(W0930-08-50) Impact of Hot Melt Extrusion Processing on Amorphous Solid Dispersion Bulk Powder Properties

Purpose: Amorphous Solid Dispersions (ASD) are an effective approach to enhance the bioavailability of poorly soluble drugs by molecularly dispersing an amorphous drug into a polymer. There is an emphasis on ASD formulation to achieve stable high drug loading tablets, but there is an overall lack of investigation of the effects of processing on bulk powder properties such as flowability, bulk density, and morphology, especially via Hot Melt Extrusion (HME). This current study utilizes a multifaceted characterization approach to understand the effect of particle size, drug load, and HME operating conditions on bulk powder properties such as flowability, bulk density, and morphology 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 with Hydroxypropyl cellulose (HPC, SL grade, Nisso America Inc., New York, NY, USA) at 0%, 10%, 20%, and 30% GF loadings (w/w). HME was performed with a 11 mm diameter co-rotating twin-screw extruder (Thermo Fisher Scientific Inc., Waltham, MA, USA) and was cooled to room temperature. Three temperatures were selected to prepare extrudates with and without residual crystallinity: 170C, 190C, and 210C. Extrudates were milled in two steps: 1) high-intensity vibrational mixer (LabRAM, Resodyn Acoustic Mixers, Inc., Butte, MT, USA) for 5 min with an acceleration of 75 G at 60 Hz with 5 stainless steel ball bearings 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 performed with the following sections: < 45 μm, 45 – 75 μ
Results: The milled extrudates were characterized with XRPD after both milling steps (Fig.1) and are consistent with existing literautre¹. The lowest, 10%, GF concentration mixture resulted in no crystalline peaks at all HME operating temperatures (Fig. 1a). In contrast, only the 190°C and 210°C HME temperatures yielded a lack of crystalline peaks (Fig. 1b) for the 20% GF blend and only the highest HME operating temperature, 210°C, yielded a lack of crystalline peaks for the highest, 30%, GF blend (Fig. 1c). There is significant interest in the high surface area of small particle sizes to obtain successful tableting and dissolution performance while avoiding excessive excipient usage. Hence, this study will focus is on sizes well below seen in ASD HME literature: < 45 μm, 45 – 75 μm, and 75 – 125 μm. The FFC and bulk density are captured in a phase map (Fig. 2) where values in the top right quadrant are desirable for downstream processing. The FFC for all blends are in the “easy flowing” regime for the two coarser sieve cuts indicating that milling to finer sizes did not compromise flowability. The drug loading has a noticeable impact on both FFC and bulk density, which is evident even at the finest particle size ( < 45 μm) since 10% GF has a FFC of 2.44 ± 0.05 to 2.7 ± 0.07 and 30% GF has a FFC of 4.33 ± 0.23 to 5.2 ± 0.7 depending on the HME temperature. Lastly, while the HME temperature has a noticeable impact on bulk density, it only has a subtle impact on flowability at each sieve cut and drug loading. For example, the 30%GF case at the smallest sieve cut improved from 0.433 ± 0.012 g/ml to 0.485 ± 0.018 g/ml by increasing the HME temperature from 170°C to 210°C, respectfully. Particle morphology is another area that influences bulk powder properties. Existing literature seldom investigates the impact of ASD manufacturing on particle morphology. The 30% GF particles were elongated shapes, but the fully amorphous particles (Fig. 3a) exhibited smooth surfaces while particles with residual crystallinity (Fig. 3b) exhibited significantly rougher surfaces. These differences in morphology emphasize the impact that HME operating temperature can alter the surface roughness.

Conclusion: The impact of size, drug loading, and HME conditions, seldom characterized for ASDs in literature, were assessed. While the particle size impact was expected, the impact of drug loading and HME processing temperature on bulk properties was not expected. These results indicate that further particle size reduction may not significantly compromise flowability and bulk density, thus opportunities for improving tableting and dissolution are the subject of an ongoing study.

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.

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).

Figure 1. X-Ray Powder Diffraction (XRPD) diffractograms of three GF-HPC blends at 3 HME temperatures and physical mixtures: a) 10% GF and 90% HPC, b) 20% GF and 80% HPC, and c) 30% GF and 70% HPC.

Figure 2. Flowability Function Coefficient (FFC) and bulk density plot of exemplary milled HME extrudate powders. The varying colors represent four drug loadings of GF. The varying marker shapes represent three difference sieve cut sizes. The varying hatch infills represent the three HME operating temperatures.

Figure 3. Scanning Electron Microscope (SEM) images of 30% GF drug loading, < 45 μm sieve cut at two HME operating temperatures: a) 210°C and b) 170°C.