Structural characteristics and crystal polymorphism of three local anaesthetic bases

Benzocaine (BZC), butambene (BTN) and isobutambene (BTI) are basic local anaesthetic agents of the ester type, preferentially used for surgery and dental procedures. The compounds, official in the USP (BZC and BTN) and Ph. Eur. (BZC), were each found to exist in two polymorphic crystal forms and their solid state characteristics have been determined by thermomicroscopy, differential scanning calorimetry (DSC), FTIR-, FT-Raman-spectroscopy as well as X-ray powder diffractometry. This work further emphasizes the comparison of solid state characteristics of three compounds with closely related structural features on molecular level, leading to opportunities for the investigation of structure-property relationships. Mod. I0 is the particular thermodynamically stable form at room temperature in all of the three systems. This form is present in commercial products and can be crystallized from solvents at room conditions. Mod. II can be obtained by annealing the supercooled melt or fast cooling of a saturated solution, respectively. The endothermic transformation of mod. II to mod. I0 upon heating confirms that mod. I0 is thermodynamically stable at ambient conditions (heat of transition rule) whereas mod. II is enantiotropically related to mod. I0, i.e. is metastable at temperatures above the transition temperature. The metastable forms show different kinetic stabilities at room temperature.