50
K. Adrjanowicz
sample. Slowing down of the crystallization tendencies for racemic ketoprofen with
increasing pressure and no evident changes in the value of the Avrami parameter is
consistent with the results reported previously for RS-ibuprofen [77]. On the other
hand, changes in the crystal morphology or growth process are expected for the
single enantiomer sample, as indicated by the decrease of the Avrami parameter with
pressure.
In agreement with the classical theory of nucleation and growth, when the kinetic
factor is under control, changes in the crystallization rate can be ascribed solely due
to thermodynamic force. Indeed, this is what we have observed for other molecular liquids, like describe above indomethacin. This argumentation can be also used
to explain the ease of crystal formation with increasing pressure for S-ketoprofen.
However, it fails for the racemic system under pressure. Note that similar slowing
down of the crystallization progress was also reported for the racemic methylated
derivative of ketoprofen in which we can exclude the hydrogen bonding contribution
(see results in Fig. 14). As we presume, the peculiar behavior of racemic compounds
must be related to the fact that it is a mixture of two “kinds” of molecules, not
a single one. It is known from experimental studies that increasing the number of
components in the mixture tends to suppress nucleation, as the chances that a critical
nucleus of one particular kind is formed are reduced. However, in this case, another
possible explanation should be also considered. As speculated by Jacques et al. [28]
at certain conditions the Wallach rule can be invalidated and more densely packed
structure of single enantiomers become suddenly more preferable under pressure,
than their racemic mixture. As a result, by the application of pressure, spontaneous
enantiomers resolution might be possible.
In the past few years, several experimental attempts (but without a success) have
been carried out to prove that by crystallizing racemic compounds from various
solvents under pressure or by squeezing racemic crystals it is possible to resolve
optical isomers [78, 79]. Intriguingly, this remains still one of the most puzzling
subjects within that field with no convincing experimental data provided so far.
On the other hand, it is important to mention that Gonnade et al. demonstrated the
occurrence of spontaneous resolution of racemates or even chiral symmetry breaking
for crystallization carried out under various nonequilibrium conditions at ambient
pressure [80]. Nevertheless, it remains rather an open question if the same effect
can be obtained by high-pressure crystallization from the metastable supercooled
liquid state, and whether the eutectic equilibrium between the racemate and single
enantiomer follows the same lines as their melting transitions.
To summarize, the problem of physicochemical stability of racemic compounds
on increased pressure is certainly an intriguing topic to study in the future, especially
how pressure affects the affinity of enantiomers to each other. This study emphasizes
the difference between the crystallization behavior of single enantiomers and their
racemic mixture and demonstrates that in case of chiral compounds/or probably in
more general sense eutectic compositions other factors should be also considered to
gain some elementary understanding of their high-pressure crystallization behavior.
K. Adrjanowicz
sample. Slowing down of the crystallization tendencies for racemic ketoprofen with
increasing pressure and no evident changes in the value of the Avrami parameter is
consistent with the results reported previously for RS-ibuprofen [77]. On the other
hand, changes in the crystal morphology or growth process are expected for the
single enantiomer sample, as indicated by the decrease of the Avrami parameter with
pressure.
In agreement with the classical theory of nucleation and growth, when the kinetic
factor is under control, changes in the crystallization rate can be ascribed solely due
to thermodynamic force. Indeed, this is what we have observed for other molecular liquids, like describe above indomethacin. This argumentation can be also used
to explain the ease of crystal formation with increasing pressure for S-ketoprofen.
However, it fails for the racemic system under pressure. Note that similar slowing
down of the crystallization progress was also reported for the racemic methylated
derivative of ketoprofen in which we can exclude the hydrogen bonding contribution
(see results in Fig. 14). As we presume, the peculiar behavior of racemic compounds
must be related to the fact that it is a mixture of two “kinds” of molecules, not
a single one. It is known from experimental studies that increasing the number of
components in the mixture tends to suppress nucleation, as the chances that a critical
nucleus of one particular kind is formed are reduced. However, in this case, another
possible explanation should be also considered. As speculated by Jacques et al. [28]
at certain conditions the Wallach rule can be invalidated and more densely packed
structure of single enantiomers become suddenly more preferable under pressure,
than their racemic mixture. As a result, by the application of pressure, spontaneous
enantiomers resolution might be possible.
In the past few years, several experimental attempts (but without a success) have
been carried out to prove that by crystallizing racemic compounds from various
solvents under pressure or by squeezing racemic crystals it is possible to resolve
optical isomers [78, 79]. Intriguingly, this remains still one of the most puzzling
subjects within that field with no convincing experimental data provided so far.
On the other hand, it is important to mention that Gonnade et al. demonstrated the
occurrence of spontaneous resolution of racemates or even chiral symmetry breaking
for crystallization carried out under various nonequilibrium conditions at ambient
pressure [80]. Nevertheless, it remains rather an open question if the same effect
can be obtained by high-pressure crystallization from the metastable supercooled
liquid state, and whether the eutectic equilibrium between the racemate and single
enantiomer follows the same lines as their melting transitions.
To summarize, the problem of physicochemical stability of racemic compounds
on increased pressure is certainly an intriguing topic to study in the future, especially
how pressure affects the affinity of enantiomers to each other. This study emphasizes
the difference between the crystallization behavior of single enantiomers and their
racemic mixture and demonstrates that in case of chiral compounds/or probably in
more general sense eutectic compositions other factors should be also considered to
gain some elementary understanding of their high-pressure crystallization behavior.