Wang Xin, Wang Xiu Juan, Ching Chi Bun
Department of Chemical and Environmental Engineering, National University of Singapore, Singapore.
Chirality. 2002 May 5;14(4):318-24. doi: 10.1002/chir.10049.
Characterization of the racemic species, which can be a racemic compound, a racemic conglomerate, or a pseudoracemate (solid solution), is a prerequisite for the design of crystallization resolution processes. It is useful to determine the solid/liquid equilibrium solubility of the enantiomer mixtures for crystallization operation. For the beta-blocker drug propranolol hydrochloride, Gibbs free energy of formation of racemic compound and entropy of mixing of the (R)- and (S)- enantiomers in the liquid state for racemic conglomerate were calculated. The structural differences between (R, S)-propranolol hydrochloride and its (S)-enantiomer were further investigated by powder X-ray diffraction patterns, infrared spectra, and solid-state NMR spectra. The solubility and metastable zone width of (R, S)- propranolol hydrochloride in a mixed solvent of methanol and acetone were determined by cooling crystallization over the temperature range 3.5-42.5 degrees C. The ternary solubility diagram of (R)-, (S)-propranolol hydrochloride was constructed using the same mixed solvent. The diagram will be useful as a guide for choosing crystallization operation conditions to produce pure enantiomers.
外消旋体的表征，其可以是外消旋化合物、外消旋聚集体或假外消旋体（固溶体），是结晶拆分过程设计的前提条件。确定对映体混合物的固/液平衡溶解度对于结晶操作是有用的。对于β-受体阻滞剂药物盐酸普萘洛尔，计算了外消旋化合物的生成吉布斯自由能以及外消旋聚集体中（R）-和（S）-对映体在液态下的混合熵。通过粉末X射线衍射图谱、红外光谱和固态核磁共振光谱进一步研究了（R，S）-盐酸普萘洛尔与其（S）-对映体之间的结构差异。通过在3.5-42.5℃的温度范围内冷却结晶，测定了（R，S）-盐酸普萘洛尔在甲醇和丙酮混合溶剂中的溶解度和亚稳区宽度。使用相同的混合溶剂构建了（R）-、（S）-盐酸普萘洛尔的三元溶解度图。该图将作为选择结晶操作条件以生产纯对映体的指南。
