Solid-Phase and Oscillating Solution Crystallization Behavior of (+)- and (-)-N-Methylephedrine.

This work involves the study of the solid-phase and solution crystallization behavior of the N-methylephedrine enantiomers. A systematic investigation of the melt phase diagram of the enantiomeric N-methylephedrine system was performed considering polymorphism. Two monotropically related modifications of the enantiomer were found. Solubilities and the ternary solubility phase diagrams of N-methylephedrine enantiomers in 2 solvents [isopropanol:water, 1:3 (Vol) and (2R, 3R)-diethyl tartrate] were determined in the temperature ranges between 15°C and 25°C, and 25°C and 40°C, respectively. Preferential nucleation and crystallization experiments at higher supersaturation leading to an unusual oscillatory crystallization behavior as well as a successful preferential crystallization experiment at lower supersaturation are presented and discussed.

The binary phase diagram of propranolol hydrochloride and crystallization-based enantioseparation.

Inconsistent results were reported for the solid-state nature of the racemic species of the pharmaceutical relevant compound propranolol hydrochloride. In this work the binary phase diagram of the propranolol hydrochloride enantiomers is studied. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and high performance liquid chromatography (HPLC) were used as analytical methods. The type of the racemic species, the presence and extent of partial solid solutions and the stability regions of polymorphic forms in the system were investigated. The identified binary phase diagram is sketched. Finally, the feasibility of crystallization-based resolution is discussed.

Potential of different techniques of preferential crystallization for enantioseparation of racemic compound forming systems.

Recently the feasibility of preferential crystallization for enantioseparation of racemic compound forming systems has been demonstrated (Lorenz et al., Application of preferential crystallization to resolve racemic compounds in a hybrid process. Chirality 2006;18:828-840; Polenske et al., Separation of the propranolol hydrochloride enantiomers by preferential crystallization: thermodynamic basis and experimental verification. Cryst Growth Des 2007;7:1628-1634). Here, the development and the potential of an efficient separation process operated via two different techniques of preferential crystallization are studied: (1) seeded isothermal preferential crystallization and (2) auto-seeded polythermal preferential crystallization. Both techniques were investigated in the batch and in the cyclic operation mode. On the example of mandelic acid as a typical racemic compound forming system, it is demonstrated that a cyclic auto-seeded polythermal process is feasible and significantly more efficient than the seeded isothermal one.

Application of preferential crystallization to resolve racemic compounds in a hybrid process.

The application of preferential crystallization is at present limited to conglomerate forming systems, which cover only a minor part of chiral substances. In this paper, a hybrid process is proposed that extends the applicability of the preferential crystallization principle to the more common racemic compound forming systems. It comprises a preliminary (e.g., chromatographic) enantiomeric enrichment step and preferential crystallization to finally produce the desired pure enantiomer(s). The applicability of preferential crystallization to racemic compounds is demonstrated on the example of mandelic acid as a model system. Direct monitoring of the separation progress is performed using combined online polarimetry and online density measurements. A cyclic crystallization process, which provides alternating the pure mandelic acid enantiomer and the racemic compound, is feasible and allows the resolution of rac-mandelic acid as part of the proposed hybrid approach.