(M1430-08-48) Hot-Melt Extrusion Enabled Amorphous Solid Dispersions: A Comparative Study of Binary and Ternary Polymer Systems for Solubility and Dissolution Enhancement

Purpose: The present study aims to enhance the solubility and dissolution of fenofibrate, a poorly water-soluble BCS Class II drug, through the development of hot melt extruded amorphous solid dispersions (ASDs) using binary and ternary combinations of miscible and immiscible polymers. The focus was on understanding the role of hydrogen bonding and polymer interactions in stabilizing the amorphous state and maintaining supersaturation.

Methods: ASDs were prepared by hot-melt extrusion using Soluplus®, Kollicoat® IR, Kollidon® VA64, Kollidon® 12 PF, HPMC E5, and their combinations. Characterization included FTIR spectroscopy for hydrogen bonding confirmation, differential scanning calorimetry (DSC) for crystallinity, and in-vitro dissolution testing in 0.01 M SLS and 0.1% Tween 80 to study spring-parachute behavior. Stability was assessed at 40°C/75% RH over 4 weeks. Saturation solubility was evaluated at 25°C in water.

Results: Formulations F18 (Fenofibrate + HPMC E5) and F19 (Fenofibrate + HPMC E5 + KIR) exhibited the highest solubility (385 and 362 µg/mL, respectively). FTIR confirmed hydrogen bonding in these systems, correlating with reduced crystallinity and enhanced stability. In 0.1%w/w Tween 80, F16(Soluplus+KVA 64) maintained supersaturation over 60 minutes, demonstrating effective parachute behavior. DSC revealed that formulations like F12 (KVA64 + K12) and F14 (KVA64) were less stable, with increased crystallinity over time. The binary and ternary systems with HPMC, Soluplus, and KIR showed better miscibility, lower recrystallization, and superior dissolution enhancement.

Conclusion: Molecular characterization confirmed that hydrogen bonding and polymer-polymer compatibility are critical for the performance and stability of fenofibrate Ternary ASDs. Binary and ternary polymer systems incorporating Soluplus offered superior solubility, sustained supersaturation, and resistance to crystallization. These findings support their use in ASD-based delivery strategies for poorly soluble drugs.

References: Deng, W., Majumdar, S., Singh, A., Shah, S., Mohammed, N. N., Jo, S., … Repka, M. A. (2012). Stabilization of fenofibrate in low molecular weight hydroxypropylcellulose matrices produced by hot-melt extrusion. Drug Development and Industrial Pharmacy, 39(2), 290–298. https://doi-org.umiss.idm.oclc.org/10.3109/03639045.2012.679280
Yang, B., Wu, L., Ke, J. et al. Effects of Polymer/Surfactant as Carriers on the Solubility and Dissolution of Fenofibrate Solid Dispersion. AAPS PharmSciTech 20, 102 (2019). https://doi-org.umiss.idm.oclc.org/10.1208/s12249-018-1273-z
Sun D.D, Lee P.I. 2015. Probing the mechanism of drug release from amorphous solid dispersions in medium-soluble and medium-insoluble carriers. J Control Release. 211: 85-93.

Solubility Data and Spring-Parachute effect study

Recrystallisation during storage at 40°C/75%RH

FTIR Spectrum and DSC Thermogram