(M1430-11-65) Particle Engineering Approach to Formulating Hot Melt Extrusion Amorphous Solid Dispersion Tablets

Purpose: Amorphous Solid Dispersion (ASD) is a promising path forward to increase the bioavailability of active pharmaceutical ingredients, yet fundamental understanding lacks for the creation of high-performance solid dosage forms. This current study assesses polymer type, drug loading, particle size, and compaction parameters on the tabletability to improve the understanding of downstream processing of milled HME ASD materials.

Methods: Griseofulvin (GF; Letco Medical, Decatur, AL, USA) was used as the model Biopharmaceutics Classification System (BCS) class II drug and processed 1) Hydroxypropyl cellulose (HPC, SL grade, Nisso America Inc., New York, NY) at 0%, 10%, 20%, and 30% GF loadings (w/w) and 2)  PVPVA (Kollidon VA 64, a vinylyrrolidone-vinyl acetate copolymer, BASF, New York, NY) at 0%, 10%, and 50% GF loadings (w/w). Moreover, formulated tablets were prepared with Microcrystalline Cellulose Avicel PH-102 (FMC Corporation, St. Louis, MO) as a binder, Sodium Chloride (Sigma Aldrich St. Louis, MO), to reduce gelling, and Kollidon CL (BASF, New York, NY) as a disintegrant. HME was performed with a 11 mm diameter co-rotating twin-screw extruder (Thermo Fisher Scientific, Waltham, MA). Three temperatures were selected to prepare extrudates with and without residual crystallinity: 170C, 190C, and 210C. Extrudates were milled: 1) electric burr grinder (DBM-8P1, Cuisinart, Stamford, CT) at the finest grinding setting and 2) Fluid Energy Mill with a feed rate of 1 g/min, feed pressure of 75 psi, and grind pressure of 70 psi. Sieve cuts were taken: < 45, 45 – 75, 75 – 125, 125 – 355, and 355 – 500 μm. Solid state characterization was performed on the milled extrudates after both milling steps via X-Ray Powder Diffraction (XRPD) (PANalytical, Westborough, MA). The 100 mg tablets were prepared with a Gamlen D1000-series tablet press (Gamlen Tableting) with a 6mm single punch die set. Tablets were prepared at four compaction pressures: 39, 77, 116, and 155 MPa, with five replicates each. The tablet breaking force was measured with Gamlen TTA. The GF concentration was determined by a Thermo Scientific Evolution 300 UV-vis UV-vis spectrometer (Thermo Fisher Scientific) by measuring the UV absorbance at a wavelength of 297 nm. The dissolution study of milled GF/PVPVA ASD formulated tablets were tested via the USP II method (USP II, SOTAX) in supersaturated conditions, Sink Index of 0.142, with deionized water and a paddle speed of 50 rpm.

Results: The milled extrudates were characterized with XRPD after both milling steps (Fig.1) and are consistent with existing literature (Buyukgoz et al., 2021). The lowest, 10%, GF concentration mixture resulted in no crystalline peaks at all HME operating temperatures (Figs. 1.a and 1.e) for both polymer systems. In contrast, only the 190°C and 210°C HME temperatures yielded a lack of crystalline peaks (Fig. 1.b) for the 20% GF/HPC blend, but the 190°C HME temperature yielded crystalline peaks for the 50% GF/PVPVA system while only the highest HME operating temperature, 210°C, yielded a lack of crystalline peaks for the highest drug loading, 30% GF/HPC blend (Fig. 1.c) and 50% GF/PVPVA blend (Fig. 1.e). The tabletability behavior of five particle size sieve cuts of neat milled extrudates, < 45, 45 – 75, 75 – 125, 125 – 355, and 355 – 500 μm for GF/HPC system with drug loadings of 0%, 10%, 20%, 30% shown in Fig. 2.1 and GF/PVPVA system with drug loadings of 0%, 10%, and 50% shown in Fig. 2.2. In general, the overall range of tablet tensile strength for GF/HPC decreased from the neat polymer of 1.674 ± 0.182 to 5.306 ± 0.216 MPa and 0.036 ± 0.013 to 3.773 ± 0.151 MPa for 30% GF. Moreover, the tensile strength of the GF/PVPVA system ranged from 0.169 ± 0.026 to 3.915 ± 0.379 MPa and 0.215 ± 0.019 to 4.913 ± 0.673 MPa for 50% GF. In contrast to the GF/HPC system, the GF/PVPVA system does not significantly vary across the 3 drug loadings studied. The dissolution of the formulated 50%GF/PVPVA tablets with MCC, NaCl, and Kollidon CL for 5 sieve cuts is shown in Fig. 3. The compaction pressure used for each sieve cut was varied to ensure a similar tensile strength across to isolate the particle size effect on the dissolution. Unexpectedly, the smallest and largest sieve cuts obtained saturation concentrations of 22.881 ± 0.840 and 27.053 ± 0.422, respectively. All sieve cuts resulted in a supersaturated concentration notably greater than the crystalline solubility of 14.2 mg/L.

Conclusion: The particle size of milled extrudates was systematically evaluated to determine the optimal particle size for sufficient tablet tensile strength without excessive particle size reduction. For both polymers, it was only necessary to mill down to 75 – 125 μm rather than < 45 μm. In terms of the particle size effects on dissolution, it was unexpectedly found that the larger sieve cuts obtained a greater saturation concentration compared to the finer sieve cuts for the formulated tablets.

References: 1. Buyukgoz, Guluzar Gorkem, Christopher Gordon Kossor, and Rajesh N. Davé. 2021. "Enhanced Supersaturation via Fusion-Assisted Amorphization during FDM 3D Printing of Crystalline Poorly Soluble Drug Loaded Filaments" Pharmaceutics 13, no. 11: 1857. https://doi.org/10.3390/pharmaceutics13111857

Acknowledgements: This work was supported by the Center for Integrated Materials Science and Engineering for Pharmaceutical Products (CIMSEPP), which is funded by the National Science Foundation (grant IIP-2137209).


X-Ray Powder Diffraction (XRPD) diffractograms of three GF-HPC blends at 3 HME temperatures and physical mixtures: (a) 10% GF 90% HPC, (b) 20% GF 80% HPC, and (c) 30% GF 70% HPC and two GF-PVPVA blends at 2 HME temperatures and physical mixtures: (d) 10% GF 90% PVPVA64, and (e) 50% GF 50% PVPVA.


Tablet tensile strength of 4 drug loadings of GF/HPC and 3 drug loadings of GF/PVPVA ASDs for 5 particle sieve cuts at 4 compaction pressures: (2.1) 38 MPa, (2.2) 77 MPa, (2.3) 118 MPa, and (2.4) 155 MPa.


Dissolution of 40% ASD load (50% GF and 50% PVPVA64), 45% Avicel 105, 10% NaCl, and 5% Kollidon CL tablet blend for 5 particle sieve cuts: a) time less than 60 minutes and b) up to 180 minutes.