Safinamide mesylate (SM), the pure active pharmaceutical ingredient (API) recently used in Parkinson disease treatment, recrystallized employing water-ethanol mixture of solvents (vol/vol 1:9) gives a different crystallographic form compared to SM in Xadago tablets. Pure SM crystallizes as a hemihydrate in the monoclinic system with the P21 space group. Its crystal and molecular structure were determined by means of cryo X-ray crystallography at 100 K. SM in the Xadago tablet exists in anhydrous form in the orthorhombic crystallographic system with the P212121 space group. The water migration and thermal processes in the crystal lattice were monitored by solid-state NMR spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. SM in Xadago in the high-humidity environment undergoes phase transformation to the P21 form which can be easily reversed just by heating up to 80 °C. For the commercial form of the API, there is also a reversible thermal transformation observed between Z' = 1 ↔ Z' = 3 crystallographic forms in the 0-20 °C temperature range. Analysis of molecular motion in the crystal lattice proves that the observed conformational polymorphism is forced by intramolecular dynamics. All above-mentioned processes were analyzed and described employing the NMR crystallography approach with the support of advanced theoretical calculations.
Keywords: API; DFT-D; GIPAW; Parkinson disease; Phase transition; Xadago; disorder structures; molecular dynamics; quantum mechanics calculations; very-fast MAS NMR.