The Amorphous State of the Antiepileptic Clobazam: Preparation and Characterization

Abstract

The aim of this study was to prepare and characterize amorphous clobazam (CLOB) and investigate its devitrification under various stressors (temperature/humidity, compaction and mechanical/thermal stresses). Amorphous CLOB was prepared by melt-quenching in liquid nitrogen. The quench-cooled sample (CLOB-q) was characterized via polarized light and hot-stage microscopies (PLM and HSM), X-ray powder diffraction (XRPD), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), conventional and modulated DSC (DSC-c and MDSC®), thermogravimetry (TG), dynamic mechanical analysis (DMA), X-ray photoelectron spectroscopy (XPS) and contact angle measurements. Stability of CLOB-q toward temperature/humidity, compaction, and combined mechanical and thermal stress were also evaluated. CLOB-q was a truly amorphous form, as revealed by DSC-c, MDSC® and DMA. Its calorimetric glass transition temperature (Tg) was 67.0 °C (20 °C/min) and the ratio Tm/Tg was 1.34, indicating a fragile glass. The water contact angle of CLOB-q (121.8° ± 1.7°) was lower than that of crystalline CLOB (CLOB-c, 131.3° ± 3.6°), likely due to its higher concentration of surface CL, as determined by XPS. Storage of CLOB-q at - 20 °C/0% RH, 25 °C/0% RH and 40 °C/75% RH resulted in its complete devitrification to CLOB-c within 60 days, 4 days, and 42 h respectively. Subjection of CLOB-q to compaction (19.6 kN) and combined mechanical-thermal stresses also resulted in complete crystallization to CLOB-c. In conclusion, amorphous CLOB was successfully prepared in the laboratory for the first time and thoroughly characterized. It easily devitrified to CLOB-c by effect of different stressors, and thus it could not have advantages over CLOB-c in terms of physical stability.

Graphical Abstract