Chiral Separation of Pharmaceutical Molecules by Crystallization Resolution

An efficient method to produce enantiopure compounds on an industrial scale is direct crystallization or diastereomeric crystallization. The present work focuses on the most challenging issues: 1) enhancing the possibility of conglomerate formation for direct crystallization application, and 2) investigating the chiral discrimination mechanism to set up a rational method for resolving agent selection in a diastereomeric crystallization application. Chloromandelic acid and sertraline of pharmaceutical significance are employed as model compounds.;In order to enhance the conglomerate formation, a comprehensive method was adapted to identify the solid-state nature of a racemate. The method includes establishing a binary melting point diagram of enantiomeric mixture, characterizing the solid forms by various spectroscopy and X-ray diffraction, and screening polymorphs of racemates and enantiomers. The model compound 2-chloromandelic acid can exist either as racemic compound or conglomerate depending on the crystallization conditions. The sertraline racemate has been proved as a stable racemic compound.;The chiral discrimination mechanism in diastereomeric crystallization is studied by investigating the crystal structures of the resulting diastereomeric salts. CH/pi interaction and herringbone-like packing of aromatic groups are dominant factors contributing to the chiral discrimination in the chloromandelic acid and phenylethylamine systems. A 1-D hydrogen-bonding network and a unique crystal packing mode are disclosed in the less soluble salt of sertraline and mandelic acid. The two cases studied demonstrate that the stable hydrogen-bonding pattern, herringbone-like arrangement of aromatic rings and planar boundary surfaces in hydrophobic region are the three most important structural characteristics in less soluble salts. The stability of the diastereomeric salt is determined by the existence and magnitude of hydrogen bond, CH/pi and van der Waals interactions associated with these characteristic structures. It is found that hydrogen bond is not necessarily the primary factor in chiral discrimination. The synergy and optimization of all major intermolecular interactions account for chiral recognition.;Resolution processes of the model compounds used in chiral discrimination mechanism investigation were developed. Enantiopure (R)-4-chloromandelic acid was achieved in purity of 99.0% e.e and yield of 50% by using a less expensive resolving agent (R)-phenylethylamine. ( 1S, 4S)-sertraline enantiomer with purity of 99.8% e.e. and yield of 82% was obtained using less than one mole equivalent of resolving agent, resulting in savings of25% of resolving agent and 25% of solvent in comparison with one mole equivalent of resolving agent employed.;Keywords: crystallization resolution, direct crystallization, diastereomeric crystallization, racemate, enantiomer, conglomerate, racemic compound, diastereomeric salt, crystal structure, chloromandelic acid, sertraline, phenylethylamine, polymorphism, chiral discrimination mechanism, chiral recognition ability, hydrogen bonding, CH/pi interaction.