual stage of growth.

Erratum: Growth of organic crystals via attachment and transformation of nanoscopic precursors.

This corrects the article DOI: 10.1038/ncomms15933.

The Molecular Mechanism of Iron(III) Oxide Nucleation.

A molecular understanding of the formation of solid phases from solution would be beneficial for various scientific fields. However, nucleation pathways are still not fully understood, whereby the case of iron (oxyhydr)oxides poses a prime example. We show that in the prenucleation regime, thermodynamically stable solute species up to a few nanometers in size are observed, which meet the definition of prenucleation clusters. Nucleation then is not governed by a critical size, but rather by the dynamics of the clusters that are forming at the distinct nucleation stages, based on the chemistry of the linkages within the clusters. This resolves a longstanding debate in the field of iron oxide nucleation, and the results may generally apply to oxides forming via hydrolysis and condensation. The (molecular) understanding of the chemical basis of phase separation is paramount for, e.g., tailoring size, shape and structure of novel nanocrystalline materials.