substantial molecular rearrangement caused a reconstructive phase transformation
into multiple smaller crystals. Further compression of this phase showed a transition
that they speculated to be the α’-polymorph that they observed previously, but the
diffraction was not of sufficient quality for unequivocal assignment. In helium and
paraffin oil, the β-form transforms to a structurally similar phase β
I
HP at 0.3 and
0.1 GPa, respectively, but there were differences in the behaviour of the crystals. In
the helium medium, the single crystal was retained; however, in the paraffin oil, the
crystal fractured into several new domains. Further compression in helium to
0.7 GPa initiated a change to β
II
HP where the crystal fractured over the transition.
There are similarities to the low-temperature phases, but they could not be fit to the
data. In paraffin oil, there is a transition to a triclinic phase that is designated β
III
HP
with further fracture of crystal between 0.1 and 0.3 GPa. The very distinct behaviour
in each of these media was explained by the interaction of the media with the crystal
itself. In the case of helium, it is known to enter the structures of
4-hydroxycyanobenzene [49], silicates and even diamond itself (the cause of many
broken diamonds at very high pressure). The phase transitions are facilitated by a
combination of internal and external pressure. Paraffin oil interacts with the surface
promoting the change in the polymorph. The fact it is a collection of alkyl molecules
and that pentane/isopentane mixture interacts with the surface may allow that
hypothesis to hold true. For neon, the size of the atom will exclude the penetration
into the crystal structure; hence, thermodynamics may be playing a more significant
role in this transition. Unfortunately, the authors were not able to perform the loading
again to investigate the kinetics of the transition further.
3.4.3 Dalcetrapib (III)
This example typifies the strategy that has been explored to help to inform the
discovery of new polymorphs of pharmaceutical materials. The study of Neumann
et al. [6] explores the combination of crystal structure prediction together with the
high-pressure techniques to explore the energy landscape of dalcetrapib. Typically,
the energy landscapes calculated ab-initio reveal hundreds of crystal structures that
are energetically reasonable. However, depending on the compound, only a handful
of these may have been characterised through experimental procedures. Density or
packing coefficient is usually plotted along with the energy of the structures; hence,
it is a very clear method to identify potentially new unobserved forms that may be
more thermodynamically stable than the known forms of a drug. This is a red flag for
pharmaceutical companies, but if one has exhausted ambient pressure polymorph
screens, there is a possibility that pressure can be used to access new forms. This
study used recrystallisation at high pressure to isolate a new polymorph of
dalcetrapib from tetrahydrofuran. At very low pressures, a new polymorph was
identified and compared well with one of the predicted forms albeit it was not the
most stable global minimum structure. The authors attempted to recover the sample,
but it was thermodynamically less stable than the known form and converted over
the course of a few hours.
Crystallography Under High Pressures
173
into multiple smaller crystals. Further compression of this phase showed a transition
that they speculated to be the α’-polymorph that they observed previously, but the
diffraction was not of sufficient quality for unequivocal assignment. In helium and
paraffin oil, the β-form transforms to a structurally similar phase β
I
HP at 0.3 and
0.1 GPa, respectively, but there were differences in the behaviour of the crystals. In
the helium medium, the single crystal was retained; however, in the paraffin oil, the
crystal fractured into several new domains. Further compression in helium to
0.7 GPa initiated a change to β
II
HP where the crystal fractured over the transition.
There are similarities to the low-temperature phases, but they could not be fit to the
data. In paraffin oil, there is a transition to a triclinic phase that is designated β
III
HP
with further fracture of crystal between 0.1 and 0.3 GPa. The very distinct behaviour
in each of these media was explained by the interaction of the media with the crystal
itself. In the case of helium, it is known to enter the structures of
4-hydroxycyanobenzene [49], silicates and even diamond itself (the cause of many
broken diamonds at very high pressure). The phase transitions are facilitated by a
combination of internal and external pressure. Paraffin oil interacts with the surface
promoting the change in the polymorph. The fact it is a collection of alkyl molecules
and that pentane/isopentane mixture interacts with the surface may allow that
hypothesis to hold true. For neon, the size of the atom will exclude the penetration
into the crystal structure; hence, thermodynamics may be playing a more significant
role in this transition. Unfortunately, the authors were not able to perform the loading
again to investigate the kinetics of the transition further.
3.4.3 Dalcetrapib (III)
This example typifies the strategy that has been explored to help to inform the
discovery of new polymorphs of pharmaceutical materials. The study of Neumann
et al. [6] explores the combination of crystal structure prediction together with the
high-pressure techniques to explore the energy landscape of dalcetrapib. Typically,
the energy landscapes calculated ab-initio reveal hundreds of crystal structures that
are energetically reasonable. However, depending on the compound, only a handful
of these may have been characterised through experimental procedures. Density or
packing coefficient is usually plotted along with the energy of the structures; hence,
it is a very clear method to identify potentially new unobserved forms that may be
more thermodynamically stable than the known forms of a drug. This is a red flag for
pharmaceutical companies, but if one has exhausted ambient pressure polymorph
screens, there is a possibility that pressure can be used to access new forms. This
study used recrystallisation at high pressure to isolate a new polymorph of
dalcetrapib from tetrahydrofuran. At very low pressures, a new polymorph was
identified and compared well with one of the predicted forms albeit it was not the
most stable global minimum structure. The authors attempted to recover the sample,
but it was thermodynamically less stable than the known form and converted over
the course of a few hours.
Crystallography Under High Pressures
173