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

Abstract

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 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.

Cooperative Kinetic Model to Describe Crystallization in Solid Solution Forming Systems

“…Therefore, for solid solution forming systems the meaning of the equilibrium concentration diverges from typical definition of solubility. The equilibrium concentration is determined by the following set of the mass balances (eqs –12) coupled with the closure equation, eq , and the SLE relationship, eq (Figure ): − where F is the mass of feed delivered to the crystallizer, m L the mass of the mother liquor, m S the mass of the crystalline phase, m S o l , the mass of the solvent, and m M the whole mass of the system obtained after mixing (at the mixing point); the function x e q ,i L = f p ( x i S ) is specific for each of components, i , and each of polymorphs, p (in case when they are formed, i.e., for System II).…”

“…Though mixtures of chiral organic compounds rarely exhibit continuous solid solutions, partial solid solutions are reported to occur relatively often. − The separation of such mixtures requires multistage crystallization, in which the target compound can be enriched either in the solid or in the liquid phase, depending on the solubility properties of the mixture. Multistage crystallization in solid solution forming systems has been described in several studies, − in which the process design was based on the solid–liquid equilibrium (SLE) data. Up to now, the issue of crystallization kinetics in such systems has not been tackled quantitatively.…”

“…The mixture forms solid solutions in the crystalline phase. Multistage batch-wise crystallization was exploited to resolve pseudobinary mixtures of the two racemates, one of which was the target product that contained the most active stereoisomer. , …”

“…The crystallization of citalopram diastereoisomers occurred in a relatively typical manner, in which reproducible equilibrium states were established regardless of the composition of the mixture . Nafronyl oxalate revealed a complex phase behavior, which manifested itself in multiple equilibrium states, which established over a certain composition range of the mixtures . The occurrence of a desired equilibrium state could be imposed by seeding the supersaturated solutions.…”

Development of a Route to the Most Active Nafronyl Stereoisomer by Coupling Asymmetric Synthesis and Chiral Chromatography Separation

“…Two main approaches have been used to prepare the stereoisomer with the desired configuration: (i) non‐selective synthesis of a quaternary mixture of the stereoisomers followed by their resolution to isolate the most active stereoisomer (2 S ,2′ R ), or (ii) selective synthesis of a pair of two diastereoisomers (2 R ,2′ R ) and (2 S ,2′ R ), which were subsequently resolved to obtain the target compound. The former involved complex multistep separation procedures, which exploited fractional crystallization or coupling of crystallization and chromatography 5–7. The latter was based on stereoselective synthesis of nafronyl oxalate from ( R )‐tetrahydrofurfuryl alcohol, which provided the compound molecules with defined configuration on the stereogenic center C 2′ (Fig.…”