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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - MagnaPharm (Magnetic Control of Polymorphism in Pharmaceutical Compounds)

Teaser

Summary

The arrangement of molecules in an organic crystal can be achieved in a number of different ways. These variations, or polymorphs, can have a profound effect on the physical properties of the resultant crystal. Control over which polymorph grows can be extremely difficult and has been long sought after, especially in the pharmaceutical industry where the differing properties of polymorphs can have a drastic effect on the efficacy of a drug.
This H2020-FETOPEN project initiates a major international effort to direct polymorphism in pharmaceutical compounds through crystallizing in high magnetic fields. The ability to direct polymorphism would have a transformative effect on almost all pharmaceutical compounds, and hence on society.
It is proposed that MagnaPharm will drive forward innovation in pharmaceuticals by exploiting our new discovery that the polymorph and properties of carbamazepine, indomethacin and coronene can be controlled through the application of magnetic fields. We will apply our method to a range of pharmaceutical compounds, initially targeting 12 of the most high-profile, high-worth generic drugs with the aim of controllably synthesizing the desired polymorph of each (the lowest-energy polymorph and/or most processable form with desired properties).
We aim for this goal via an international multidisciplinary approach centred around our discovery, underpinned by the development of a profound theoretical understanding of the effects of magnetic fields on organic crystal growth that will direct the synthetic effort, all drawing on results from cutting edge spectroscopic and crystallographic characterisations.
With the 12 representative generic drug molecules targeted in the initial stages of MagnaPharm responsible for â‚¬18 billion of sales per year worldwide, and the development of many new pharmaceuticals being hampered by solid form issues, control over the production of the most pharmaceutically desired crystal is a truly paradigm-shifting prospect.

Work performed

Work has been successful in controlling the crystal polymorph using magnetic fields of the pharmaceuticals Carbamazepine and Flufenamic acid. UNIVBRIS is currently preparing a paper in close collaboration with UCL, having directed research efforts based on WP2 and vice versa. Pre-nucleation cluster data on three systems featured in this paper has been collected and are in the process of being refined. In addition, macromorphological control has been demonstrated in Mefenamic acid, Flufenamic acid and Ibuprofen. Furthermore, crystals of an ethanol solvate of Lamotrigine has been grown for the first time and the crystal structure determined. In addition, work is continuing on 50 key pharmaceuticals.
In collaboration with UCL and Gonzaga University in Washington State, USA, we are investigating the polymorphological control of 127 chalcones, the majority of which have never been characterised. To-date, we have solved 16 new crystal structures in the chalcone system and have uncovered concomitant polymorphism, UV-induced cycloaddition in the solid-state and fluorescence. All of these data are being continually passed to UCL to correlate with their modelling. Under the application of magnetic fields, we are investigating polymorph control and selection in the chalcones.
RADBOUD has focused on developing methods and designing magnet probes to study the onset of nucleation in magnetic fields. This work was initiated due to the consistently observed depression of crystal growth temperature in WP1. Currently work focusses on two methods beyond the UV-VIS technique: i) Dynamic Light Scattering and ii) Brownian Microscopy using a Schwarzschild objective.
The methodology development for WP2 is developing as per the workplan. UCL have now pioneered the calculation of the diamagnetic susceptibility of organic crystals and are applying it to a variety of systems looking for chemically intuitive trends.
The first experiments of diffraction tomography on Coronene, Delta-Indomethacin and flufenamic acid have been carried out at ULIM. Observations of the behaviour/development of FFA, IMC and CBZ crystals in ethanol have been carried out in-situ in the TEM. For CBZ in-situ observations revealed non-crystalline particles, and for IMC they revealed growth and dissolution of non-crystalline particles. First diffraction tomography experiments have also been carried out on CBZ crystals regarding in-liquid crystallographic identification of crystal growth.

Final results

So far, we have demonstrated (with carbamazepine and Flufenamic acid) that the polymorph of a target molecule that is crystallised under an applied field is different than that observed under no field. Determining the exact moment of nucleation as well as the size of particles and their development (RADBOUD) could aid to elucidate the underlying mechanism of the observed polymorph selection in magnetic fields. These empirical observations obtained in WP1 can then direct WP2 to focus on those candidates.
ULIM are also in the course of investigating this via collection of electron diffraction tomography data sets and associated structure solution analysis of these data sets. This will allow us to identify the polymorphs of the sub-micron sized crystals produced by growing these in a magnetic field, and to compare and contrast this scenario with crystals grown without magnetic field.
The crystal energy landscapes completed so far in D2.1 (UCL) all show that the observed polymorphs are amongst the most stable computer generated structures, and in most cases the most stable experimental polymorph corresponds to the most stable CSP structure. We have calculated the diamagnetic susceptibilities of the polymorphs, and now have a theory which may explain why it is so rare that the field affects the crystallisation.
ULIM are also in the course of investigating this by solving the EDT data sets and producing crystal structures from the data collections. We can then compare these with known polymorphs and the predictions made in WP2 to gain insights into how the new polymorphs crystallise and analyse how the interplay of the functional groups and observed structures may affect the crystal formation. Impactful first results from in-situ observations have now been obtained by ULIM, particularly under D3.2 and D3.3, and we are in the process of reconstructing the crystal structure from electron diffraction tomography data.
In addition, we have discovered an entirely new way to solubilise poorly-soluble pharmaceuticals in extremely high concentrations, using a novel deep eutectic method. This method, where one component of the deep eutectic is volatile at room temperature and pressure, allows for the spontaneous formation of a pharmaceutical, either leading to new polymorphs, or the selection of a desired polymorph. This so-called â€˜deep eutomicâ€™ system has enabled the production of the more efficacious polymorph of paracetamol (form II) for the first time at room temperature without the need for any templates or crystal coformers. This key discovery, along with polymorph/morphological control in 12 different pharmaceuticals and calorimetry/ dissolution kinetics data taken by AstraZeneca will be reported in a paper to be submitted early in 2019. We have also submitted a patent application for this novel method to be able to exploit this discovery in full.