August 2020

The meta- and para-nitro isomers of (E)-3′-dimethylamino-nitrochalcone (Gm8m and Gm8p) are shown to exhibit concomitant color polymorphism, with Gm8m appearing as yellow (P21/c) or orange (P1̅) crystals and Gm8p appearing as red (P21/n) or black (P21/c) crystals. Each of the polymorphs was characterized optically via UV–vis spectroscopy, and their thermal behavior was characterized via differential scanning calorimetry and low-temperature powder X-ray diffraction. To assess the effect of molecular configuration and crystal packing on the colors of crystals of the different polymorphs, time dependent density functional theory (ωB97x) calculations were carried out on isolated molecules, dimers, stacks, and small clusters cut from the crystal structures of the four polymorphs. The calculated color comes from several excitations and is affected by conformation and most intermolecular contacts within the crystal, with the color differences between polymorphs mainly being due to the differences in the π–π stacking. The visual differences between these related polymorphic systems make them particularly useful for studying polymorph behavior such as phase transitions and concomitant polymorph growth.

February 2020

Here, we show that the development of nuclei and subsequent growth of a molecular organic crystal system can be induced by electron beam irradiation by exploiting the radiation chemistry of the carrier solvent. The technique of Liquid Cell Electron Microscopy was used to probe the crystal growth of flufenamic acid; a current commercialised active pharmaceutical ingredient. This work demonstrates liquid phase electron microscopy analysis as an essential tool for assessing pharmaceutical crystal growth in their native environment while giving insight into polymorph identification of nano-crystals at their very inception. Possible mechanisms of crystal nucleation due to the electron beam with a focus on radiolysis are discussed along with the innovations this technique offers to the study of pharmaceutical crystals and other low contrast materials.

January 2020

Understanding why crystallization in strong magnetic fields can lead to new polymorphs requires methods to calculate the diamagnetic response of organic molecular crystals. We develop the calculation of the macroscopic diamagnetic susceptibility tensor, χcryst, for organic molecular crystals using periodic density functional methods. The crystal magnetic susceptibility tensor, χcryst, for all experimentally known polymorphs, and its molecular counterpart, χmol, are calculated for flexible pharmaceuticals such as carbamazepine, flufenamic acid and chalcones, and rigid molecules, like benzene, pyridine, acridine, anthracene and coronene, whose molecular magnetic properties have been traditionally studied. A tensor addition method is developed to approximate the crystal diamagnetic susceptibility tensor, χcryst, from the molecular one, χmol, giving good agreement with those calculated directly using the more costly periodic density functional method for χcryst. The response of pharmaceutical molecules and crystals to magnetic fields, as embodied by χcryst, is largely determined by the packing in the crystal, as well as the molecular conformation. The anisotropy of χcryst can vary considerably between polymorphs though the isotropic terms are fairly constant. The implications for developing a computational method of predicting whether crystallization in a magnetic field could produce a novel or different polymorph are discussed.

July 2019

Orthocetamol is a regioisomer of the well‐known pain medication paracetamol and a promising analgesic and an anti‐arthritic medicament itself. However, orthocetamol cannot be grown as single crystals suitable for X‐ray diffraction, so its crystal structure has remained a mystery for more than a century. Here, we report the ab‐initio structure determination of orthocetamol obtained by 3D electron diffraction, combining a low‐dose acquisition method and a dedicated single‐electron detector for recording the diffracted intensities. The structure is monoclinic, with a pseudo‐tetragonal cell that favors multiple twinning on a scale of a few tens of nanometers. The successful application of 3D electron diffraction to orthocetamol introduces a new gold standard of total structure solution in all cases where X‐ray diffraction and electron‐microscope imaging methods fail.

March 2019

A new class of deep eutectic solvents are presented where one component of the system is inherently volatile, enabling a premeditated, auto-destructive capability which leads inexorably to a series of novel crystal structures. These deep eutomic solvents are easily-formed liquids with a greatly depressed melting point and exhibit all of the physical characteristics of classical deep eutectic solvents, with the exception that the hydrogen-bond donor component is volatile when exposed to the atmosphere at room temperature. We demonstrate the effectiveness of this concept through the exquisite control of pharmaceutical polymorphism, among which is a more efficacious form of acetaminophen, which can be formed spontaneously for the first time at room temperature.

