Nadine Candoni

Solution cocrystallization, an effective tool to explore the variety of cocrystal systems: caffeine/dicarboxylic acid cocrystals

Although cocrystals have undergone a recent boost in popularity, limited time is spent on exploring the variety of possible cocrystal phases, which is likely due to the popularity and success of grinding methods. The number of studies where cocrystallization is systematically applied in solution remains limited. In this contribution, we present a rapid method for cocrystal synthesis in solution, which not only provides single crystals suitable for X-ray diffraction structural analysis but also allows one to explore the variety of cocrystal systems (polymorphs and solvates). Applying this approach to caffeine/dicarboxylic acid systems,we discovered 7 cocrystals and solved the structures for 6 of them. Astonishingly, the caffeine/mesaconic acid cocrystal system not only seems to be stoichiometrically diverse but furthermore also shows no less than 4 polymorphs of the 2 : 1 cocrystal.

Practical Physics Behind Growing Crystals of Biological Macromolecules

The aim of this review is to provide biocrystallographers who intend to tackle protein-crystallization with theory and practical examples. Crystallization involves two separate processes, nucleation and growth, which are rarely completely unconnected. Here we give theoretical background and concrete examples illustrating protein crystallization. We describe the nucleation of a new phase, solid or liquid, and the growth and transformation of existing crystals obtained by primary or secondary nucleation or by seeding. Above all, we believe that a thorough knowledge of the phase diagram is vital to the selection of starting position and path for any crystallization experiment.

Are conductance plateaus independent events in atomic point contact measurements? A statistical approach

Conductance-elongation curves of gold atomic wires are measured using a scanning tunneling microscope break junction technique at room temperature. Landauers conductance plateaus are individually identified and statistically analyzed. Both the probabilities to observe and the lengths of the two last plateaus (at conductance values close to 2e(2)/h and 4e(2)/h) are studied. All results converge to show that the occurrences of these two conductance plateaus on a conductance-elongation curve are statistically independent events.

Solvent and additive interactions as determinants in the nucleation pathway: general discussion

Sarah Price opened a general discussion of the paper by Sven Schroeder: I have been generating the thermodynamically plausible crystal structures of organic molecules for many years, and back in 2004 we did a crystal structure prediction (CSP) study on imidazole1 and found that it was relatively straightforward. Following your paper, we have reclassified the low energy structures according to the tilt within the hydrogen-bonded chain and the relative direction of the chains. Although the observed structure was the global minimum, two other structures with a displacement of otherwise identical layers are very close in energy. Do you think that if imidazole had crystallised in one of these alternative structures it would be distinguishable by NEXAFS? This would be a very sensitive test of whether NEXAFS combined with CSP could be used in characterising crystal structures.

Nanotechnologies dedicated to nucleation control

This paper highlights the work of our group on the control and the observation of nucleation with techniques using nanotechnologies. This control is performed either by triggering nucleation in time with an external field or by localising it spatially in a microdroplet. Localisation in time using light irradiation induces nucleation by forming radicals; the use of electric field acts locally on the density of the solution. Localisation in space with a microfluidic device produces hundreds of nanovolume crystallisers where concentration and temperature are easily monitored. Thus, accurate statistical studies lead to the nucleation parameters (metastable zone, nucleation rate and polymorphism). Lastly, confinement with a microdroplet generator permits to reach very high supersaturations in fL to pL volumes allowing nucleation of a single crystal per microdroplet. All these methods clearly enhance nucleation in the metastable zone. Finally, they use small quantities of products offering potentialities for the screening of crystallisation conditions and phases (polymorphism).

Crystallization via tubing microfluidics permits both in situ and ex situ X-ray diffraction

A microfluidic platform was used to address the problems of obtaining diffraction-quality crystals and crystal handling during transfer to the X-ray diffractometer. Crystallization conditions of a protein of pharmaceutical interest were optimized and X-ray data were collected both in situ and ex situ.

Addressing the Stochasticity of Nucleation: Practical Approaches

This chapter presents different practical ways to address nucleation stochasticity. The methods use either statistical studies on spontaneous nucleation or local control of nucleation. Techniques developed in our laboratory are described: droplet-based microfluidics, microinjectors in oil, and external electrical or mechanical fields in confined systems. Results of nucleation kinetics obtained on various molecules are presented in terms of metastable zone, critical supersaturation, nucleation rate, induction time, interfacial energy of the critical nucleus, polymorphism, and detection of the critical nucleus. These practical approaches show considerable potential to increase understanding and control of the nucleation mechanism.