was precipitated. We were able to isolate the orthorhombic phase using the pressureprecipitation methodology at a range of pressures from 0.2 GPa (acetone) to 1.1 GPa
(ethanol) in a DAC without any indication of further phases in these solvents
[42, 43]. However, from a 0.06 M aqueous solution at 1.1 GPa, a dihydrate can be
formed, but, given the pressure that it was formed, there may be a drive for inclusion
of water into the structure [42]. Other observations of this kind have been observed
for piracetam, where the precipitation occurred with the solidification of ice [44], and
the crystallisation of γ-aminobutyric acid [45]. The relative stability of the pure
paracetamol polymorphs at high pressure was confirmed by high-pressure differential scanning calorimetry studies which identified that the orthorhombic phase is the
most thermodynamically stable form at high pressure between pressures of 0.29 and
0.45 GPa (maximum pressure of the calorimeter) [46]. Even scale-up to larger
volumes was possible through the use of large volume press and quench
cooling [43].
Recently we have developed the method for performing anti-solvent addition at
high pressure using the large volume press [47]. We investigated this methodology
to aid the crystallisation of compounds at high pressure as well as to potentially
stabilise the recovery of high-pressure solid forms. We chose paracetamol as an
exemplar material as the literature on its high-pressure behaviour was extensive. In
this study we chose a mixed solvent system that showed a rapid decrease in solubility
with addition of anti-solvent (64% w/w aqueous methanol). One of the challenges
with this method is that the large volume press is not transparent so we
complemented these studies with DAC work. We were able to show that precipitation can occur and that the high-pressure orthorhombic form could be recovered to
ambient pressure. During this investigation, using the DAC, we observed a further
methanol solvate that is structurally similar to the known phase but possesses a
Z
0
¼ 3. Due to the small changes in the structure, we surmised that the change in the
solvent used may have had a subtle effect on the structure of the crystallised form
that manifests itself as a change in the crystal structure. Figure 2 depicts the phase
behaviour of paracetamol through recrystallisation methods under the range of
conditions.
Piracetam
Piracetam is a fantastic example of how the concentration and pressure can be
combined to access multiple different solid-state forms (Fig. 3). Fabbiani et al.
explored the use of different concentrations of solution in different solvents as
well as simple compression techniques to successfully identify four different solid
modifications of piracetam (Forms III–V and a dihydrate) [44, 48]. The ‘simple’
compression technique applied here involved the annealing of the powder at low
pressure in 2-propanol to bypass the issues of cutting the crystal to the correct size
before the application of pressure. In this system, there is a general observation for
the precipitation experiments that at higher concentrations of solution, Form IV
could be accessed (1.6 M methanolic solution or 6 M aq. solution) whilst at lower
Crystallography Under High Pressures
149
(ethanol) in a DAC without any indication of further phases in these solvents
[42, 43]. However, from a 0.06 M aqueous solution at 1.1 GPa, a dihydrate can be
formed, but, given the pressure that it was formed, there may be a drive for inclusion
of water into the structure [42]. Other observations of this kind have been observed
for piracetam, where the precipitation occurred with the solidification of ice [44], and
the crystallisation of γ-aminobutyric acid [45]. The relative stability of the pure
paracetamol polymorphs at high pressure was confirmed by high-pressure differential scanning calorimetry studies which identified that the orthorhombic phase is the
most thermodynamically stable form at high pressure between pressures of 0.29 and
0.45 GPa (maximum pressure of the calorimeter) [46]. Even scale-up to larger
volumes was possible through the use of large volume press and quench
cooling [43].
Recently we have developed the method for performing anti-solvent addition at
high pressure using the large volume press [47]. We investigated this methodology
to aid the crystallisation of compounds at high pressure as well as to potentially
stabilise the recovery of high-pressure solid forms. We chose paracetamol as an
exemplar material as the literature on its high-pressure behaviour was extensive. In
this study we chose a mixed solvent system that showed a rapid decrease in solubility
with addition of anti-solvent (64% w/w aqueous methanol). One of the challenges
with this method is that the large volume press is not transparent so we
complemented these studies with DAC work. We were able to show that precipitation can occur and that the high-pressure orthorhombic form could be recovered to
ambient pressure. During this investigation, using the DAC, we observed a further
methanol solvate that is structurally similar to the known phase but possesses a
Z
0
¼ 3. Due to the small changes in the structure, we surmised that the change in the
solvent used may have had a subtle effect on the structure of the crystallised form
that manifests itself as a change in the crystal structure. Figure 2 depicts the phase
behaviour of paracetamol through recrystallisation methods under the range of
conditions.
Piracetam
Piracetam is a fantastic example of how the concentration and pressure can be
combined to access multiple different solid-state forms (Fig. 3). Fabbiani et al.
explored the use of different concentrations of solution in different solvents as
well as simple compression techniques to successfully identify four different solid
modifications of piracetam (Forms III–V and a dihydrate) [44, 48]. The ‘simple’
compression technique applied here involved the annealing of the powder at low
pressure in 2-propanol to bypass the issues of cutting the crystal to the correct size
before the application of pressure. In this system, there is a general observation for
the precipitation experiments that at higher concentrations of solution, Form IV
could be accessed (1.6 M methanolic solution or 6 M aq. solution) whilst at lower
Crystallography Under High Pressures
149