Multiplicity of Equilibrium States in Separating Stereoisomeric Mixtures of Nafronyl Oxalate by Crystallization

作者：Olbrycht Maksymilian; Kiwala Dawid; Balawejder Maciej; Seidel Morgenstern Andreas; Piatkowski Wojciech; Antos Dorota^*

来源：Crystal Growth & Design, 2016, 16(9): 5049-5058.

DOI：10.1021/acs.cgd.6b00624

Nafronyl oxalate (2-(diethylamino)ethyl 3-(naphthalen-1-yl)-2-((tetrahydrofuran-2-yl)methyl)propanoate oxalate) is a pharmacologically active compound, which is used as a drug ingredient. The nafronyl molecule possesses two stereogenic centers. It is manufactured as a stereoisomeric mixture of two pairs of racemates being diastereoisomers to each other. The mixture components are characterized by different biological activity. Only one of the racemates contains the stereoisomer with the highest pharmacological efficacy. To separate the racemates, an efficient crystallization process was designed and performed. This was based on Solid-Liquid Equilibrium (SLE) data, which were acquired in a wide composition range at temperatures between 10 and 40 degrees C. A specific SLE region was detected with an unusual phase behavior, where different equilibrium states could be established. The crystalline products of each state differed with respect to the excess of the target racemate. This phenomenon was found to be temperature dependent; it diminished with decreasing temperature. The occurrence of a desired equilibrium state could be induced either by altering the process temperature or by seeding the supersaturated solutions. The separation was implemented by applying a multistage crystallization process, which provided the pure target racemate. The process performance was further improved by adjusting the temperature in each crystallization stage.

• 出版日期2016-9