key to the solution of a number of high-pressure phases including RDX [118] and
paracetamol methanolate [41]. In this study the authors used multiple crystals to
increase the proportion of the reciprocal lattice that could be observed to 69%
compared with a typical dataset completeness for a triclinic system being ~30%.
Chlorothiazide demonstrates one of the key features of high-pressure studies
whereby the torsional angles of the molecular systems are the first changes to
molecular geometry that take place. At 4 GPa, chlorothiazide undergoes an
isostructural phase transformation where the thiazide ring is distorted due to the
proximity of the intermolecular interactions between the SO 2 moiety and the ring
system of a neighbouring molecule; the sulfonyl group also shows a large conformational change due to the shear of the molecular planes in the crystal. The phase
transition is reversible so it is not particularly useful in terms of the polymorph
discovery, but the study demonstrates methodologies that have been used to counteract the issues around data completeness and structural solutions of systems at high
pressure albeit the latter has somewhat been overcome by newer solution packages,
e.g. ShelXT [119].
3.4.2 Chlorpropamide (II)
Chlorpropamide, (4-chloro-N-(propylaminocarbonyl)benzenesulfonamide), is one
of the best examples of how high pressure may affect the nucleation and growth of
high-pressure phases. It is a complex molecule used as an anti-diabetic and possesses
five different polymorphs (α-ε) that can be obtained under a range of crystallisation
conditions under ambient conditions. The α-form is the most thermodynamically
stable polymorph but does not possess the highest density. On cooling the β and
ε-forms, the structures undergo transitions to structurally similar low-temperature
forms, β
II & β
III and ε’, respectively [120, 121]. The α-δ-forms have been shown to
transform to the ε-form near the melting point [122]. The extensive polymorphic
behaviour at ambient pressure suggests that the application of pressure would enable
the transformation to further high-pressure polymorphs. In a range of papers exploring the effects of pressure, the group of Boldyreva have observed a number of new
phases and some interesting effects related to the PTM used.
During their studies Boldyreva et al. employed a number of different highpressure techniques from simple compression of a dry powder through to the
alteration of the pressure-transmitting media used for the study. We have already
touched on many of these concepts in this chapter though this example demonstrates
the choice of experiment available to investigate molecular forms. In this example,
Boldyreva et al. showed that pure compression of a system can induce a polymorphic transition in the case of both the α-, β- and δ-forms. In one of the first studies,
they investigated the α-γ transition that had previously been reported to occur on
compression during the tabletting procedure [123]. The α-form crystallises in orthorhombic P2 1 2 1 2 1 with Z
0
¼ 1. Initial X-ray powder diffraction experiments showed
little change to the dry powder on compression except a general broadening of the
pattern through the non-hydrostatic compression. There were small inconsistencies
170
S. A. Moggach and I. D. H. Oswald
paracetamol methanolate [41]. In this study the authors used multiple crystals to
increase the proportion of the reciprocal lattice that could be observed to 69%
compared with a typical dataset completeness for a triclinic system being ~30%.
Chlorothiazide demonstrates one of the key features of high-pressure studies
whereby the torsional angles of the molecular systems are the first changes to
molecular geometry that take place. At 4 GPa, chlorothiazide undergoes an
isostructural phase transformation where the thiazide ring is distorted due to the
proximity of the intermolecular interactions between the SO 2 moiety and the ring
system of a neighbouring molecule; the sulfonyl group also shows a large conformational change due to the shear of the molecular planes in the crystal. The phase
transition is reversible so it is not particularly useful in terms of the polymorph
discovery, but the study demonstrates methodologies that have been used to counteract the issues around data completeness and structural solutions of systems at high
pressure albeit the latter has somewhat been overcome by newer solution packages,
e.g. ShelXT [119].
3.4.2 Chlorpropamide (II)
Chlorpropamide, (4-chloro-N-(propylaminocarbonyl)benzenesulfonamide), is one
of the best examples of how high pressure may affect the nucleation and growth of
high-pressure phases. It is a complex molecule used as an anti-diabetic and possesses
five different polymorphs (α-ε) that can be obtained under a range of crystallisation
conditions under ambient conditions. The α-form is the most thermodynamically
stable polymorph but does not possess the highest density. On cooling the β and
ε-forms, the structures undergo transitions to structurally similar low-temperature
forms, β
II & β
III and ε’, respectively [120, 121]. The α-δ-forms have been shown to
transform to the ε-form near the melting point [122]. The extensive polymorphic
behaviour at ambient pressure suggests that the application of pressure would enable
the transformation to further high-pressure polymorphs. In a range of papers exploring the effects of pressure, the group of Boldyreva have observed a number of new
phases and some interesting effects related to the PTM used.
During their studies Boldyreva et al. employed a number of different highpressure techniques from simple compression of a dry powder through to the
alteration of the pressure-transmitting media used for the study. We have already
touched on many of these concepts in this chapter though this example demonstrates
the choice of experiment available to investigate molecular forms. In this example,
Boldyreva et al. showed that pure compression of a system can induce a polymorphic transition in the case of both the α-, β- and δ-forms. In one of the first studies,
they investigated the α-γ transition that had previously been reported to occur on
compression during the tabletting procedure [123]. The α-form crystallises in orthorhombic P2 1 2 1 2 1 with Z
0
¼ 1. Initial X-ray powder diffraction experiments showed
little change to the dry powder on compression except a general broadening of the
pattern through the non-hydrostatic compression. There were small inconsistencies
170
S. A. Moggach and I. D. H. Oswald