Analysis of Pseudo-polymorphism Conversion of Theophylline During Wet Granulation and Drying Processes and Effect of Binder on Dehydration and Amorphization

Abstract

We conducted a time-course analysis of the pseudo-polymorphism conversion (i.e., the hydration and dehydration) of the xanthine-related compound theophylline during wet granulation and drying processes, using terahertz spectroscopy. We also investigated the amorphization mechanism of theophylline hydrate during a drying process in a vacuum using terahertz, mid-infrared (mid-IR), and near-infrared (near-IR) spectroscopy. After a high-shear granulation process using a mixture of theophylline, hydroxypropyl cellulose (HPC), and water, the terahertz spectrum (which was similar to that of an anhydride) was changed to a spectrum that was quite similar to that of a monohydrate. This result suggests that (1) an anhydride was converted to a monohydrate during the wet granulation process and (2) the spectrum was changed to the original waveform after the drying process with heat. This phenomenon indicates that the theophylline monohydrate was reconverted to an anhydride during the drying process. When wet granules were dried in a vacuum, the terahertz absorption lessened and finally disappeared with the passage of time, suggesting that the theophylline monohydrate in the granules was converted to an amorphous state. During the drying process with heat, the dehydration progressed temperature dependently regardless of the presence/absence of HPC. In addition, the reconversion from a monohydrate to an anhydride was completed concurrently with the completion of dehydration. The conversion rate of theophylline from a monohydrate to an amorphous form in granules (with HPC) was faster than that without HPC. This observation suggests that HPC promotes the amorphization of theophylline.