20 Twenty-Five Years’ History, Mechanism, and Generality …
421
racemic ketoprofen always showed much higher solubility than coformers [39].
Next, although the cocrystal of racemic naproxen with bipyridine or piperazine was
successfully prepared, both cocrystals failed to show PE because of the violation
of the solubility requirement (i) in the Sect. 20.3; the solubility of the pure enantiomer was lower than that of the racemate in various solvents [42]. Furthermore,
the crystal structure of the cocrystal of racemic ibuprofen with 4,4
-ethane-1,2diyldipyridine (P–1) or nicotinamide (Pca2 1 ) was known. However, these cocrystals failed to exhibit PE, because they did not have an appropriate crystal structure
described in the requirement (ii) [39]. Instead we have found that the 1:1 cocrystal
(5) (P2 1 /n) of racemic CPPPA [anti-hyperlipoproteinemia drug (EMD 31 647)] and
isonicotinamide (Fig. 20.4), shows an excellent PE phenomenon [39].
20.5.1 Phenylalanine-Fumaric Acid Cocrystal (2) [35]
The 1:1 cocrystal (2) of DL-Phe and fumaric acid, which has a eutectic ee value
as high as 99% in water, satisfied all the requirements (i)–(v) and thereby showed
an efficient PE phenomenon (Fig. 20.14). The XRPD pattern of the deposited nonFig. 20.14 Successive
recrystallization of cocrystal
2. Conditions: a H 2 O
(10.0 mL, six-fold
supersaturation) at 5 °C for
60 h. b H 2 O (9.2 mL) at 5 °C
for 48 h. c H 2 O (8.7 mL) at
5 °C for 42 h. d H 2 O
(7.8 mL) at 5 °C for 24 h.
e H 2 O (6.9 mL) at 5 °C for
24 h. f Removal of the
solvent by evaporation. Data
cited from Ref. [35]
421
racemic ketoprofen always showed much higher solubility than coformers [39].
Next, although the cocrystal of racemic naproxen with bipyridine or piperazine was
successfully prepared, both cocrystals failed to show PE because of the violation
of the solubility requirement (i) in the Sect. 20.3; the solubility of the pure enantiomer was lower than that of the racemate in various solvents [42]. Furthermore,
the crystal structure of the cocrystal of racemic ibuprofen with 4,4
-ethane-1,2diyldipyridine (P–1) or nicotinamide (Pca2 1 ) was known. However, these cocrystals failed to exhibit PE, because they did not have an appropriate crystal structure
described in the requirement (ii) [39]. Instead we have found that the 1:1 cocrystal
(5) (P2 1 /n) of racemic CPPPA [anti-hyperlipoproteinemia drug (EMD 31 647)] and
isonicotinamide (Fig. 20.4), shows an excellent PE phenomenon [39].
20.5.1 Phenylalanine-Fumaric Acid Cocrystal (2) [35]
The 1:1 cocrystal (2) of DL-Phe and fumaric acid, which has a eutectic ee value
as high as 99% in water, satisfied all the requirements (i)–(v) and thereby showed
an efficient PE phenomenon (Fig. 20.14). The XRPD pattern of the deposited nonFig. 20.14 Successive
recrystallization of cocrystal
2. Conditions: a H 2 O
(10.0 mL, six-fold
supersaturation) at 5 °C for
60 h. b H 2 O (9.2 mL) at 5 °C
for 48 h. c H 2 O (8.7 mL) at
5 °C for 42 h. d H 2 O
(7.8 mL) at 5 °C for 24 h.
e H 2 O (6.9 mL) at 5 °C for
24 h. f Removal of the
solvent by evaporation. Data
cited from Ref. [35]