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

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.甲磺酸沙非酰胺（Safinamide mesylate, SM）是近年应用于帕金森病治疗的纯原料药（active pharmaceutical ingredient, API）。采用体积比为1:9的水-乙醇混合溶剂对其进行重结晶，所得产物的晶型与Xadago片剂中的SM晶型存在差异。纯SM以半水合物形式结晶于单斜晶系，空间群为P21；其晶体与分子结构通过100 K下的低温X射线晶体学（cryo X-ray crystallography）得以解析。Xadago片剂中的SM则以无水形式存在于正交晶系，空间群为P212121。研究通过固体核磁共振波谱法（solid-state NMR spectroscopy）、差示扫描量热法（differential scanning calorimetry）与热重分析（thermogravimetric analysis），对晶格内的水迁移与热过程进行了监测。Xadago中的SM在高湿度环境下会发生相变，转变为P21晶型，该相变仅需加热至80 ℃即可可逆恢复。对于该API的商用晶型，在0~20 ℃的温度区间内还存在Z′=1与Z′=3两种晶型间的可逆热相变。对晶格内分子运动的分析证实，所观测到的构象多晶型现象由分子内动力学所驱动。上述所有过程均通过核磁共振晶体学（NMR crystallography）方法，并辅以先进理论计算进行了分析与描述。