Polymorphism and Pseudopolymorphism of Salicaine and Salicaine Hydrochloride Crystal Polymorphism of Local Anaesthetic Drugs, Part V

The local anaesthetic drug salicaine hydrochloride (hydroxytetracaine hydrochloride, 4-butylamino-2-hydroxybenzoic acid 2-dimethylaminoethyl ester hydrochloride, SLCHC) and the free-base salicaine (SLC) were characterized by thermal analysis, vibrational and solid-state NMR-spectroscopy, X-ray powder diffraction, X-ray single crystal structure analysis, and water vapor sorption analysis. Additionally, the crystal structures of the anhydrate mod. II° (monoclinic, space group P21/n), the hydrated mod. I (triclinic, space group P1¯), and of the free base (SLC) in the form of the hemihydrate (triclinic, space group P1¯) are discussed. Mod. II° of the polymorphic SLCHC is the thermodynamically stable form at room temperature and is present in commercial products mostly contaminated with a hydrated form that is isomorphic with mod. I. Mod. II° crystallizes from most organic solvents and from the melt below 110°C. Mod. I crystallizes from the melt at temperatures above 110°C, and additionally appears on dehydration of the hydrated mod. I. A third polymorph monotropically related to mod. II° was found by freeze-drying. The free-base SLC was found to crystallize from ethanol/water as a triclinic hemihydrate.