2.2.3 Recrystallisation
In recent years the use of solutions to explore the solid-state forms has become more
prevalent as it provides an orthogonal approach that can be used to explore materials
that possess melting points that are too high to anneal with increased temperature. To
explain the methodology, we will use a series of studies of molecular systems to
demonstrate a large number of scenarios that we and other researchers in this field
have observed.
Paracetamol
Prior to 2003, paracetamol was known to exist in two polymorphic forms: the
thermodynamically stable monoclinic P2 1 /c phase [36] and the metastable orthorhombic Pbca phase [37]. The interest in paracetamol lies in the fact that the
orthorhombic polymorph possesses better compaction properties compared with
the stable monoclinic polymorph. The metastable form can be isolated easily from
the melt and is stable for approximately 50 h during experiments to test sublimation
[38] or 30 min in contact with solvent [39]. Paracetamol had been explored using
high pressure via compression methods by the group of Boldyreva. Their paper
demonstrated that through compression one could induce the transformation to the
orthorhombic phase in a powder sample through pressure alone although the transition was incomplete and slow due to the large rearrangement of the molecules
required between the two phases [40]. To aid the isolation of the orthorhombic form,
Fabbiani et al. investigated the use of recrystallisation at high pressure [41]. By using
solutions in this way, they utilised the solvation energy to help overcome the kinetic
barrier to transformation. In their study they loaded a ca. 1 M methanol solution of
paracetamol into the DAC and treated the solution in the same way as pure liquids
had been investigated in prior studies through heat annealing. From this solution, a
new methanol solvate was precipitated, and by repeated heat/cool cycles, a single
crystal was formed that could be analysed by single-crystal X-ray diffraction. This
was a significant and novel approach to materials preparation, and it opened the door
to the analysis of high-melting compounds such as pharmaceutical products.
We have been employing these methods routinely and have found that a key
difference from the manipulation of pure liquids is the reaction of the crystals and
solution to heat. Crystals obtained from a pure liquid react almost instantaneously to
the application of heat or on cooling; hence, the growth of the crystal can be
controlled very easily. Generally, the response to heating or cooling of solutions
is, naturally, much more delayed due to the dissolution process; hence, even more
care is required when trying to isolate one crystallite during the annealing procedure.
As with the pure liquid method, the pressure can be tuned to increase or decrease the
rate of crystal growth, but there is still a lag present.
Further studies of paracetamol at high pressure have indicated that the solid form
observed can be dependent on the solvent as well as the pressure at which the phase
148
S. A. Moggach and I. D. H. Oswald
In recent years the use of solutions to explore the solid-state forms has become more
prevalent as it provides an orthogonal approach that can be used to explore materials
that possess melting points that are too high to anneal with increased temperature. To
explain the methodology, we will use a series of studies of molecular systems to
demonstrate a large number of scenarios that we and other researchers in this field
have observed.
Paracetamol
Prior to 2003, paracetamol was known to exist in two polymorphic forms: the
thermodynamically stable monoclinic P2 1 /c phase [36] and the metastable orthorhombic Pbca phase [37]. The interest in paracetamol lies in the fact that the
orthorhombic polymorph possesses better compaction properties compared with
the stable monoclinic polymorph. The metastable form can be isolated easily from
the melt and is stable for approximately 50 h during experiments to test sublimation
[38] or 30 min in contact with solvent [39]. Paracetamol had been explored using
high pressure via compression methods by the group of Boldyreva. Their paper
demonstrated that through compression one could induce the transformation to the
orthorhombic phase in a powder sample through pressure alone although the transition was incomplete and slow due to the large rearrangement of the molecules
required between the two phases [40]. To aid the isolation of the orthorhombic form,
Fabbiani et al. investigated the use of recrystallisation at high pressure [41]. By using
solutions in this way, they utilised the solvation energy to help overcome the kinetic
barrier to transformation. In their study they loaded a ca. 1 M methanol solution of
paracetamol into the DAC and treated the solution in the same way as pure liquids
had been investigated in prior studies through heat annealing. From this solution, a
new methanol solvate was precipitated, and by repeated heat/cool cycles, a single
crystal was formed that could be analysed by single-crystal X-ray diffraction. This
was a significant and novel approach to materials preparation, and it opened the door
to the analysis of high-melting compounds such as pharmaceutical products.
We have been employing these methods routinely and have found that a key
difference from the manipulation of pure liquids is the reaction of the crystals and
solution to heat. Crystals obtained from a pure liquid react almost instantaneously to
the application of heat or on cooling; hence, the growth of the crystal can be
controlled very easily. Generally, the response to heating or cooling of solutions
is, naturally, much more delayed due to the dissolution process; hence, even more
care is required when trying to isolate one crystallite during the annealing procedure.
As with the pure liquid method, the pressure can be tuned to increase or decrease the
rate of crystal growth, but there is still a lag present.
Further studies of paracetamol at high pressure have indicated that the solid form
observed can be dependent on the solvent as well as the pressure at which the phase
148
S. A. Moggach and I. D. H. Oswald