(M1130-08-52) Development of Organic Solvent-Free Amorphous Solid Dispersions of Felodipine with PEGs via Supercritical CO₂ Processing: A Green Strategy for Enhanced Dissolution and ODT Formulation

Purpose: The objective of this study was to enhance the solubility and dissolution rate of Felodipine (FDP) with polyethylene glycol (PEG) carriers of varying molecular weights (MW: 4000, 6000, 10000, 20000), a poorly water-soluble BCS Class II drug, through the development of amorphous solid dispersions (ASDs) using a green, organic solvent-free supercritical carbon dioxide (scCO₂) platform. The study also aimed to assess the downstream manufacturability of optimized ASDs into orally disintegrating tablets (ODTs), leveraging pharmaceutically acceptable excipients and robust formulation design [1, 2].

Methods: A design of experiments (DoE)-driven approach was employed to evaluate the impact of PEG molecular weight (4000, 6000, 10000, and 20000 Da), drug loading levels (10%, 20%, and 30% w/w), and processing temperature (45 - 60°C) on the physicochemical properties of ASDs generated via scCO₂ batch static mode processing (25 mL/min, 100 bar, 1 h). Drug-polymer miscibility and phase transition thresholds were initially screened using high-pressure visual phase monitoring. The ASDs were characterized for solid-state properties using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR-ATR), and scanning electron microscopy (SEM). In vitro performance was assessed through dissolution testing in phosphate buffer (pH 6.5) with 1% SLS using USP Apparatus II. ASDs with the best dissolution profiles were further evaluated for downstream processing into ODTs, using a direct compression method. Critical quality attributes (CQAs) such as flowability, compressibility, hardness, friability, disintegration time, and content uniformity were assessed to confirm tablet manufacturability.

Results: The scCO₂ process effectively generated ASDs of FDP with reduced or eliminated crystallinity, depending on PEG molecular weight and processing temperature. DSC and XRPD confirmed full amorphization in formulations containing PEG 4K and PEG 20K at 45°C and 60°C, respectively, whereas incomplete amorphization was observed for PEG 20K at 45°C due to inadequate polymer melting and solubilization kinetics. Phase behavior studies corroborated these findings, showing PEG 20K required higher thermal input for phase transition in the scCO₂ medium. At 10% drug loading, PEG 4K SDs exhibited rapid dissolution (~90% within 15 min), while PEG 20K at 60°C showed comparable release kinetics (~85% in 10 min) at 30% drug loading, indicating a balance between molecular weight, viscosity, and hydrogen bonding potential. The optimized high drug-load SDs (30% FDP in PEG 4K and PEG 20K) were successfully compressed into ODTs. PEG 20K-based ODTs demonstrated superior compactibility and robustness (friability: 0.45%, hardness: 25 - 32 N), with disintegration within 24 seconds, satisfying Ph. Eur. and FDA requirements for ODTs. In contrast, PEG 4K ODTs, although disintegrating faster (~18 s), failed friability testing due to poor mechanical integrity (hardness < 22 N). The dissolution performance of ODTs was equivalent to their ASD counterparts, validating the preservation of API amorphicity post-compression

Conclusion: This study demonstrates the successful application of scCO₂ processing as a viable, green manufacturing platform for the development of high drug-load amorphous solid dispersions without the use of organic solvents. The tunability of scCO₂ parameters enabled optimized polymer–drug miscibility, critical for achieving complete amorphization and enhanced dissolution. The downstream development of ODTs from ASDs was achieved using direct compression, a scalable and cost-effective unit operation, yielding tablets with appropriate disintegration and mechanical properties. PEG 20K emerged as the optimal carrier polymer for high-load FDP ODTs due to its favorable plasticity, thermal stability, and drug-polymer interaction profile. This solvent-free platform aligns with QbD principles, reduces environmental and regulatory burden, and holds significant potential for industrial-scale production of bioavailability-enhanced oral dosage forms for poorly soluble APIs.

References: [1]. Guo, Y. et al (2023). Screening and optimization of supercritical fluid process for the preparation of albendazole solid dispersion. J. Drug. Deliv. Sci. Technol., 88, 104852
[2]. Nandi, U. et al (2021). Preparation of Solid Dispersions of Simvastatin and Soluplus Using a Single-Step Organic Solvent-Free Supercritical Fluid Process for the Drug Solubility and Dissolution Rate Enhancement. Pharmaceuticals, 14, 846

Formulation design

Phase monitor studies: A). bulk FDP (100°C/100 bar), B). PEG 4K (45°C/100 bar), C). PEG 20K (45°C/100 bar), D). PEG 20K (55°C/100 bar), E). PEG 4K 30% PM (45°C/100 bar), and F) PEG 20K 30% PM (60°C/100 bar)

In vitro dissolution profiles