Solid-State Study of the Structure, Dynamics, and Thermal Processes of Safinamide Mesylate─A New Generation Drug for the Treatment of Neurodegenerative Diseases

Abstract

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 P 2 1 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 P 2 1 2 1 2 1 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 P 2 1 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.

Spherical Agglomeration of Safinamide Mesylate: A Case Study of a Simultaneous Control of Crystalline Landscape and Micromeritic Properties

“…As reported in the patent of Schlueter and Pawlak et al article, SAFIM could crystallize as a hemihydrate. However, the behavior upon hydration and dehydration of SAFIM is less detailed.…”

“…The polymorphic transition of the anhydrous forms has been thoroughly described by Pawlak et al Both forms crystallize in a P 2 1 2 1 2 1 space group with similar crystallographic parameters (Table ).…”

“…All these results are concordant with the literature. 17 Considering the different data obtained, a revision of the stability diagram at the atmospheric pressure of SAFIM solid phases is proposed in Figure 6.…”

“…To date, three crystalline phases of SAFIM have been reported: two enantiotropically related polymorphs with a solid–solid transition temperature of 20 °C ( A1 and A2 high- and low-temperature forms, respectively) and a hemihydrate ( H1 ). , As structural purity is of key importance for the pharmaceutical industry, the study aims at proving that SAFIM can be obtained as A1 solid form with desirable flowability properties after an agglomeration process.…”

Deuteron-proton isotope correlation spectroscopy of molecular solids

“…[29][30][31][32][33] In particular, two-dimensional (2D) experiments such as 1 H-X (X= 1 H, 13 C, 14/15 N, 19 F, and 35 Cl) enabled the local structures and interactions in neat APIs and solid formulations to be elucidated. [30,[34][35][36][37][38][39][40] Owing to the high-sensitivity of 1 H NMR, the 1D and the 2D 1 H-1 H correlation experiments coupled with the frequency selective pulses and spin diffusion durations, and the 1 H-detected 2D 1 H-14 N and 14 N-filtered 2D 1 H-1 H correlation experiments have been used to selectively detect APIs in solid formulations. [37] , [41,42] Recently, 2 H MAS and 1 H-2 H correlation NMR experiments have been used to selectively detect partially deuterated APIs in solid formulations.…”