are challenges to be overcome, such as solution-mediated transformations; however,
the potential for the stabilisation of high-pressure forms in larger quantities is there.
Quenching of High-Pressure Forms
Whilst the identification of new high-pressure forms has been very successful, there
have only been a few forms that have been quenched to ambient pressure. The
observation of the recovery of materials from high pressure is likely to be
underestimated as it has not been the primary goal of many pressure studies and
hence may not have been recorded. The ability to quench novel forms to ambient
pressure opens up the possibility for solid-form discovery and use as viable forms for
delivery of pharmaceutical materials. Routes to manufacture through use of the large
volume press and subsequent seeding are viable.
Fabbiani et al. investigated the neurotransmitter γ-aminobutyric acid (GABA)
using pressure-induced recrystallisation techniques using a variety of concentrations
from 6 to 12 M aqueous solutions as well as aqueous methanol solutions (4 M)
[45]. In all cases, recrystallisation and crystal growth through temperature annealing
formed a monohydrate of the GABA at 0.4 GPa which was the sole route to this
novel hydrate. The enthalpy of hydration of the monohydrate was lower at all
pressures and is the drive for its formation. Quenching GABA hydrate to ambient
pressure was possible due to the similar enthalpies of hydration between the
monohydrate and its constituent parts. In this case the monohydrate could be used
as a seed in ambient pressure crystallisations. 5,6-Dimethylbenzimidazole shows
similar behaviour where the hemihydrate is only accessed at high pressure [67]. The
hemihydrate displays, unusually, a smaller molecular volume compared to the
anhydrous form and can be recovered to ambient pressure and retained for several
months. The thermodynamic drivers for the change were not investigated; however,
the large volume change between the forms will contribute through the pV term of
the free energy.
The most recent example from the pharmaceutical field is that of galunisertib
[7]. Galunisertib has been investigated as a potential treatment for advanced metastatic malignancies and as part of that process was subject to solid-form screening
protocols. It has a vast solid-form landscape that includes 50 solvated forms and
9 polymorphic forms. As part of this study, Bhardwaj et al. used crystal structure
prediction to reveal hundreds of potential structures that were of high density and
more importantly more thermodynamically stable than the known polymorphs. For
these reasons high-pressure techniques were employed to explore this system. After
a considerable search of the pressure phase space, they successfully elucidated the
structure of a tenth polymorph (Form X, from a melt at high pressure; 0.4 GPa) that
was shown to be recoverable to ambient pressure. Attempts were made to seed
solutions; however, the small sample size restricted the ability to extend the experimental conditions.
Whilst recovery of materials from high pressure in a DAC is a step in the right
direction, scaling up of the activity is where the major developments in this area will
158
S. A. Moggach and I. D. H. Oswald
the potential for the stabilisation of high-pressure forms in larger quantities is there.
Quenching of High-Pressure Forms
Whilst the identification of new high-pressure forms has been very successful, there
have only been a few forms that have been quenched to ambient pressure. The
observation of the recovery of materials from high pressure is likely to be
underestimated as it has not been the primary goal of many pressure studies and
hence may not have been recorded. The ability to quench novel forms to ambient
pressure opens up the possibility for solid-form discovery and use as viable forms for
delivery of pharmaceutical materials. Routes to manufacture through use of the large
volume press and subsequent seeding are viable.
Fabbiani et al. investigated the neurotransmitter γ-aminobutyric acid (GABA)
using pressure-induced recrystallisation techniques using a variety of concentrations
from 6 to 12 M aqueous solutions as well as aqueous methanol solutions (4 M)
[45]. In all cases, recrystallisation and crystal growth through temperature annealing
formed a monohydrate of the GABA at 0.4 GPa which was the sole route to this
novel hydrate. The enthalpy of hydration of the monohydrate was lower at all
pressures and is the drive for its formation. Quenching GABA hydrate to ambient
pressure was possible due to the similar enthalpies of hydration between the
monohydrate and its constituent parts. In this case the monohydrate could be used
as a seed in ambient pressure crystallisations. 5,6-Dimethylbenzimidazole shows
similar behaviour where the hemihydrate is only accessed at high pressure [67]. The
hemihydrate displays, unusually, a smaller molecular volume compared to the
anhydrous form and can be recovered to ambient pressure and retained for several
months. The thermodynamic drivers for the change were not investigated; however,
the large volume change between the forms will contribute through the pV term of
the free energy.
The most recent example from the pharmaceutical field is that of galunisertib
[7]. Galunisertib has been investigated as a potential treatment for advanced metastatic malignancies and as part of that process was subject to solid-form screening
protocols. It has a vast solid-form landscape that includes 50 solvated forms and
9 polymorphic forms. As part of this study, Bhardwaj et al. used crystal structure
prediction to reveal hundreds of potential structures that were of high density and
more importantly more thermodynamically stable than the known polymorphs. For
these reasons high-pressure techniques were employed to explore this system. After
a considerable search of the pressure phase space, they successfully elucidated the
structure of a tenth polymorph (Form X, from a melt at high pressure; 0.4 GPa) that
was shown to be recoverable to ambient pressure. Attempts were made to seed
solutions; however, the small sample size restricted the ability to extend the experimental conditions.
Whilst recovery of materials from high pressure in a DAC is a step in the right
direction, scaling up of the activity is where the major developments in this area will
158
S. A. Moggach and I. D. H. Oswald