CrystEngComm Blog

Nano-sized crystals (or nanocrystals) have better solubilities and dissolution characteristics than larger crystals do.   Preparation of nanocrystals of drug molecules is therefore of interest to the pharmaceutical industry, particularly in cases where poor solubility is an issue.  However, preparation of crystals of the desired size and crucially, the correct polymorph, is not straightforward.  Problems include the long times required and the unwanted formation of amorphous material. One promising method of nanocrystal preparation  is to grow crystals in pores where the size of the pores limits the size of the crystals formed.

A recent paper in CrystEngComm by Myerson and co-workers reports the growth of three nanocrystals of pharmaceutical ingredients (APIs) – ibuprofen, fenofibrate and griseofulvin – using silica, where the pores of the silica structure provide so-called rigid confinement. The formation process is simple, involving loading of the API into the silica, washing to remove any API adhering to the surface (rather than inside the pores, see diagram below), crystallisation and drying. These steps can be varied to optimise the outcomes.

The nanocrystals exhibit enhanced solubilities and improved stabilities, due to the protection offered from e.g. moisture by the pores. The pores also limit possible reorganisations which would result in undesired crystal forms. The authors also highlight that the samples can be directly formulated into capsules without any additional steps, decreasing the formulation time significantly.

Read the full paper for more information:

Formation of organic molecular nanocrystals under rigid confinement with analysis by solid state NMR
X. Yang, T. C. Ong, V. K. Michaelis, S. Heng, J. Huang, R. G. Griffin and A. S. Myerson
CrystEngComm, 2014, DOI: 10.1039/C4CE01087F, Paper

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Gwenda Kyd has a PhD in metallocarborane chemistry from the University of Edinburgh. Other research work includes the spectroscopic study of the structure of glasses and organometallic electron-transfer reactions and the preparation of new inorganic phosphors. She has recently published a book on chemicals from plants.

A new paper by Behrens and co-workers in CrystEngComm details the modulated syntheses of a Zinc-fumarate MOF in both water and DMF. The authors performed kinetic studies for each synthesis, showing that, contrary to what was expected, the modulator increased the rate of formation of the MOF in DMF.

Modulating agents (usually monocarboxylic acids) are added to a MOF reaction mixture to increase the reproducibility and crystallinity of the final product. In coordination modulation, the modulating agent competes with the organic linkers in binding to the metal centre, preventing the formation of impurities but slowing down the reaction. In this current work, the authors chose formic acid as their modulator and performed in situ energy dispersive x-ray diffraction, which allowed for quantitative kinetic data to be produced.

When the authors carried out the synthesis in water, the modulating agent behaved as expected, decreasing the nucleation and growth rates as the formic acid concentration increased. However, when formic acid was added to the DMF-containing reaction mixture, the rate of growth increased. The authors theorise this occurs due to trace water in their commercial formic acid which they investigated by keeping the formic acid concentration constant but increasing water content. This showed remarkable results, increasing the rate constant by 2 orders of magnitude.

By observing that both the presence of a modulator and the water concentration have a large effect on the crystal formation, the authors added to the body of evidence that successful MOF syntheses are highly dependent on subtle changes in reagents and conditions.

Read the full article to find out more

Insight into the mechanism of modulated syntheses: in situ synchrotron diffraction studies on the formation of Zr-fumarate MOF
Gesa Zahn, Philip Zerner, Jann Lippke, Fabian L. Kempf, Sebastian Lilienthal, Christian A. Schröder, Andreas M. Schneidera and Peter Behrens
CrystEngComm, 2014, 16, 9198-9207

Josh Campbell is a PhD student, currently at the University of Southampton, UK studying crystal structure prediction of organic semiconductors. He received his BSc from the University of Bradford.