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

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 °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 temper...