20 Twenty-Five Years’ History, Mechanism, and Generality …
417
(a) Usual stagnant crystallization conditions without either vigorous stirring or
abrasive grinding can be applied to the PE experiment, except that approximately
four to 25-fold supersaturated solutions are employed because the supersolubility of the racemates showing PE is considerably higher than the solubility at
25 °C. The attainment of such a high supersolubility is closely associated with
the preferential formation of homochiral 1D R and S chains even in the racemic
solution. Usually, at the supersaturated concentrations below fourfold, PE does
not efficiently occur.
(b) Racemic or non-racemic samples less than 10% ee are more suitable for the
PE experiment than those of higher ee values to achieve a very efficient resolution, resulting in the regular deposition of non-racemic mixed crystals slightly
enriched (around 5% ee) with the opposite enantiomer.
(c) When the original supersaturated solution used for crystallization is strictly
racemic (0.0% ee), the probability for either the R or the S enantiomer to be
enriched in the mother liquor after the first crystallization is 0.5. This is because
initial capricious formation of the first-formed non-racemic metastable crystal
nucleus should determine which enantiomer is enriched in the mother liquor
thereafter. Since generally the racemic synthesis of 1.0 mol of a chiral compound
produces a racemic sample with a standard deviation of ca. 1.3 × 10
–10 % ee, it
is noteworthy that chiral amplification of nearly 10
12 -fold occurs easily during
the PE process [32].
(d) Only racemic or non-racemic samples have to be crystalline to implement the PE
experiment efficiently. It does not matter whether the enantiomerically enriched
samples with high ee values exist as solids or oils; this is in sharp contrast to
PC of racemic conglomerate crystals.
(e) Seed crystals are not necessary at all and should not be added to induce
crystallization, because PE is sometimes inhibited by them.
20.4 Ketoprofen [34]
To extend the scope of PE to pharmaceutically relevant compounds, we carried out
an extensive search using the Cambridge Structural Database (CSD) regarding chiral
nonsteroidal anti-inflammatory drugs (NSAID) with an appropriate crystal structure
exhibiting PE, according to the requirement (ii) in the Sect. 20.3. We found that
ibuprofen (space group: P2 1 /c), ketoprofen (P–1), and naproxen (Pbca) (Fig. 20.4)
have the desired stable racemic crystal structure containing RS dimer chains as well
as homochiral 1D R and S chains (Fig. 20.11). Among them, only ketoprofen with
a relatively high eutectic point at 82% ee satisfied all the five requirements (i)–(v)
for the occurrence of PE listed in the Sect. 20.3. Indeed, ketoprofen showed a good
PE phenomenon as long as crystallization began from tenfold supersaturated H 2 O–
EtOH (v/v 1:1) solution of non-racemic ketoprofen of more than 1% ee at –16 °C
(Fig. 20.12), despite being a single-component organic crystal. However, ibuprofen
417
(a) Usual stagnant crystallization conditions without either vigorous stirring or
abrasive grinding can be applied to the PE experiment, except that approximately
four to 25-fold supersaturated solutions are employed because the supersolubility of the racemates showing PE is considerably higher than the solubility at
25 °C. The attainment of such a high supersolubility is closely associated with
the preferential formation of homochiral 1D R and S chains even in the racemic
solution. Usually, at the supersaturated concentrations below fourfold, PE does
not efficiently occur.
(b) Racemic or non-racemic samples less than 10% ee are more suitable for the
PE experiment than those of higher ee values to achieve a very efficient resolution, resulting in the regular deposition of non-racemic mixed crystals slightly
enriched (around 5% ee) with the opposite enantiomer.
(c) When the original supersaturated solution used for crystallization is strictly
racemic (0.0% ee), the probability for either the R or the S enantiomer to be
enriched in the mother liquor after the first crystallization is 0.5. This is because
initial capricious formation of the first-formed non-racemic metastable crystal
nucleus should determine which enantiomer is enriched in the mother liquor
thereafter. Since generally the racemic synthesis of 1.0 mol of a chiral compound
produces a racemic sample with a standard deviation of ca. 1.3 × 10
–10 % ee, it
is noteworthy that chiral amplification of nearly 10
12 -fold occurs easily during
the PE process [32].
(d) Only racemic or non-racemic samples have to be crystalline to implement the PE
experiment efficiently. It does not matter whether the enantiomerically enriched
samples with high ee values exist as solids or oils; this is in sharp contrast to
PC of racemic conglomerate crystals.
(e) Seed crystals are not necessary at all and should not be added to induce
crystallization, because PE is sometimes inhibited by them.
20.4 Ketoprofen [34]
To extend the scope of PE to pharmaceutically relevant compounds, we carried out
an extensive search using the Cambridge Structural Database (CSD) regarding chiral
nonsteroidal anti-inflammatory drugs (NSAID) with an appropriate crystal structure
exhibiting PE, according to the requirement (ii) in the Sect. 20.3. We found that
ibuprofen (space group: P2 1 /c), ketoprofen (P–1), and naproxen (Pbca) (Fig. 20.4)
have the desired stable racemic crystal structure containing RS dimer chains as well
as homochiral 1D R and S chains (Fig. 20.11). Among them, only ketoprofen with
a relatively high eutectic point at 82% ee satisfied all the five requirements (i)–(v)
for the occurrence of PE listed in the Sect. 20.3. Indeed, ketoprofen showed a good
PE phenomenon as long as crystallization began from tenfold supersaturated H 2 O–
EtOH (v/v 1:1) solution of non-racemic ketoprofen of more than 1% ee at –16 °C
(Fig. 20.12), despite being a single-component organic crystal. However, ibuprofen