(in collaboration with Dr David Allan, Dr Simon Parsons and using the facilities in the Centre for Science at Extreme Conditions

The application of pressures in the range 0.5-150 kbar to small inorganic and organic molecules can induce very dramatic changes in the way that molecules interact with each other in the solid state. These changes can be followed spectroscopically using Raman and infrared techniques, and by single crystal X-ray diffraction and by powder X-ray and neutron diffraction. Such pressures are generated using a diamond-anvil cell.

Sample squeezed between two diamonds supported by a tungsten gasket

One method is to apply pressure directly to a single crystal, but this frequently results in the destruction of the crystal when it undergoes a phase transition, although on occasions the crystal can survive. One way around this problem is to apply pressure instead to a powder sample, and this can be a very effective means of accessing new phases. However, the application of pressure alone can often be insufficient to overcome the kinetic barriers for molecular rearrangement in solid state, particularly when molecules become more complex. This means that phase transitions can be sluggish or even fail to occur.

An alternative method is therefore to load a diamond-anvil cell with a pure liquid (or a solid that melts close to ambient temperature) and so grow a single crystal from the melt. This has proved to be a very powerful method for accessing new phases of simple ketones, alcohols, carboxylic acids, and mineral acids.
The sequence of images (courtesy of Dr David Allan) shows the growth at high pressure of a single crystal of acetic acid in a diamond-anvil cell viewed through crossed polarizers. Under the influence of external heating, the polycrystalline mass begins to melt until finally there remains only a tiny single crystal. On cooling back to room temperature, a single crystal grows to fill the cell.

Whilst crystal growth from the liquid is very effective at discovering new polymorphs, it is less useful for compounds that melt at higher temperatures (> 40 °C). This is because some compounds, particularly organic compounds, often decompose before the onset of melting. This is exacerbated by the effect of pressure, as can be seen from a typical phase diagram. The melting point increases sharply with increasing pressure - the application of only a few kbar can cause an increase in melting point of over 100 °C

These limitations severely restrict the range of organic compounds that can be studied at high pressure. In order to overcome these limitations, we have developed a new technique that involves high-pressure recrystallisation from solution. This involves the loading of the diamond-anvil cell with a solution of the compound, and removes the need for high temperatures since the lattice energy of the solid is now overcome by the solvation energy.

The technique enables us to study a much wider range of compounds and also allows access to pressure-induced formation of new solvates.

High-pressure studies are proving to be a powerful method for exploring polymorphism and solvate formation in a wide range of molecular compounds. Listed below are just a few of the compounds that we have studied at high pressure:

Sulfuric acid monohydrate
Phenanthrene
Paracetamol
Parabanic acid
Piracetam

Single crystal grown from the liquid in a diamond-anvil cell at 1.3 GPa (13 kbar)

Structure at atmospheric pressure (density = 2.002 g cm-3)	Structure at 1.3 GPa (density = 2.243 g cm-3)

Note the increase in density of the high-pressure phase and the much more extensive degree of hydrogen bonding.

A simple polycyclic aromatic (mp 101 °C) extensively studied by a range of techniques. 1 M solution of phenanthrene in CH2Cl2 loaded into DAC, pressurised to ca. 0.7 GPa, and then temperature cycled near 353 K to dissolve all but one of the crystallites. On slow cooling to 293 K, a single crystal grew from solution to fill ~ 50% of the gasket hole.
Ambient-pressure phase (density = 1.221 g cm-3)	High-pressure phase (density = 1.371 g cm-3)

"High-pressure recrystallisation - a route to new polymorphs and solvates". F.P.A. Fabbiani, D.R. Allan, W.I.F. David, S.A. Moggach, S. Parsons, and C.R. Pulham, CrystEngComm., (2004), 6, 504-511.

Paracetamol is a widely used analgesic drug. It exists as a stable monoclinic form, a metastable orthorhombic form, and a much less stable form III. We recently prepared a monohydrate and trihydrate at ambient pressure.
Paracetamol recrystallised from methanol at 0.6 GPa to give a new 1:1 methanol solvate
F.P.A. Fabbiani, D.R. Allan, A.D. Dawson, W.I.F. David, P.A. McGregor, I.D.H. Oswald, S. Parsons, and C.R. Pulham, Chem. Commun. (2003), 3004-3005.	Note hydrophobic cavity formed by methyl groups
Paracetamol recrystallised from water at 1.1 GPa to give a new dihydrate
By contrast, recrystallisation of monoclinic paracetamol from ethanol at 1.1 GPa gives the metastable orthorhombic polymorph, recoverable at ambient pressure.

"High-pressure recrystallisation - a route to new polymorphs and solvates". F.P.A. Fabbiani, D.R. Allan, W.I.F. David, S.A. Moggach, S. Parsons, and C.R. Pulham, CrystEngComm., (2004), 6, 504-511.

Parabanic acid is an analogue of barbituric acid. Structural studies have shown that one of the oxygen atoms does not take part in hydrogen bonding. In collaboration with Dr Bill Marshall, a powder neutron diffraction study of parabanic acid-d2 was performed at the ISIS Neutron Facility, Rutherford-Appleton Laboratory. This involved direct compression of a powder sample using Paris-Edinburgh Cell on the PEARL instrument.
No phase change up to 2.1 GPa, but the unit-cell volume decreased by 11% and the N3-D3...O5 distance was reduced from 1.82(1) Å to 1.70(1) Å.
A different experiment involved crystallisation of parabanic acid from aqueous solution under pressure, leading to the preparation of a new sesquihydrate of parabanic acid.

High-pressure recrystallisation - a route to new polymorphs and solvates of acetamide and parabanic acid F.P.A. Fabbiani, D.R. Allan, W.G. Marshall, S. Parsons, C.R. Pulham and R.I. Smith, J. Cryst. Growth, (2005), 275, 185-192.

Piracetam is a nootropic agent which improves memory recall. It is used for the treatment of dyslexia, alcoholism, and age-associated mental decline. Three structurally characterised polymorphs are known - Forms I, II, and III
Piracetam was recrystallised from solution (H2O or MeOH) under a range of pressures. Single crystals of all 3 known forms were obtained depending on conditions. In addition, recrystallisation from water at 0.4 GPa gave a new form, denoted form IV.
FORM I	FORM II and III
FORM IV

"An exploration of the polymorphism of piracetam using high pressure." F.P.A. Fabbiani, D.R. Allan, S. Parsons and C.R. Pulham, CrystEngComm, (2005), 7, 179-186

Mail to C.R.Pulham@ed.ac.uk