compression or phase transitions [107, 109, 117]. In this case, L-alanine was
compressed to an extreme where only 11.11 Å of the total cell volume was
attributable to voids at 13.6 GPa and where the void volume has reached a minimum
before amorphisation is induced.
The latest study of an amino acid, L-threonine, has achieved the greatest pressure
to date for these materials [115]. The study of Giordano et al. demonstrated that
L-threonine can be compressed to 22 GPa and still achieve molecular level detail of
the changes that occurred in the system. They observed that L-threonine undergoes
three phase transitions at ~3.2, ~9 and ~17.5 GPa of which the initial two transitions
are isosymmetric. The reasons for the transformations are all different with the first
transition due to a molecular rotation of the carboxylate group; the second indicates a
change in the compression behaviour of the phase, whilst the last is driven by the
reduction in the molecular volume through conformational change in the hydroxyl
group. Staggeringly, despite the pressures achieved, the authors noted that the
hydrogen bonding present remained within the bounds of the normal distribution
that is observed under ambient conditions using data from the Cambridge Structural
Database. Reference to the CSD mean values has been used previously to rationalise
polymorphic transitions in molecular systems [109].
3.4 Pharmaceutically Relevant Materials
In this next section, we will explore the pressure dependence of drug compounds and
compounds related to pharmaceutical processing. The increase in hydrogen bonding
groups and flexibility make them particularly susceptible to polymorphism which is
one of the greatest challenges for the pharmaceutical industry. To this end polymorph screening is a regular process during the drug discovery pipeline. During a
polymorph screen, different solvents and crystallisation conditions are explored
under ambient pressure conditions, but the variation of pressure is not used. As we
have observed, the variation of pressure can have a marked effect on the
crystallisation outcomes of fairly simple molecules; hence, it is intuitive that more
complex molecules with a wide variety of hydrogen bonding groups and flexibility
will form new polymorphs at elevated pressure. Many groups have investigated
pharmaceutical materials, and here we discuss a selection of them to highlight some
of the key findings and/or experimental procedures that have helped to characterise
the new forms (Fig. 11).
3.4.1 Chlorothiazide (I)
Chlorothiazide is a diuretic and can help to reduce swelling caused by cases of
kidney or liver diseases. The interest in chlorothiazide stems from it being a
pharmaceutical product but also that it is a relatively rigid molecule. The rigidity
of the molecule was important at the time of the study due to the difficulty of solving
168
S. A. Moggach and I. D. H. Oswald
compressed to an extreme where only 11.11 Å of the total cell volume was
attributable to voids at 13.6 GPa and where the void volume has reached a minimum
before amorphisation is induced.
The latest study of an amino acid, L-threonine, has achieved the greatest pressure
to date for these materials [115]. The study of Giordano et al. demonstrated that
L-threonine can be compressed to 22 GPa and still achieve molecular level detail of
the changes that occurred in the system. They observed that L-threonine undergoes
three phase transitions at ~3.2, ~9 and ~17.5 GPa of which the initial two transitions
are isosymmetric. The reasons for the transformations are all different with the first
transition due to a molecular rotation of the carboxylate group; the second indicates a
change in the compression behaviour of the phase, whilst the last is driven by the
reduction in the molecular volume through conformational change in the hydroxyl
group. Staggeringly, despite the pressures achieved, the authors noted that the
hydrogen bonding present remained within the bounds of the normal distribution
that is observed under ambient conditions using data from the Cambridge Structural
Database. Reference to the CSD mean values has been used previously to rationalise
polymorphic transitions in molecular systems [109].
3.4 Pharmaceutically Relevant Materials
In this next section, we will explore the pressure dependence of drug compounds and
compounds related to pharmaceutical processing. The increase in hydrogen bonding
groups and flexibility make them particularly susceptible to polymorphism which is
one of the greatest challenges for the pharmaceutical industry. To this end polymorph screening is a regular process during the drug discovery pipeline. During a
polymorph screen, different solvents and crystallisation conditions are explored
under ambient pressure conditions, but the variation of pressure is not used. As we
have observed, the variation of pressure can have a marked effect on the
crystallisation outcomes of fairly simple molecules; hence, it is intuitive that more
complex molecules with a wide variety of hydrogen bonding groups and flexibility
will form new polymorphs at elevated pressure. Many groups have investigated
pharmaceutical materials, and here we discuss a selection of them to highlight some
of the key findings and/or experimental procedures that have helped to characterise
the new forms (Fig. 11).
3.4.1 Chlorothiazide (I)
Chlorothiazide is a diuretic and can help to reduce swelling caused by cases of
kidney or liver diseases. The interest in chlorothiazide stems from it being a
pharmaceutical product but also that it is a relatively rigid molecule. The rigidity
of the molecule was important at the time of the study due to the difficulty of solving
168
S. A. Moggach and I. D. H. Oswald