Conformational Polymorphism in Safinamide Acid Hydrochloride (Z′=3 and Z′=1) and Observation of a Temperature-Dependent Reversible Single-Crystal to Single-Crystal Phase Transformation of High-Z′ form (Z′=3 ⇆ H Z′=2 via an Intermediate Z′=4)

Two concomitant polymorphs of safinamide acid hydrochloride were obtained in an attempt to prepare the O-protonated amide salt of safinamide from ethanolic HCl solution. Polymorph I crystallized in the triclinic space group P1 with three molecules in the asymmetric unit (Z' = 3) while polymorph II crystallized in the orthorhombic space group P212121 with a single molecule in the asymmetric unit (Z' = 1). Structural differences at the conformational level and their influence on intermolecular interactions in the crystals led to the occurrence of polymorphism in the title compound. Both Z' = 1 and Z' = 3 polymorphic forms of safinamide acid hydrochloride were sustained by similar strong OH center dot center dot center dot Cl and N+H center dot center dot center dot Cl hydrogen-bonded interactions but differed significantly in the molecular conformations and hence their molecular arrangements in the crystal lattice. The CH center dot center dot center dot O and CH center dot center dot center dot F hydrogen bonds along with the strong hydrogen bonds facilitated one-dimensional supramolecular aggregates and caused the occurrence of the Z' > 1 situation. The high-Z' polymorph showed an interesting phase transition behavior during variable-temperature single-crystal X-ray diffraction studies (VT-SCXRD). When the sample was rapidly cooled from 293 K (room temperature) to 100 K (low temperature), the Z' = 3 polymorph was stable; however, when the same crystal was subjected to gradual cooling from room temperature to 100 K, the Z' = 3 polymorph transformed to a novel Z' = 2 structure (in the transition temperature range 260-265 K). When the sample was warmed from 100 K to RT, the phase transition was found to be reversible from Z' = 2 to Z' = 3 (in the transition temperature range 270-275 K). Differential scanning calorimetry studies were conducted to confirm the reversible phase transition nature (Z' = 3 ? Z' = 2). An intermediate short-lived crystal form with four molecules in the asymmetric unit (Z' = 4) was captured at 272 K during the VT-SCXRD warming cycle, which facilitated a better understanding of the structural reorganization process during the phase transition. The Z' = 4 structure can be referred as a crystal on the way in the Z' = 2 to Z' = 3 phase transition. The close structural similarities among Z' = 3, 2, and 4 accounted for the phase transformation in a single-crystal to single-crystal manner.

Automated summary

The two concomitant polymorphs of safinamide acid hydrochloride exhibit differences in molecular arrangements in the crystal lattice due to structural variances at the conformational level, resulting in the occurrence of polymorphism in the compound.