(M1530-02-12) Powder-Discharge KinetiSol® Process Produces Nano- and Micron-Sized Particle Aggregates for Drug Delivery

Purpose: The purpose of this study is to explore the impact of excipient properties and specific processing parameters on powder morphology achieved through powder-discharge KinetiSol (pKSD). Previously, the application of KinetiSol technology (KSD) was expanded from conventional melt agglomeration to the pKSD process, enabling the formation of nano- and micron-sized particles/aggregates rather than amorphous solid dispersions (Figure 1A-C) (1). This work demonstrated pKSD's capability to enhance the solubility of Fenbendazole, a molecule known for its limited solubility and thermal stability, which complicates its formulation via conventional KSD or other heat-intensive methods. While our initial investigation employed excipients to explore pKSD as a viable method for improving drug solubility, the present work uses FBZ as a model active pharmaceutical ingredient (API) (FBZ, Figure 1D-E) to study the morphological differences arising from pKSD processing of amorphous excipients (i.e., HPMC, HPMCAS) compared to crystalline excipients (i.e., lactose, leucine).

Methods: Powder discharge-based KinetiSol® processing (pKSD): The following excipients were tested: Methocel™ E5 Premium LV hydroxypropyl methylcellulose E5 (HPMC, The Dow Chemical Company, Midland, MI), Hypromellose Acetate Succinate (HPMCAS, Shin-Etsu AQOAT® AS-MF, Shin-Etsu, Tokyo, Japan), L-Leucine (Leucine, Alphaesar, Fisher Scientific, Pittsburgh, PA, USA) and LactoHale 300 (Lactose, DFE Pharma, Goch, Germany). The FBZ-excipient blends (FBZ 5% w/w) were initially admixed using a mortar and pestle. Magnesium stearate was then added at 0.5% w/w of the mixture’s total weight. The powder blends were subsequently introduced into the KinetiSol chamber (KinetiSol research formulator, KBC20, AustinPx, LLC, Georgetown, TX), the blends underwent an initial processing phase at 1000 RPM for 5 seconds, followed by a secondary processing phase at 4000 or 5000 RPM for 30 seconds. To mitigate dust generation, a final processing phase was incorporated at 1000 RPM for 5 seconds. In pKSD, the KinetiSol chamber discharges a powder blend instead of a molten mass. Scanning electron microscope (SEM): The samples were placed onto carbon tape and mounted onto aluminum stubs. They were then sputter-coated with gold/palladium using an EMS Sputter Coater (Hatfield, PA, USA) before capturing the images with an Apreo 2 C LoVac SEM instrument (Waltham, MA, USA). Wide-angle X-ray Scattering (WAXS): Samples were analyzed using a SAXSLab instrument (WAXSLab, Northampton, MA, USA) equipped with a PILATUS3 R 300 K detector (DECTRIS Ltd., Philadelphia, PA, USA). The instrument was operated using the Ganesha instrument software (SAXSLab, Northampton, MA, USA).

Results: FBZ-excipient blends were prepared by pKSD, as depicted in Figure 1A-C. Following pKSD processing, distinct morphological outcomes were observed based on the excipient. The amorphous excipient, HPMC (Figure 2A-B), yielded particles consistent with recent reports, characterized by FBZ nano- and micron-sized particles embedded on HPMC fragments (Figure 2C-D). This suggests the FBZ crystalline particles were effectively integrated into the amorphous excipient's surface. Conversely, the FBZ-HPMCAS pKSD sample displayed a different morphology, primarily consisting of large FBZ crystalline particles. These appeared as a crystalline agglomerate in Figure 2G and larger crystalline particles with smaller surface fragments as shown in Figure 2H. These discrepancies in particle morphology are attributed to differences in initial particle size. Smaller particles generally possess greater plastic stiffness, which can hinder their morphological alteration during processing (2). On the other hand, the FBZ-leucine pKSD and FBZ-lactose pKSD samples (Figure 2K-L and Figure 2O-P, respectively) exhibited distinct characteristics. Unlike the HPMC-based samples, embedded FBZ particles were absent when leucine and lactose were employed as excipients. Instead, smaller FBZ particle fragments were observed adhering to the surface of the crystalline excipients. These morphological differences are attributed to the inherent higher plastic stiffness of crystalline materials, which is a result of their more robust crystalline lattice (2). A limitation in this observation was the difficulty in identifying FBZ using SEM, as the excipients themselves (leucine and lactose) also underwent particle size reduction during the pKSD process, making their distinct identification challenging. Regarding the solid state post-pKSD processing, FBZ remained crystalline in all samples, as indicated by WAXS measurements (Figure 3). However, detecting FBZ crystallinity was more challenging in the FBZ-HPMC pKSD sample due to a more noticeable reduction in FBZ particle size (Figure 2C-D). This particle size reduction also accounts for the observed peak broadening of lactose and leucine. Conversely, FBZ-HPMCAS samples exhibited larger FBZ crystals, indicated by the increased peak intensity in their WAXS diffractograms (Figure 3C-D).

Conclusion: The present study expands pKSD's scope to include crystalline excipients. The morphological differences observed in the resulting pKSD samples demonstrate KinetiSol technology's utility for particle engineering as a novel, fast, and solvent-free manufacturing method. Our findings indicate that differences in excipient properties (e.g., amorphous vs. crystalline) and initial particle size are relevant for determining particle breakage and morphology during pKSD, which is fundamental for designing particles effectively.

References: 1. Jara MO, Behrend-Keim B, Bedogni G, Michelena LV, Davis DA, Miller DA, et al. Comparative study of Hot-Melt Extrusion, spray drying, and KinetiSol® processing to formulate a poorly water-soluble and thermolabile drug. Int J Pharm. 2025 Apr 8;125582.
2. Pazesh S, Persson AS, Berggren J, Alderborn G. Effect of milling on the plastic and the elastic stiffness of lactose particles. Eur J Pharm Sci. 2018 Mar 1;114:138–45.

Acknowledgements:

Funding: Jara and Behrend-Keim were supported by a gift to support graduate education by AustinPx, (Georgetown, TX).

Figure 1. pKSD and KSD process diagrams, and (A) macroscopic, (B) SEM, and (C) schematic views of resulting materials. (D-E) SEM images showing the morphology of FBZ raw material.

Figure 2. Scanning Electron Microscopy (SEM) images showing the morphology of: (A–B) HPMC; (C-D) FBZ-HPMC pKSD; (E–F) HPMCAS; (G-H) FBZ-HPMCAS pKSD, red arrows indicate the location of FBZ crystals; (I–J) leucine; (K-L) FBZ-leucine pKSD; (M-N) lactose; and (O-P) FBZ-lactose pKSD samples.

Figure 3. Wide-angle X-ray diffractogram of FBZ, excipients, and pKSD samples, including detailed close-up views. (A–B) FBZ-HPMC pKSD, (C–D) FBZ-HPMCAS pKSD, (E-F) FBZ-leucine pKSD, and (G-H) FBZ-lactose pKSD samples.