Discovery of a solid solution of enantiomers in a racemate-forming system by seeding.
A racemic liquid of opposite enantiomers usually crystallizes as a racemic compound (racemate), rarely as a conglomerate, and even more rarely as a solid solution. We discovered a Type II solid solution (mixed crystal) of the enantiomers of the chiral drug tazofelone (TZF) by seeding its racemic liquid with enantiomerically pure crystals (enantiomorphs). Without seeding, the racemic liquid crystallized as a racemic compound. The crystal structure of this solid solution resembles that of the enantiomorph but has static disorder arising from the random substitution of enantiomers. This solid solution is a kinetic product of crystallization made possible by its faster growth rate compared to that of the competing racemate (by 4- to 40-fold between 80 and 146 degrees C). The free energy of the solid solution continuously varies with the enantiomeric composition between those of the conglomerate and the racemates. The existence of the TZF solid solution explains the absence of eutectic melting between crystals of different enantiomeric compositions. The ability of TZF to simultaneously form racemate and solid solution originates from its conformational flexibility. Similar solid solutions of enantiomers may exist in other systems and may be discovered in similar ways. The study demonstrates the use of cross-nucleation for discovering and engineering crystalline materials to optimize physical properties.
Huang
Jun
J
School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
Chen
Shuang
S
Guzei
Ilia A
IA
Yu
Lian
L
D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics; D053778:Thiazolidines / Q000737:chemistry*
D010636:Phenols; D053778:Thiazolidines; C109841:tazofelone