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

Tomasz Pawlak,Marek J Potrzebowski,Małgorzata Szczesio,Marcin Oszajca

doi:10.1021/acs.molpharmaceut.1c00779

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 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.

Highlights

Neurodegenerative diseases affect millions of people worldwide.[1,2] With increasing global population and average lifespan, the prevalence of neurological disorders is on the rise
We began our study with powder X-ray diffraction (PXRD) and 13C Cross-polarization magic-angle spinning (CP MAS) NMR measurements carried out at ambient temperature for a commercially available Xadago tablet (Figure 2)
According to the product characteristic declaration, the Xadago drug apart from the safinamide mesylate (SM) substance contains a series of following excipients: cellulose, polyvidone, magnesium stearate, and colloidal anhydrous silica.[10]

Summary

■ INTRODUCTION

Neurodegenerative diseases affect millions of people worldwide.[1,2] With increasing global population and average lifespan, the prevalence of neurological disorders is on the rise. The assignment of signals (c−e) is shown according to the results from Thermal Transformations of Sample SM_E and Determination of SM_D Crystal Structure Based on the Data Obtained in a PXRD Measurement and Its Validation Using. The most probable explanation of this phase change is that while SM_D form is cooled, molecular dynamic is slowing down what causes the formation of three slightly different conformers of safinamide (Figure 16) In this way, the system reduces its symmetry in the crystal lattice and has to be described by a unit cell 3 times as large as the one observed for SM_D. Torsions and low-energy conformers have a greater likelihood of exhibiting conformational polymorphism.[100]

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES