3.4.4 Tolazamide (IV)
At ambient pressure tolazamide possesses three polymorphs, two of which crystallise concomitantly (Forms I and II). Form I is an ordered structure and is suggested to
be the thermodynamically stable form, whereas Form II displays disorder around the
azepane ring. The energies between the two phases are similar, but Form II converts
to Form I in solution. Form III was isolated once from a hot dioxane solution but
never obtained again and hence may require very specific experimental conditions to
crystallise [127]. The study of Fedorov et al. investigated the pressure effects on both
Forms I and II and explored the use of different PTM building on the work on
chlorpropamide [128]. This is another case where there is a kinetic barrier to the
transition due to the molecular rearrangement required. Using pentane/isopentane as
the PTM, both of the polymorphs can be characterised to 6 GPa without any
indication of phase transitions. The density of Form I is higher than Form II
indicating the stability of this phase over the entire pressure range and beyond
25 GPa (through computational approaches). The bulk moduli of the two phases
are similar with Form II being slightly more compressible (Form I 6.4(3) GPa and
Form 5.8(2) GPa). This is reflected in the hydrogen bonding where they compress
more rapidly in Form II than in Form I. In addition, the disorder in Form II is ‘frozen
out’ at 3.3 GPa. This also aligns well with many other studies of molecular materials at
pressure that show a reduction in void volume [109]. In this system it can be surmised
that due to the disorder present, the structure possesses a greater volume of void space
that can be compressed; hence, there is a lack of phase transformation; we have noted
this in the compression of 3,4-methylenedioxymethamphetamine hydrochloride [129].
The exploration of tolazamide in methanol indicated a change in Form II to Form
I at 0.1 GPa which is observed at ambient pressure. Whilst the change in the phase
cannot be attributed to the pressure, the conversion was not fully complete when
conducted in the DAC. The authors do not specify the length of time that the sample
was left at 0.1 GPa, but they do conclude that the lack of solubility in methanol
prevents the complete conversion. We have also noticed this phenomenon in paminobenzoic acid where we believe that pABA is saturated in the medium and the
viscosity of the solution prevents the conversion to the new phase.
3.4.5 Other Pharmaceuticals
Ibuprofen (V) is a well-known chiral non-steroidal anti-inflammatory. Its racemic
form is known to exist in two polymorphic forms. Form I is the most stable
polymorph with the second polymorph being observed only after quench cooling
and annealing at 143 K for an hour and 258 K for 15 h [130]. Pure (s)-(+)-ibuprofen
is only observed in one polymorph [131]. Ostrowska et al. investigated the racemic
compound using both recrystallisation and compression methodologies to a pressure
of 4 GPa with a view that it may be chirally resolved using pressure [132]. Despite
the use of many solvents (chiral and achiral) and range of pressures and temperatures
(0.1–1.15 GPa; up to 553 K), the known Form I was always produced. Even
attempted co-crystallisations with mandelic acid and tartaric acid failed. The idea
174
S. A. Moggach and I. D. H. Oswald
At ambient pressure tolazamide possesses three polymorphs, two of which crystallise concomitantly (Forms I and II). Form I is an ordered structure and is suggested to
be the thermodynamically stable form, whereas Form II displays disorder around the
azepane ring. The energies between the two phases are similar, but Form II converts
to Form I in solution. Form III was isolated once from a hot dioxane solution but
never obtained again and hence may require very specific experimental conditions to
crystallise [127]. The study of Fedorov et al. investigated the pressure effects on both
Forms I and II and explored the use of different PTM building on the work on
chlorpropamide [128]. This is another case where there is a kinetic barrier to the
transition due to the molecular rearrangement required. Using pentane/isopentane as
the PTM, both of the polymorphs can be characterised to 6 GPa without any
indication of phase transitions. The density of Form I is higher than Form II
indicating the stability of this phase over the entire pressure range and beyond
25 GPa (through computational approaches). The bulk moduli of the two phases
are similar with Form II being slightly more compressible (Form I 6.4(3) GPa and
Form 5.8(2) GPa). This is reflected in the hydrogen bonding where they compress
more rapidly in Form II than in Form I. In addition, the disorder in Form II is ‘frozen
out’ at 3.3 GPa. This also aligns well with many other studies of molecular materials at
pressure that show a reduction in void volume [109]. In this system it can be surmised
that due to the disorder present, the structure possesses a greater volume of void space
that can be compressed; hence, there is a lack of phase transformation; we have noted
this in the compression of 3,4-methylenedioxymethamphetamine hydrochloride [129].
The exploration of tolazamide in methanol indicated a change in Form II to Form
I at 0.1 GPa which is observed at ambient pressure. Whilst the change in the phase
cannot be attributed to the pressure, the conversion was not fully complete when
conducted in the DAC. The authors do not specify the length of time that the sample
was left at 0.1 GPa, but they do conclude that the lack of solubility in methanol
prevents the complete conversion. We have also noticed this phenomenon in paminobenzoic acid where we believe that pABA is saturated in the medium and the
viscosity of the solution prevents the conversion to the new phase.
3.4.5 Other Pharmaceuticals
Ibuprofen (V) is a well-known chiral non-steroidal anti-inflammatory. Its racemic
form is known to exist in two polymorphic forms. Form I is the most stable
polymorph with the second polymorph being observed only after quench cooling
and annealing at 143 K for an hour and 258 K for 15 h [130]. Pure (s)-(+)-ibuprofen
is only observed in one polymorph [131]. Ostrowska et al. investigated the racemic
compound using both recrystallisation and compression methodologies to a pressure
of 4 GPa with a view that it may be chirally resolved using pressure [132]. Despite
the use of many solvents (chiral and achiral) and range of pressures and temperatures
(0.1–1.15 GPa; up to 553 K), the known Form I was always produced. Even
attempted co-crystallisations with mandelic acid and tartaric acid failed. The idea
174
S. A. Moggach and I. D. H. Oswald