in the unit cell parameters above 3.7 GPa that indicate the transition to the new phase
as well as small shoulders on some peaks that may support this conclusion. A followup study used single-crystal diffraction to investigate the compression so that
structural changes could be followed as a function of pressure as well as to provide
conclusive evidence of any phase transitions [124]. For this experiment ethanol was
used as the PTM to ensure hydrostatic compression. The addition of a PTM is a
necessary and may alter the behaviour on compression. However, in this case, the
transition could be observed into a new monoclinic (P2 1 ) structure with Z
0
¼ 2 at
2.8 GPa (designated α’); the crystal of the high-pressure phase is twinned due to the
reduction in the symmetry. The authors also highlight the difference in the transition
pressure between the powder diffraction experiment and the single-crystal experiment and attribute this to the presence of nuclei in the crystal. For a transition in a
single crystal, there only needs to be one nucleation point for the entire sample to
transform. For a powder, every particle requires a site of nucleation that may delay
the onset of the transition. From a structural perspective, chlorpropamide shows that
the packing of the molecules takes precedence over the hydrogen bonding; cf. simple
alcohols. Of the three hydrogen bonds present, two increase in length to accommodate the packing of the molecules where there is a change in the torsional angles
around the phenyl and alkyl groups.
Boldyreva et al. continued their exploration of chlorpropamide in an interesting
competitive experiment where they investigated the role of nucleation and seeding
(Fig. 12) [125]. For this experiment, they chose a PTM (1:1 pentane/isopentane) in
which chlorpropamide was visibly ‘insoluble’. In fact, they observed a difference in
the solubility of each polymorph where the α- and δ-forms were visibly unchanged
but the metastable β-form showed rounding of the edges of the crystal. This is a
critical observation as the slight solubility of the crystal impacts on the behaviour of
β-form at high pressure which was demonstrated in a later study [126]. The
solubilisation of the β-form in the PTM allowed the transformation to the γ-form
alone without any seeds present or to γ- and δ-form if seeds of α- and δ-forms were
present. The transformation to γ-form was rationalised due to the similarity in the
packing between the β- and γ-forms, hence providing a low barrier to interconversion. The authors conclude that in solution molecular clusters are retained which is
aided by the confined geometry of the DAC sample chamber. Transition to the
α-form is inhibited due to the substantial rearrangement required. The increase in the
δ-form was attributed to the seed crystal providing a template that enables the
facilitation of the transition despite the large molecular rearrangement required. It
is also the densest phase; hence, the pV term of the Gibbs free energy equation will
provide a thermodynamic driving force.
In their final study of chlorpropamide (at time of writing), the Boldyreva group
explored the properties of the PTM further using β-chlorpropamide.
β-Chlorpropamide showed slight solubility in the 1:1 pentane/isopentane mixture;
hence, the authors explored the use of PTMs in which there was going to be no
solubility, e.g. helium, neon and paraffin oil [126]. They observed very different
behaviour depending on the use of each of these media. In neon, they observed
transition of the β-form to the α-form over the course of 2 days at 0.6 GPa. The
Crystallography Under High Pressures
171
as well as small shoulders on some peaks that may support this conclusion. A followup study used single-crystal diffraction to investigate the compression so that
structural changes could be followed as a function of pressure as well as to provide
conclusive evidence of any phase transitions [124]. For this experiment ethanol was
used as the PTM to ensure hydrostatic compression. The addition of a PTM is a
necessary and may alter the behaviour on compression. However, in this case, the
transition could be observed into a new monoclinic (P2 1 ) structure with Z
0
¼ 2 at
2.8 GPa (designated α’); the crystal of the high-pressure phase is twinned due to the
reduction in the symmetry. The authors also highlight the difference in the transition
pressure between the powder diffraction experiment and the single-crystal experiment and attribute this to the presence of nuclei in the crystal. For a transition in a
single crystal, there only needs to be one nucleation point for the entire sample to
transform. For a powder, every particle requires a site of nucleation that may delay
the onset of the transition. From a structural perspective, chlorpropamide shows that
the packing of the molecules takes precedence over the hydrogen bonding; cf. simple
alcohols. Of the three hydrogen bonds present, two increase in length to accommodate the packing of the molecules where there is a change in the torsional angles
around the phenyl and alkyl groups.
Boldyreva et al. continued their exploration of chlorpropamide in an interesting
competitive experiment where they investigated the role of nucleation and seeding
(Fig. 12) [125]. For this experiment, they chose a PTM (1:1 pentane/isopentane) in
which chlorpropamide was visibly ‘insoluble’. In fact, they observed a difference in
the solubility of each polymorph where the α- and δ-forms were visibly unchanged
but the metastable β-form showed rounding of the edges of the crystal. This is a
critical observation as the slight solubility of the crystal impacts on the behaviour of
β-form at high pressure which was demonstrated in a later study [126]. The
solubilisation of the β-form in the PTM allowed the transformation to the γ-form
alone without any seeds present or to γ- and δ-form if seeds of α- and δ-forms were
present. The transformation to γ-form was rationalised due to the similarity in the
packing between the β- and γ-forms, hence providing a low barrier to interconversion. The authors conclude that in solution molecular clusters are retained which is
aided by the confined geometry of the DAC sample chamber. Transition to the
α-form is inhibited due to the substantial rearrangement required. The increase in the
δ-form was attributed to the seed crystal providing a template that enables the
facilitation of the transition despite the large molecular rearrangement required. It
is also the densest phase; hence, the pV term of the Gibbs free energy equation will
provide a thermodynamic driving force.
In their final study of chlorpropamide (at time of writing), the Boldyreva group
explored the properties of the PTM further using β-chlorpropamide.
β-Chlorpropamide showed slight solubility in the 1:1 pentane/isopentane mixture;
hence, the authors explored the use of PTMs in which there was going to be no
solubility, e.g. helium, neon and paraffin oil [126]. They observed very different
behaviour depending on the use of each of these media. In neon, they observed
transition of the β-form to the α-form over the course of 2 days at 0.6 GPa. The
Crystallography Under High Pressures
171