(T0930-04-20) Effect of Processing Method on Release Profile of Fenofibrate Amorphous Solid Dispersion Prepared by Hot Melt Extrusion and 3D Printing

Purpose: It is estimated that 40% of new compounds and 60% of synthetic pharmaceutical drug substances have poor water solubility (1). Poorly water-soluble drugs are rapidly eliminated from the gastrointestinal tract before getting absorbed to reach the systemic circulation. Poor water-soluble drugs could be physically altered to increase their solubility by converting the drug's physical state from crystalline to amorphous by developing amorphous solid dispersion.  Hot Melt Extrusion and 3D printing are commonly used processing methods to prepare amorphous solid dispersion (2). In addition, the hot melt extruded filaments could be used as a feedstock for fused deposition modeling (FDM) 3D printing. Studying drug release from amorphous dispersion formulations with various methods of processing can reveal important information on how these methods affect the drug's performance and dissolution profile.  The aim of this research work was to use HME and FDM 3D printing to prepare an amorphous solid dispersion of fenofibrate that would improve its solubility and in vitro release profile. Furthermore, to investigate the impact of the processing method on the formulation characteristics.

Methods: Different ratios of polyethylene oxide (PEO N80) and Soluplus were screened to determine the optimal ratio to produce printable filaments. The physical mixture was fed in an 11 mm co-rotating twin screw hot melt extruder (Process 11, Thermo Scientific). The temperature was set at 25°C, 50°C, 80°C, 125°C, 125°C, 125°C, 110°C, 110°C from zone 2 till the die zone respectively. After the extrusion process, the filaments were split into two parts: one was utilized as feedstock for the FDM 3D printer (Prusa i3 MK3 3D printer), while the other part was milled and filled in size 0 gelatin capsules. Three different infill densities—50%, 70%, and 90%—were used for designing the 3D-printed tablet using Tinkercad. The tablets were printed and the printing temperature was set to 200°C. Using differential scanning calorimetry (DSC), the physical state of fenofibrate in the formulation was assessed. FTIR analysis was performed for pure fenofibrate, polymers, the physical mixture, extruded filament, and 3D printed tablets to check the compatibility between fenofibrate and the polymeric carriers. Further, scanning electron microscopy (SEM) was used to examine the morphology of the formulation on both the 3D-printed tablet and the pure fenofibrate. Moreover, the drug content and release studies were performed for fenofibrate capsules and 3D-printed tablets.

Results: DSC thermogram (Figure 1) showed a sharp endothermic melting peak at 80.5°C for fenofibrate. The absence of this melting peak in the HME filaments and 3Dprinted tablets suggests that the drug was converted into an amorphous state. The SEM images (Figure 2) of the pure drug showed sharp cylindrical crystals while the tablet showed a smooth surface and no signs of any crystals. The FTIR spectrum of pure fenofibrate shows stretching at 2985 cm−1, which represents the benzene ring: aromatic stretching. The peak at 1725 cm−1 (indicating a C=O stretching of ester group), 1647 cm−1  ( C=O of the ketone group), 1595 cm−1  (lactone carbonyl functional group). The drug content of the 3D-printed tablet was 99±1.3, whereas the filament was 98±0.9. Among all the 3D-printed tablets, the ones with 50% infill exhibited the maximum drug release of 97%± 0.19 in four hours, whereas the tablets with 70% and 90% infill released 86%± 1.65 and 78%± 2.89 respectively (Figure 3). One the other hand, capsule dosage form showed 86.32%± 0.91 in four hours (Figure 3).

Conclusion: In this study, HME and 3D-printing were successfully used to prepare an amorphous solid dispersion of fenofibrate. This study demonstrates how different methods of preparation for the same amorphous solid dispersion can alter the drug's release rate.  This approach can be used to deliver the same formulation in different release profiles.

References: 1. Deng W, Majumdar S, Singh A, Shah S, Mohammed NN, Jo S, et al. Stabilization of fenofibrate in low molecular weight hydroxypropylcellulose matrices produced by hot-melt extrusion. Drug Dev Ind Pharm. 2013 Feb 1;39(2):290–8.
2. Vo CLN, Park C, Lee BJ. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm. 2013 Nov 1;85(3, Part B):799–813.


DSC thermogram of pure fenofibrate, polymers, extruded filament and 3D printed tablet.


SEM image; A) pure fenofibrate. B) 3D printed tablet.


In vitro drug release of pure fenofibrate, capsule, 50%, 70%, 90% infill 3D printed tablets.