Polymorphism of racemic felodipine and the unusual series of solid solutions in the binary system of its enantiomers

The aim of this study was to investigate the binary phase diagram and the polymorphism and pseudopolymorphism of racemic and enantiomeric felodipine, including their spectroscopic and thermodynamic properties. Different crystal forms were obtained by crystallization from solvents or from the annealed melt and investigated by thermal analysis (hot stage microscopy, differential scanning calorimetry, thermogravimetric analysis), spectroscopic methods (Fourier transform infrared-and Fourier transform-Raman spectroscopy), and X-ray powder diffractometry. The binary melting phase diagram was constructed based on thermoanalytical investigations of quantitative mixtures of (+)- and (±)-felodipine. Two polymorphic forms of racemic felodipine, mod. I (mp, ∼145°C) and mod. II (mp, ∼135°C), as well as an acetone solvate (S_Ac) were characterized. Melting equilibria of felodipine crystal forms decrease due to thermal decomposition. Enantiomeric felodipine was found to be dimorphic (En-mod. I: mp, ∼144°C; En-mod. II: mp, ∼133°C), Evaluation of the binary system of (+)- and (-)-felodipine results in the formation of a continuous series of mixed crystals between the thermodynamically stable and higher melting modifications, mod. I and En-mod. I. Their unusual curve course, termed as Roozeboom Type 2 b, passes through a maximum in the racemic mixture and is flanked by a minimum at 20% and at 80% (+)-felodipine. From the thermodynamic parameters, racemic mod. I and II are monotropically related. In contrast to S_Ac, the thermodynamically unstable mod. II shows a considerable kinetic stability. Because its crystallization is badly reproducible, the use of mod. II is not advisable for processing. However, desolvation of S_Ac leads to a profitable crystal shape of mod. I, representing a pseudoracemate by definition.