Study of System Thermodynamics and the Feasibility of Chiral Resolution of the Polymorphic System of Malic Acid Enantiomers and Its Partial Solid Solutions

Abstract

The appearance of mixed crystals of organic compounds is frequently discussed in recent literature and it can cause difficulties in the downstream process of drug purification. The chiral malic acid system is an example of a system of enantiomers that exhibits partial solid solutions in a large composition range. Measurements and analyses of the binary melting phase diagram and the ternary solution phase diagram were conducted, and the existing phases were characterized by X-ray powder diffraction. Within this study the formations of two phases of mixed crystals were observed and assigned to the underlying polymorphism of the racemic compound. A suggestion for the complex phase diagram of this system is made. Preferential crystallization was performed to assess the feasibility of chiral resolution by crystallization for a system exhibiting high enantiomeric excess at the eutectic point and partial solid solutions. Primary nucleation and seeded crystallization experiments revealed (a) that an initial incorporation of the enantiomer in excess into the crystal lattice of the racemic compound can be altered by the choice of crystallization conditions and (b) why partial solid solutions must be taken into account for the design of separation procedures. Considerations on the crystal structures of malic acid helped to understand the formation of particular partial solid solutions for this compound.