Hot-melt extrusion as a continuous manufacturing process to form ternary cyclodextrin inclusion complexes

Area of Science:

• Pharmaceutical Technology
• Drug Delivery Systems
• Materials Science

Background:

• It is crucial to enhance the solubility and dissolution rate of poorly soluble drugs like itraconazole (ITZ), a Biopharmaceutics Classification System Class II drug.
• Cyclodextrins (CDs) are widely used to form inclusion complexes, improving drug properties, but their thermoplasticity can be a challenge for processing.
• Hot-melt extrusion (HME) offers a continuous manufacturing process for solid dispersions and inclusion complexes.

Purpose of the Study:

• To evaluate hot-melt extrusion (HME) for creating cyclodextrin (CD) ternary inclusion complexes with itraconazole (ITZ).
• To improve the solubility and dissolution rate of itraconazole (ITZ) using various CD derivatives and Soluplus® (SOL) as a polymer.
• To assess the processability and efficacy of different CD formulations manufactured via HME.

Main Methods:

• Investigated various cyclodextrin derivatives (βCD, HPβCD, Rameb®, Captisol®, Crysmeb®) with itraconazole (ITZ) at a 1:1 molar ratio in the presence of Soluplus® (SOL).
• Utilized rheology testing and mini extrusion to assess the processability of CD/SOL/ITZ mixtures.
• Employed hot-melt extrusion (HME) with a twin-screw extruder for selected formulations, followed by saturation concentration measurements and biphasic dissolution tests.
• Characterized the final formulations using differential scanning calorimetry (DSC) and attenuated total reflectance infrared spectroscopy (ATR-FTIR).

Main Results:

• Captisol® and Crysmeb® were excluded due to high viscosity impact on the Soluplus® (SOL)/itraconazole (ITZ) mixture during initial processing.
• All four remaining cyclodextrin (CD) formulations demonstrated enhanced itraconazole (ITZ) solubility compared to the SOL/ITZ solid dispersion.
• Biphasic dissolution tests showed faster itraconazole (ITZ) release from all CD formulations; HPβCD 0.63 and Rameb® formulations achieved 95% release within 1 hour.
• Thermal and spectroscopic analyses confirmed the formation of ternary inclusion complexes, correlating with the improved drug release.

Conclusions:

• Hot-melt extrusion (HME) is a viable continuous process for fabricating cyclodextrin (CD) ternary inclusion complexes.
• The developed CD/SOL/ITZ formulations significantly enhance itraconazole (ITZ) solubility and dissolution rates.
• Hydroxypropyl-β-cyclodextrin (HPβCD) and randomly methylated β-cyclodextrin (Rameb®) showed particularly promising results for improving itraconazole (ITZ) delivery.