July 2018

Crystal structure prediction based on searching for the global minimum in the lattice

energy (CSP_0) is growing in use for guiding the discovery of new materials, for

example, new functional materials, new phases of interest to planetary scientists and

new polymorphs relevant to pharmaceutical development. This Faraday Discussion can

assess the progress of CSP_0 over the range of types of materials to which CSP is

currently and could be applied, which depends on our ability to model the variety of

interatomic forces in crystals. The basic hypothesis, that the outcome of crystallisation

is determined by thermodynamics, needs examining by considering methods of

modelling relative thermodynamic stability not only as a function of pressure and

temperature, but also of size, solvent and the presence of heterogeneous templates or

impurities (CSP_thd). Given that many important materials persist, and indeed may be

formed, when they are not the most thermodynamically stable structure, we need to

define what would be required of an ideal CSP code (CSP_aim).

April 2018

Lamotrigine is an active pharmaceutical ingredient used as a treatment for epilepsy and psychiatric disorders. Single crystals of an ethanolate solvate, C9H7Cl2N5C2H5OH, were produced by slow evaporation of a saturated solution from anhydrous ethanol. Within the crystal structure, the lamotrigine molecules form dimers through N—HN hydrogen bonds involving the amine N atoms in the ortho position of the triazine group. These dimers are linked into a tape motif through hydrogen bonds involving the amine N atoms in the para position. The ethanol and lamotrigine are present in a 1:1 ratio in the lattice with the ethyl group of the ethanol molecule exhibiting disorder with an occupancy ratio of 0.516 (14):0.484 (14).

January 2018

Jason Potticary, Michael P.Avery, Doug Mills, Simon R.Hall

Hardware X

Available online 10 January 2018

The permanent magnet apparatus described herein is based upon the C-shaped permanent magnet. It is designed to maximise field strength while increasing the pole gap to 5 mm, providing a sample volume large enough for wide applicability. The production of this equipment aims to provide a homogeneous, high field (∼2.5 T) magnetic sample environment with a volume large enough to accommodate solution crystallisation experiments in sample chambers such as NMR tubes and cuvettes whilst simultaneously allowing direct observation of the sample from a wide angle. Although the resulting rig is not lightweight at 26.5 kg it is eminently more portable than an equivalent electromagnet system (of the order of 625 kg), provides a max field strength of 2.468 T with relatively low stray field.

May 2016

Jason Potticary, Lui R. Terry, Christopher Bell, Alexandros N. Papanikolopoulos, Peter C. M. Christianen, Hans Engelkamp, Andrew M. Collins, Claudio Fontanesi, Gabriele Kociok-Köhn, Simon Crampin, Enrico Da Como & Simon R. Hall

Nature Communications 7, Article number: 11555 (2016)


The continued development of novel drugs, proteins, and advanced materials strongly rely on our ability to self-assemble molecules in solids with the most suitable structure (polymorph) in order to exhibit desired functionalities. The search for new polymorphs remains a scientific challenge, that is at the core of crystal engineering and there has been a lack of effective solutions to this problem. Here we show that by crystallizing the polyaromatic hydrocarbon coronene in the presence of a magnetic field, a polymorph is formed in a β-herringbone structure instead of the ubiquitous γ-herringbone structure, with a decrease of 35° in the herringbone nearest neighbour angle. The β-herringbone polymorph is stable, preserves its structure under ambient conditions and as a result of the altered molecular packing of the crystals, exhibits significant changes to the optical and mechanical properties of the crystal.

August 2017

Jan Gerit Brandenburg, Jason Potticary, Hazel A. Sparkes, Sarah L. Price, and Simon R. Hall


J. Phys. Chem. Lett., 2017, 8, pp 4319–4324
DOI: 10.1021/acs.jpclett.7b01944

We report systematic temperature-dependent X-ray measurements on the most stable carbamazepine polymorph. This active pharmaceutical ingredient is used to demonstrate how the thermal expansion can probe certain intermolecular interactions resulting in anisotropic expansion behavior. We show that most structural features can be captured by electronic structure calculations at the quasi-harmonic approximation (QHA) provided a dispersion-corrected density functional based method is employed. The impact of thermal expansion on the phonon modes and hence free energy contributions is large enough to impact the relative stability of different polymorphs.

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This project has received funding from the European Union's Horizon 2020 Research and Innovation programme under grant agreement number 736899.