High pressure methodologies to discover novel physical forms and promote structural variation amongst biological and pharmaceutical materials
Final Report Abstract
The vast majority of our knowledge of the physical and life sciences is derived from experiments carried out at or near Earth's atmospheric pressure. Yet, starting with the few hundred megapascals employed to study protein folding up to the terapascals obtained in dynamic compression experiments, a vast pressure scale is nowadays accessible. At the level of fundamental science, high pressure is a powerful tool for studying the structural, mechanical, electronic, magnetic and vibrational properties of elements and materials. Building on these considerations, the number of high-pressure structural studies on molecular organic-based materials has increased exponentially over the course of the last 10-15 years. In situ high-pressure crystallography plays a very prominent role here, enabling detailed monitoring of structural parameters as a function or pressure, and consequently providing data that can be further analysed to gain a better understanding of structural phenomena and ultimately derive structureproperty relationships. The aim of this DFG-funded project was to use a combination of in situ crystallisation and direct compression experiments to probe phenomena such as conformational flexibility, hydration and polymorphism predominantly for crystals of pharmaceutical and biological relevance at the lower end of the high-pressure scale (below 1 GPa). The most important contributions of this project to the field can be summarised as follows: It has been shown that the technique of high-pressure crystallisation from solution can be extended to the crystallisation of organic molecules of considerable complexity, both in terms of number of atoms in their chemical formula and of available degrees of torsional freedom. The technique is suitable to study biomolecules such as vitamin B12 and cyclodextrins, for which access to third-generation synchrotron X-ray sources was pivotal to elucidate structural details at the atomic level. Active pharmaceutical ingredients of current interest are also amenable to the technique, as was shown for the drug molecule Dalcetrapib in a study carried out with industrial collaborators. The combination of high-pressure crystallographic and computational methodologies has led to a better understanding of intermolecular interactions and solid-state polymorphism. While energy calculations such as those based on periodic DFT or the PIXEL methods can help explain why phase transitions occur or which crystalline forms are the most stable under a given set of pressure/temperature conditions, molecular dynamics gives an insight into how pressure modifies structures at the molecular level and how molecular transformations can occur. The combined approach has been used for rational polymorph screening (Dalcetrapib), to study hydration and solvation (α-cyclodextrin, γ-amino butyric acid, diphenylanthracene) and to study highpressure polymorphism (rubrene, tert-butylamine). High-pressure techniques, particularly high-pressure crystallisation, have shown to be a very powerful and effective means to fill in potential or suspected gaps in a crystal structure landscape that result when crystallisation space is explored by other experimental variables, particularly by temperature alone. This is true for all compounds investigated during the course of this project, most notably for ionic liquids, tertbutylamine hydrates and β-cyclodextrin hydrates.
Publications
- (2012). CrystEngComm, 14, 8664-8670. “A novel hydrate of α-cyclodextrin crystallised under highpressure conditions”
Granero-García, R., Lahoz, F. J., Paulmann, C., Saoaune, S. and Fabbiani, F. P. A.
(See online at https://doi.org/10.1039/c2ce26362a) - (2013). Acta Cryst. Sect. C, 69, 1238-1242. “Crystal structure and packing energy calculations of (+)-6-aminopenicillanic acid”
Saouane, S., Buth, G. and Fabbiani, F. P. A.
(See online at https://doi.org/10.1107/S0108270113025924) - (2013). Chem. Sci., 4 1270-1280. “Pinning down the solid-state polymorphism of the ionic liquid [bmim][PF6]”
Saouane, S., Norman, S. E., Hardacre, C. and Fabbiani, F. P. A.
(See online at https://doi.org/10.1039/c2sc21959j) - (2014), Acta Cryst. Sect. B., 70, 586-594. “β- Cyclodextrin dimethylformamide 12.5 hydrate: a deeper insight into β-cyclodextrin crystal packing”
Granero-García, R. and Fabbiani, F. P. A.
(See online at https://doi.org/10.1107/S2052520614002285) - (2014), J. Phys. Chem. C., 118, 13476- 13483. “Pressure-induced conformational change in organic semiconductors: triggering a reversible phase transition in Rubrene”
Bergantin, S., Moret, M., Buth, G. and Fabbiani, F. P. A.
(See online at https://doi.org/10.1021/jp503271h) - (2014), Z. Krist., 229(9), 667-675 “A highpressure polymorph of propionamide from in situ high-pressure crystallisation from solution”
Fabbiani, F. P. A., Pulham, C. R. and Warren, J. E.
(See online at https://doi.org/10.1515/zkri-2014-1728) - (2014). Acta Cryst. Sect. A., 70, 309-316 “On temperature dependence of H-Uiso in the riding hydrogen model”
Lübben, J., Volkmann, C., Grabowsky, S., Edwards, A., Morgenroth, W., Fabbiani, F. P. A., Sheldrick, G. M. and Dittrich, B.
(See online at https://doi.org/10.1107/S2053273314010626) - (2014). Chem. Commun., 50(15), 1817-1819. “Pharmaceutical hydrates at ambient conditions from high-pressure seeds: a case study on GABA monohydrate”
Fabbiani, F. P. A., Buth, G., Levendis, D. C., Cruz-Cabeza, A. J.
(See online at https://doi.org/10.1039/c3cc48466a) - (2015). Acta Cryst. Sect. B., 71, 247-249. “Probing the structure of framework materials by high pressure and the example of a magnetic, non-porous coordination polymer”
Fabbiani, F. P. A.
(See online at https://doi.org/10.1107/S2052520615009427) - (2015). Cryst. Growth Des., 15(8), 3875-3884. “Structural behavior of the long chain imidazolium-based ionic liquid [C10mim]Cl – water mixtures”
Saouane, S. and Fabbiani, F. P. A.
(See online at https://doi.org/10.1021/acs.cgd.5b00494) - (2015). Nat. Commun., 6, 7793. “Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening”
Neumann, M. A., van de Streek, J., Fabbiani, F. P. A., Hidber, P. and Grassmann, O.
(See online at https://doi.org/10.1038/ncomms8793) - (2016). Crystals, 6(1), 2. “Structural elucidation of αcyclodextrin- succinic acid pseudo dodecahydrate: expanding the packing types of αcyclodextrin inclusion complexes”
Saouane, S. and Fabbiani, F. P. A.
(See online at https://doi.org/10.3390/cryst6010002) - (2016). CrystEngComm, 18, 2173-2181. “X-ray diffraction and computational studies of the pressure-dependent tetrachloroethane-solvation of diphenylanthracene”
Fabbiani, F. P. A., Bergantin, S. Gavezzotti, A., Rizzato, S. and Moret, M.
(See online at https://doi.org/10.1039/c6ce00055j) - (2017). Chem Eur. J., 23, 3691-3698. “Dense Semi-Clathrates at High Pressure: A Study of the Water – tert-Butylamine System”
Granero-García, R., Falentj, A. and Fabbiani, F. P. A.
(See online at https://doi.org/10.1002/chem.201605090)
