410
R. Tamura et al.
following four experimental and theoretical studies; (1) the polymorphic transition
process could be directly followed by using in situ techniques such as attenuated total
reflectance FT infrared (ATR-FTIR) spectroscopy [25–30], temperature-controlled
(TC) video-microscopy [31], and time-resolved X-ray powder diffraction (XRPD)
measurement [31], (2) the regular enrichment of one enantiomer in the mother liquor
was successfully rationalized by the kinetic/thermodynamic studies on the solubility
properties of two enantiomers [32], (3) the crystal structures of the deposited fine
polycrystalline powder samples were solved from the XRPD data by the direct-space
approach employing the Monte Carlo method with the subsequent Rietveld refinement [26, 27, 29], and the resulting brittle crystal structures were characterized in
terms of the occurrence of partial crystal disintegration of the once deposited crystals
on the basis of the graph set analysis of hydrogen bond motifs [33], and (4) a ternary
phase diagram that is fully in accord with all experimental data and the elucidated
mechanism of PE was proposed [32].
Consequently, PE with regard to the first generation of racemic organic salts
1 was found to be initiated by the solvent-assisted solid-to-solid transformation
of a metastable polymorphic form into another thermodynamically more stable
one during crystallization from the supersaturated solution of the racemic organic
salts composed of two enantiomers without the aid of any external chiral element
(Fig. 20.3c) [15–19]. Most notably, this polymorphic transition process was accompanied by selective redissolution of the excess one enantiomer from the incomplete
hydrogen bonding sites inside the transformed disordered crystal lattice into the
mother liquor until the deposited crystals were slightly enriched with the opposite
enantiomer (<10% ee) with full reproducibility (Fig. 20.3d, e). Thus, the interplay
of (i) such a solvent-assisted solid-to-solid polymorphic transition (Fig. 20.3c), (ii)
the subsequent selective redissolution process of the excess one enantiomer from
the deposited brittle mixed crystals (Fig. 20.3d), (iii) the regular enrichment of one
enantiomer in the mother liquor, and (iv) the deposition of eventually disintegrated,
powdered mixed crystals which can retain the resulting fairly-random alignment of
two enantiomers inside the crystal lattice so as to memorize the regular chiral fluctuation and symmetry breaking (Fig. 20.3e) turned out to be responsible for this unique
chiral resolution phenomenon.
Furthermore, on the basis of the requirements of PE clarified for a series of the
first generation of racemic organic salts 1, we have successfully expanded the scope
of PE to common racemic crystals, such as (1) an acidic chiral nonsteroidal antiinflammatory drug (ketoprofen) [34] and (2) the second generation of dimorphic
cocrystals composed of (a) a racemic neutral or basic α-amino acid (Phe, Leu, or
Arg) and an achiral dicarboxylic acid (fumaric acid or oxalic acid) as the coformer
(cocrystal former) [35–38] and (b) a racemic acidic anti-hyperlipoproteinemia drug
(CPPPA) and an achiral isonicotinamide as the coformer (Fig. 20.4) [39]. Although a
little bit modified mechanism was necessary for each of these cocrystals, these results
strongly support the generality of our initially proposed requirements and mechanism
of PE clarified for a series of the first generation of racemic organic salts 1. Thus,
PE is expected to become a general chiral resolution method by crystallization, with
high flexibility and versatility, and full reproducibility.
R. Tamura et al.
following four experimental and theoretical studies; (1) the polymorphic transition
process could be directly followed by using in situ techniques such as attenuated total
reflectance FT infrared (ATR-FTIR) spectroscopy [25–30], temperature-controlled
(TC) video-microscopy [31], and time-resolved X-ray powder diffraction (XRPD)
measurement [31], (2) the regular enrichment of one enantiomer in the mother liquor
was successfully rationalized by the kinetic/thermodynamic studies on the solubility
properties of two enantiomers [32], (3) the crystal structures of the deposited fine
polycrystalline powder samples were solved from the XRPD data by the direct-space
approach employing the Monte Carlo method with the subsequent Rietveld refinement [26, 27, 29], and the resulting brittle crystal structures were characterized in
terms of the occurrence of partial crystal disintegration of the once deposited crystals
on the basis of the graph set analysis of hydrogen bond motifs [33], and (4) a ternary
phase diagram that is fully in accord with all experimental data and the elucidated
mechanism of PE was proposed [32].
Consequently, PE with regard to the first generation of racemic organic salts
1 was found to be initiated by the solvent-assisted solid-to-solid transformation
of a metastable polymorphic form into another thermodynamically more stable
one during crystallization from the supersaturated solution of the racemic organic
salts composed of two enantiomers without the aid of any external chiral element
(Fig. 20.3c) [15–19]. Most notably, this polymorphic transition process was accompanied by selective redissolution of the excess one enantiomer from the incomplete
hydrogen bonding sites inside the transformed disordered crystal lattice into the
mother liquor until the deposited crystals were slightly enriched with the opposite
enantiomer (<10% ee) with full reproducibility (Fig. 20.3d, e). Thus, the interplay
of (i) such a solvent-assisted solid-to-solid polymorphic transition (Fig. 20.3c), (ii)
the subsequent selective redissolution process of the excess one enantiomer from
the deposited brittle mixed crystals (Fig. 20.3d), (iii) the regular enrichment of one
enantiomer in the mother liquor, and (iv) the deposition of eventually disintegrated,
powdered mixed crystals which can retain the resulting fairly-random alignment of
two enantiomers inside the crystal lattice so as to memorize the regular chiral fluctuation and symmetry breaking (Fig. 20.3e) turned out to be responsible for this unique
chiral resolution phenomenon.
Furthermore, on the basis of the requirements of PE clarified for a series of the
first generation of racemic organic salts 1, we have successfully expanded the scope
of PE to common racemic crystals, such as (1) an acidic chiral nonsteroidal antiinflammatory drug (ketoprofen) [34] and (2) the second generation of dimorphic
cocrystals composed of (a) a racemic neutral or basic α-amino acid (Phe, Leu, or
Arg) and an achiral dicarboxylic acid (fumaric acid or oxalic acid) as the coformer
(cocrystal former) [35–38] and (b) a racemic acidic anti-hyperlipoproteinemia drug
(CPPPA) and an achiral isonicotinamide as the coformer (Fig. 20.4) [39]. Although a
little bit modified mechanism was necessary for each of these cocrystals, these results
strongly support the generality of our initially proposed requirements and mechanism
of PE clarified for a series of the first generation of racemic organic salts 1. Thus,
PE is expected to become a general chiral resolution method by crystallization, with
high flexibility and versatility, and full reproducibility.