Thermochemistry of Racemic and Enantiopure Organic Crystals for Predicting Enantiomer Separation
Thermochemistry of Racemic and Enantiopure Organic Crystals for Predicting Enantiomer Separation
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DOI：
10.1021/acs.cgd.7b00582
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发表时间：
2017-09-01
影响因子：
3.8
通讯作者：
Price, Sarah L.
中科院分区：
文献类型：
--
作者：
Buchholz, Hannes K.;Hylton, Rebecca K.;Price, Sarah L.
从外消旋混合物中分离对映异构体与制药工业主要相关。利用有机物的热化学性质可以设计对映体选择性结晶过程。两种晶体形式之间的热力学差异可通过两个循环获得，这两个循环给出了溶液中的低共熔组合物。“升华循环”需要计算晶体结构的晶格能和声子频率。从热容量和其他热力学测量的对映体纯和外消旋晶体的实验结果进行了比较与各种分子和晶体结构为基础的计算。这是针对具有不同程度的分子柔性的药物样分子的三个原型进行的。晶体堆积的差异导致不同的温度依赖的热容，并影响升华热力学，相对溶解度，和共晶组合物。许多简化假设的热力学和溶解度的外消旋体和对映体纯晶体的批判性评价。我们表明，使用升华循环的计算和实验信息可以指导设计的过程，以解决对映体的结晶。
The separation of an enantiomer from a racemic mixture is of primary relevance to the pharmaceutical industry. The thermochemical properties of organic enantiopure and racemate crystals can be exploited to design an enantioselective crystallization process. The thermodynamic difference between the two crystal forms is accessible by two cycles which give the eutectic composition in solution. The "sublimation cycle" requires calculating the lattice energy and phonon frequencies of the crystal structures. Experimental results from heat capacity and other thermodynamic measurements of enantiopure and racemic crystals are compared with a variety of molecular and crystal structure-based calculations. This is done for three prototypes of pharmaceutical-like molecules with different degrees of molecular flexibility. Differences in crystal packing result in varying temperature-dependent heat capacities and affect the sublimation thermodynamics, relative solubility, and eutectic composition. Many simplifying assumptions about the thermodynamics and solubilities of the racemic and enantiopure crystals are critically evaluated. We show that calculations and experimental information using the sublimation cycle can guide the design of processes to resolve enantiomers by crystallization.