of chiral resolution with pressure has been investigated by Rietveld and co-workers
who investigated mandelic acid. They observed that the chirally pure forms of
mandelic acid are stable above 0.64 GPa and 460 K based on calorimetry [133].
This has since been disputed by two articles that explore the mandelic acid system in
its chirally pure and racemic forms. The thermal event that was observed by Rietveld
and co-workers was identified as the transition between the low pressure and high
pressure phase of rac-mandelic acid [134, 135].
Indomethacin (VI) is a well-studied pharmaceutical due to the polymorphism that
it exhibits. It has three solid forms, a metastable α-polymorph, stable γ-polymorph as
well as an amorphous form. Okumura et al. explored the crystallisation behaviour of
indomethacin to 0.4 GPa to observe whether pressure would alter the phase behaviour or induce amorphisation. They discovered that as a dry powder both polymorphic forms of indomethacin were reduced at the expense of the amorphous form
(ca. 50% content to ca. 20%) at 0.4 GPa. As a slurry, the behaviour was slightly
different as recrystallisation from the solvent was possible to induce a change from
the γ-form to the α-polymorph at 0.4 GPa. There was still some transformation to the
amorphous form. The authors reasoned that the change in behaviour was due to the
increased density of the alpha form as well the increase in solubility of the amorphous form, but they noted the need for solubility measurements at pressure to
confirm this. The preparatory routes for the X-ray powder diffraction in this study
have obscured the output phases due to the grinding in a mortar and pestle prior to
data collection. This may have helped to initiate the amorphisation. Nevertheless,
this study contributes to the overwhelming observation that solvation can help to
overcome the kinetic barriers to interconversion at high pressure. We have followed
on from this study by investigating the co-crystal of indomethacin and saccharin at
pressure [136]. The co-crystal was stable over the entire pressure study to 6 GPa and
was even reproducibly formed via recrystallisation at pressure. This compression
study allowed us to investigate the effect of pressure on different types of hydrogen
bond, but it was the packing of the molecules in a host/guest manner that had an
effect over its compression. By its placement in a guest environment, the saccharin
molecules could hydrogen bond together at a distance close to a gas-phase minimum
due to the packing of the large bulky host, indomethacin.
Fluconazole (VII) is an antifungal agent that shows extensive polymorphism
albeit the polymorphs have not been fully characterised [137, 138]. There are
seven forms of fluconazole that are speculated to exist albeit that crystal structure
of Form I has not yet been determined and Form III is only speculated to exist due to
inconclusive spectroscopic data. Gorkovenko et al. investigated the pressure dependence of Form I using energy-dispersive X-ray diffraction and observed the isolation
of a new triclinic phase (Form VIII) at 0.8 GPa with the possibility of a second
transformation at 3.2 GPa. From the change in the isotropy of compression of the
unit cell parameters, the authors speculated that the transition to the new phase
would require a substantial rearrangement of the molecules. Fluconazole only
possesses one hydroxyl group that hydrogen bonds to the triazole group in the
known crystal forms or to water molecules in the hydrate. This molecular structure
gives rise to bulk moduli closer to glycolide [65], caprolactam [139] or aniline [22]
than other drug substances.
Crystallography Under High Pressures
175
who investigated mandelic acid. They observed that the chirally pure forms of
mandelic acid are stable above 0.64 GPa and 460 K based on calorimetry [133].
This has since been disputed by two articles that explore the mandelic acid system in
its chirally pure and racemic forms. The thermal event that was observed by Rietveld
and co-workers was identified as the transition between the low pressure and high
pressure phase of rac-mandelic acid [134, 135].
Indomethacin (VI) is a well-studied pharmaceutical due to the polymorphism that
it exhibits. It has three solid forms, a metastable α-polymorph, stable γ-polymorph as
well as an amorphous form. Okumura et al. explored the crystallisation behaviour of
indomethacin to 0.4 GPa to observe whether pressure would alter the phase behaviour or induce amorphisation. They discovered that as a dry powder both polymorphic forms of indomethacin were reduced at the expense of the amorphous form
(ca. 50% content to ca. 20%) at 0.4 GPa. As a slurry, the behaviour was slightly
different as recrystallisation from the solvent was possible to induce a change from
the γ-form to the α-polymorph at 0.4 GPa. There was still some transformation to the
amorphous form. The authors reasoned that the change in behaviour was due to the
increased density of the alpha form as well the increase in solubility of the amorphous form, but they noted the need for solubility measurements at pressure to
confirm this. The preparatory routes for the X-ray powder diffraction in this study
have obscured the output phases due to the grinding in a mortar and pestle prior to
data collection. This may have helped to initiate the amorphisation. Nevertheless,
this study contributes to the overwhelming observation that solvation can help to
overcome the kinetic barriers to interconversion at high pressure. We have followed
on from this study by investigating the co-crystal of indomethacin and saccharin at
pressure [136]. The co-crystal was stable over the entire pressure study to 6 GPa and
was even reproducibly formed via recrystallisation at pressure. This compression
study allowed us to investigate the effect of pressure on different types of hydrogen
bond, but it was the packing of the molecules in a host/guest manner that had an
effect over its compression. By its placement in a guest environment, the saccharin
molecules could hydrogen bond together at a distance close to a gas-phase minimum
due to the packing of the large bulky host, indomethacin.
Fluconazole (VII) is an antifungal agent that shows extensive polymorphism
albeit the polymorphs have not been fully characterised [137, 138]. There are
seven forms of fluconazole that are speculated to exist albeit that crystal structure
of Form I has not yet been determined and Form III is only speculated to exist due to
inconclusive spectroscopic data. Gorkovenko et al. investigated the pressure dependence of Form I using energy-dispersive X-ray diffraction and observed the isolation
of a new triclinic phase (Form VIII) at 0.8 GPa with the possibility of a second
transformation at 3.2 GPa. From the change in the isotropy of compression of the
unit cell parameters, the authors speculated that the transition to the new phase
would require a substantial rearrangement of the molecules. Fluconazole only
possesses one hydroxyl group that hydrogen bonds to the triazole group in the
known crystal forms or to water molecules in the hydrate. This molecular structure
gives rise to bulk moduli closer to glycolide [65], caprolactam [139] or aniline [22]
than other drug substances.
Crystallography Under High Pressures
175