Thinking of bosentan repurposing - A study on dehydration and amorphization.

Area of Science:

• Pharmaceutical Sciences
• Solid-State Chemistry
• Drug Formulation

Background:

• Bosentan, an orphan drug, requires formulation improvements for new clinical uses.
• Understanding its anhydrous form and glass-forming properties is crucial for developing enabling formulations.

Purpose of the Study:

• To analyze dehydration and amorphization phenomena of bosentan.
• To characterize the anhydrous form and assess the glass-forming ability of bosentan.

Main Methods:

• Differential Scanning Calorimetry (DSC) and X-ray Diffraction (XRD) for characterization.
• Melt cooling and high-energy ball milling for amorphous form preparation.
• Attenuated Total Reflectance Infrared (ATR-IR) and proton Nuclear Magnetic Resonance (¹H NMR) for chemical stability.

Main Results:

• The anhydrous form of bosentan was characterized for the first time.
• Two stable amorphous forms were prepared with a glass transition temperature (Tg) of 82 °C.
• Bosentan amorphization was easily achieved, with no recrystallization observed upon heating, even in semi-amorphous states.
• Amorphization significantly improved bosentan dissolution in biorelevant media.
• The amorphous form recrystallized to the monohydrate in gastric conditions, accompanied by a color change.

Conclusions:

• Bosentan can be readily amorphized, offering enhanced dissolution properties.
• The recrystallization of amorphous bosentan in the gastric milieu necessitates careful formulation strategies.
• The observed color change provides a visual indicator of the crystalline state of bosentan.