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.
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.
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).
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.
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
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.
Jan Gerit Brandenburg, Jason Potticary, Hazel A. Sparkes, Sarah L. Price, and Simon R. Hall
J. Phys. Chem. Lett., 2017, 8, pp 4319–4324
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.