(M1430-07-44) Exploring Powder Discharge-Based KinetiSol. a Modified KinetiSol® Process for Manufacturing Dry Powders for Inhalation: A Proof of Concept

Purpose: This study aimed to evaluate powders consisting of nano- and micron-sized particulate aggregates, prepared by powder discharge-based KinetiSol (pKSD) for inhalation and nasal applications. KinetiSol is a solvent-free, high-energy mixing process traditionally used to manufacture amorphous solid dispersions. Recent modifications to KinetiSol parameters have resulted in pKSD samples with unique morphologies and reduced particle sizes applicable to inhalation and nasal drug delivery (1). This study explores the use of excipients beyond those previously employed in the KinetiSol process, aiming to adapt pKSD as a particle engineering tool for preparing dry powders for inhalation and nasal delivery.

Methods: Powder discharge-based Kinetisol processing (pKSD): Powder blends of 5% w/w fenbendazole (FBZ) and L-Leucine (Leu, Alphaesar, Fisher Scientific, Pittsburgh, PA, USA) or inhalation grade lactose, LactoHale 300 (LH300, DFE Pharma, Goch, Germany) were processed using the pKSD technique (1). Briefly, the blends were initially processed at 1000 RPM for 5 s, followed by a processing phase at 4000 RPM for 30 or 45 seconds. A last processing step at 1000 RPM for 5 s was incorporated to reduce dust generation. In pKSD, the resulting samples are powders instead of a molten mass, which is commonly observed in conventional KSD studies. Scanning electron microscope (SEM): Samples were mounted on carbon tape and aluminum stubs, then sputter-coated with gold/palladium using an EMS Sputter Coater (Hatfield, PA, USA). Images were captured with an Apreo 2 C LoVac SEM instrument (Waltham, MA, USA). Particle size analysis: Particle size distribution of pKSD samples and excipients was determined using laser light diffraction (HELOS/KR, Sympatec GmbH) with a dry dispersing system at 4 bar pressure (Rodos, Sympatec). Data evaluation was performed using Windox 5 software. Aerosol performance: pKSD samples were evaluated in a Next Generation Impactor (NGI, Copley Scientific, Nottingham, UK). The formulations were aerosolized using a High Resistance RS01 Monodose DPI (Berry Global Healthcare, IN, US) at 60 L/min for 4 seconds, producing 4 kPa of pressure drop. Size 3 HPMC capsules were loaded with 40 mg of powder. The experiments were performed in triplicate using two loaded capsules per NGI run, which were recovered with DMSO. The fine particle fraction (FPF) percentage of the particles below an aerodynamic diameter of less than 5µm, according to the measured emitted dose.

Results: FBZ- LH300 samples prepared for 30 and 45 seconds (FBZ-LH300/30s and FBZ-LH300/45s, respectively) exhibited tomahawk-shaped particles with smaller FBZ or lactose nano- and micron-sized particles on their surfaces (Figure 1A and B). These samples maintained their particle size distribution after pKSD, with no difference in particle size between the samples prepared after 30 and 45 seconds of processing (Figure 2A). In contrast, Leu samples appeared as disc-like particles, also displaying nano- and micron-sized particles on their surfaces (Figure 1C and D). Unlike lactose, leucine samples showed a decrease in particle size after pKSD (Figure 2B). Specifically, FBZ-Leu/30s reduced its particle size by 3.7 times, while FBZ-Leu/45s decreased by 4.3 times. This reduction in particle size is attributed to particle breakage, which is influenced by material properties, particle size, shape, and the presence of cracks or flaws (2). Mainly, the particle size is reduced in the thin disc-like particles (leucine) as cracks propagate with lower resistance through the thin cross-section. FBZ had a d50 of 5.4 ± 0.2 µm before processing. Previous SEM of pKSD FBZ-polymer formulations showed decreased FBZ particle size after processing (1). We hypothesized a similar decrease with LH300 and Leu. However, similar fine particle morphologies of LH300, Leu, and FBZ prevented distinguishing between API and excipient when using SEM. FBZ-LH300/30s and FBZ-LH300/45s samples demonstrated similar aerosol performance, with a fine particle fraction (FPF) of approximately 30% (Table 1). In contrast, leucine samples showed improved aerosol performance, achieving an FPF of around 50%. This enhanced performance can be attributed to leucine's ability to improve dispersibility(3). The pKSD samples, having an aerosol performance of 30-50% FPF, demonstrated comparable performance to marketed dry powders for inhalation, with a reported FPF of 20-60%.(4).

Conclusion: The results demonstrate that pKSD can be employed to prepare dry powders for inhalation. The nano-micron-sized aggregates of fenbendazole produced an FPF around 30-50%, ensuring the delivery of FBZ to the lungs. Additionally, the aerosol performance of pKSD samples obtained in this study can be compared to the aerosol efficiency of marketed products. These findings suggest a promising new manufacturing technique for dry powders intended for inhalation, offering an alternative to current methods, such as micronization and spray drying(5,6). Further optimization of pKSD samples will be pursued to enhance the efficiency of pulmonary drug delivery and explore potential applications for nasal delivery. Future research will focus on elucidating the solid-state properties of pKSD samples and examining the impact of material properties on particle breakage of the API and/or excipient during Kinetisol processing and particle characterization.

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 May 15;676:125582.
2. Han J, Fitzpatrick J, Cronin K, Miao S. Investigation of the influence of powder characteristics on the breakage of dairy powders. Food Res Int. 2021 Dec 1;150:110775.
3. Huang Z, Kunnath KT, Han X, Deng X, Chen L, Davé RN. Ultra-fine dispersible powders coated with l-Leucine via two-step co-milling. Adv Powder Technol. 2018 Dec 1;29(12):2957–65.
4. Watz H, Barile S, Guastalla D, Topole E, Cocconi D, Mignot B, et al. Targeting the Small Airways with Inhaled Corticosteroid/Long-Acting Beta Agonist Dry Powder Inhalers: A Functional Respiratory Imaging Study. J Aerosol Med Pulm Drug Deliv. 2021 Sep;34(5):280–92.
5. de Boer AH, Thalberg K. Chapter 5 - Dry powder inhalers (DPIs). In: Kassinos S, Bäckman P, Conway J, Hickey AJ, editors. Inhaled Medicines [Internet]. Academic Press; 2021 [cited 2024 Nov 27]. p. 99–146.
6. Stegemann S, Faulhammer E, Pinto JT, Paudel A. Focusing on powder processing in dry powder inhalation product development, manufacturing and performance. Int J Pharm. 2022 Feb 25;614:121445.

Acknowledgements:

Funding:
Beatriz Behrend-Keim and Miguel O. Jara were supported by AustinPx, Georgetown, TX, through a gift to support graduate education.


Figure 1. SEM images of pKSD samples. A) FBZ-LH300/30s; B) FBZ-LH300/45s; C) FBZ-Leu/30s; D) FBZ-Leu/45s. (The bar shows a size of 20 µm)



Figure 2. Particle size of the excipients before the Kinetisol processing and pKSD samples. A) LactoHale 300, FBZ-LH300/30s and FBZ-LH300/45s. B) Leucine, FBZ-Leu/30s, FBZ-Leu/45s


Table 1. Aerosol performance of LH300 and Leu pKSD samples.