Huang Jun, Chen Shuang, Guzei Ilia A, Yu Lian
School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
J Am Chem Soc. 2006 Sep 13;128(36):11985-92. doi: 10.1021/ja063450l.
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.
由对映体组成的外消旋液体通常结晶为外消旋化合物（外消旋体），很少结晶为聚集体，更罕见的是结晶为固溶体。我们通过用对映体纯的晶体（对映体）晶种接种其外消旋液体，发现了手性药物他索非酮（TZF）对映体的II型固溶体（混晶）。未进行晶种接种时，外消旋液体结晶为外消旋化合物。这种固溶体的晶体结构类似于对映体的结构，但由于对映体的随机取代而产生静态无序。这种固溶体是结晶的动力学产物，与竞争的外消旋体相比，其生长速度更快（在80至146摄氏度之间快4至40倍），从而使其成为可能。固溶体的自由能随对映体组成在聚集体和外消旋体之间连续变化。TZF固溶体的存在解释了不同对映体组成的晶体之间不存在低共熔现象。TZF同时形成外消旋体和固溶体的能力源于其构象灵活性。对映体的类似固溶体可能存在于其他体系中，并且可能以类似的方式被发现。该研究展示了利用交叉成核来发现和设计晶体材料以优化物理性质的方法。
