CrystEngComm Blog

Control of the crystal form of pharmaceutically important molecules such as paracetamol is crucial to the successful development of drug molecules.  Conventional crystallisation from organic solvents can lead to unwanted forms with poor physicochemical properties.  Crystallisation from ionic liquids (ILs) offers a potential alternative.  ILs are composed entirely of ions and have low melting points as their cationic components are large and unsymmetrical, resulting in low lattice energies.

A new paper shows how the crystallisation of paracetamol, commonly used to reduce pain and fever, from ILs can be controlled.   Use of two ILs, 1-hexyl-3-methylimidazolium hexafluorophosphate ([hmim][PF₆]) and 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF₆]) was studied, under cooling crystallisation conditions.

The thermodynamically stable monoclinic I form of paracetamol was obtained from both ILs but the crystal size and shape varied with the IL used, the solution concentration and the mechanism of crystal growth.  One of the samples produced is shown below.

Crystal habits not commonly produced by conventional crystallisation could be produced – elongated prisms from [bmim][PF₆] and trigonal bipyramids from [hmim][PF₆]. These results suggest that ILs have potential value for the crystal engineering of pharmaceutically important molecules.

For full details, see the paper at:

Crystallisation control of paracetamol from ionic liquids

K. B. Smith, R. H. Bridson and G. A. Leeke

CrystEngComm, 2014, Advance Article
DOI: 10.1039/C4CE01796J

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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.

As the number of cars continues to increase, the problem of hazardous exhaust fumes such as nitrogen dioxide (NO₂) becomes more pressing.  New gas sensors are required to determine the quantities of these gases quickly and accurately.  These are often made of metal oxide semiconductors, including tungsten trioxide (WO₃), which are easily fabricated, low cost materials.  Nano-sized structures typically possess better gas adsorption properties than the bulk material due to favourable surface effects but particles of different shapes (morphologies) could also have different gas-sensing properties.

A new paper presents a method of producing three different morphologies of WO₃ nanostructures and studies their gas-sensing abilities.  In the simple hydrothermal synthesis, control of morphology is achieved using different amounts of citric acid, thereby changing the number of available carboxyl-groups.  This produces nanoparticles (0D), nanoplates (2D) and hierarchical microspheres (3D).  Among these 3 morphologies, the hierarchical structures are found to show the best gas-sensing properties towards NO₂ (see diagram below), with a high sensitivity, a fast response time and operating at a relatively low temperature (200^oC).

Authors conclude that this is due to an increased number of defects present in the structure which increases the number of gas adsorption sites on the surface, while their internal structure accelerates transport of the gas molecules to the sensing sites.

For more information, see the full article at:

Carboxyl-directed hydrothermal synthesis of WO₃ nanostructures and their morphology-dependent gas-sensing properties

Shouli Bai, Kewei Zhang, Xin Shu, Song Chen, Ruixian Luo, Dianqing Li and Aifan Chen

CrystEngComm, 2014, Advance Article
DOI: 10.1039/C4CE01167H

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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.

It gives us great pleasure to assemble a series of issues of CrystEngComm that celebrates 2014 as the International Year of Crystallography (IYCr2014).

Since its inception in 1999, CrystEngComm has been the go-to journal for publishing the highest-quality work in crystal engineering. It was the first online-only journal of the Royal Society of Chemistry and was among the very first to spur and foster an online scientific community.

During the last 15 years, CrystEngComm has witnessed and ushered explosive growth in the field of crystal engineering, as demonstrated by the increase in number of articles published from 9 in 1999 to 1325 in 2013. Indeed, the field of crystal engineering itself now has a highly-successful Gordon Research Conference (GRC) devoted to the subject. Clearly, the launch of CrystEngComm has supported crystal engineering and its numerous sub-areas as the field has developed.

A celebration provides an opportunity to both reflect and look forward. I personally recall travelling as an undergraduate student on a flight to a Chemical Institute of Canada Conference in 1992 and sitting next to a professor who was also travelling to attend the meeting. At that time, I was just beginning to learn how to grow single crystals, as well as collect and solve X-ray data. Our experiments in those days were conducted on a conventional Enraf-Nonius CAD-4 point-detector diffractometer. Data collection times were on the order of days to weeks.

While I had only been a researcher for about one year, in a conversation with the professor I was comfortable enough to remark that, “You really gain a great deal of confidence about chemistry once you have determined a crystal structure”. Clearly, I was already ‘hooked’, at an early stage, by the process of gathering and analysing X-ray data and the insight gained from the X-ray experiment.

Over the past 15 years, CrystEngComm has made many strides scientifically, meaning that we are able to readily draw on an international community to celebrate IYCr2014. To that end, we have assembled a series of issues edited by prominent researchers in crystal engineering that provide a global celebration from regions including:

Each issue contains a series of papers that reflects the wide breath and scope of crystal engineering and modern crystallographic techniques being studied in each region.

Our deepest thanks and gratitude are extended to the Guest Editors (pictures L-R below):

• Michaele Hardie, University of Leeds, UK (CrystEngComm Editorial Board Member)
• Dario Braga, University of Bologna, Italy (first CrystEngComm Scientific Editor)
• Rahul Banerjee, CSIR-National Chemical Laboratory, India (CrystEngComm Associate Editor)
• J. J. Vittal, National University of Singapore, Singapore
• Stuart Batten, Monash University, Australia
• Christer Aakeröy, Kansas State University, USA (CrystEngComm Associate Editor)
• Tomislav Friščić, McGill University, Canada (CrystEngComm Editorial Board Member)

As well as the CrystEngComm staff, for their dedication and hard work to bring such a global effort together.

Guest Editors of IYCr themed issues

All four IYCr14 themed issues have been very successful and I encourage you to take an opportunity to review all of them.

Much change has been realized in crystal engineering and X-ray diffraction during the past two decades. A major change in this regard has been the implementation of charge-coupled device (CCD) detectors, which enable typical data collection times on the order of hours versus days or weeks. The number of structures in the Cambridge Structural Database (CSD) has increased from roughly 200,000 to 700,000 during the time period (one million is coming quickly), which provides the all-important data for crystal engineers to develop improved understandings of structural relationships between solids.

Moreover, with data collection times becoming shorter and shorter, the field of crystal engineering can be expected to deliver even greater insights into the structures and dynamics of crystalline solids. Let us keep each other posted in CrystEngComm.

Leonard R. MacGillivray, Chair, CrystEngComm Editorial Board

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.