Comparative study of Hot-Melt Extrusion, spray drying, and KinetiSol® processing to formulate a poorly water-soluble and thermolabile drug

Abstract

Fenbendazole (FBZ), a benzimidazole-carbamate anthelmintic, shows promising chemotherapeutic properties. However, it is a poorly water-soluble molecule, leading to low and variable oral bioavailability. This study investigated hot-melt extrusion (HME), spray drying, and KinetiSol processing (KSD) using Soluplus (SOL) to enhance FBZ’s solubility. Formulating FBZ as an amorphous solid dispersion (ASD) by HME at a barrel temperature of 120 °C led to extensive chemical degradation of FBZ, generating the degradation product fenbendazoleamine. On the other hand, spray-drying (SD) generated an ASD, but its usefulness was greatly limited by the low solubility of FBZ in the cosolvent system required in the SD process. Given FBZ’s poor solubility in both water and organic solvents and its thermolabile propensity, KSD was explored. Conventional KSD parameters reduced the impurity levels to 6.4 % at a discharge temperature of 64 °C. To further minimize impurity levels, we investigated alternative KSD parameters that terminate the process before reaching the melt agglomeration phase. These conditions resulted in powder-discharged KSD samples (pKSD) that avoided causing chemical degradation of FBZ. The pKSD samples exhibited trace crystallinity, as confirmed by Wide Angle X-ray Scattering (WAXS). Scanning electron microscopy (SEM) revealed that these samples comprised nano- and micron-sized particle aggregates. These results were confirmed by processing FBZ with other excipients, such as semi-crystalline polymers and cyclodextrins. The pKSD samples demonstrated improved dissolution performance of FBZ compared to the physical mixture and crystalline neat FBZ due to the smaller particle size of FBZ. pKSD FBZ provides a solution for formulating thermolabile molecules like FBZ while only requiring a few seconds of exposure to the pKSD manufacturing process conditions, thus eliminating the disadvantages of SD (e.g., requiring sufficiently high solubility in the organic solvent system) and HME (e.g., exposure to high shear and heat during the process).

Introduction

Benzimidazole-carbamate anthelmintics (also called benzimidazole carbamates or benzimidazoles) have recently attracted attention for drug repurposing as chemotherapeutics (Prasher and Sharma, 2022). The pharmacologic mechanism of these molecules against parasites is similar to that of some chemotherapeutics, affecting microtubule formation and metabolism (Peng et al., 2022). Benzimidazoles include albendazole; ricobendazole, mebendazole, flubendazole, parbendazole, oxibendazole, oxfendazole, and fenbendazole (Son et al., 2020). Unfortunately, these molecules have low aqueous solubility, leading to their low and variable oral bioavailability (Sutar et al., 2021).
A strategy to improve the dissolution and solubility properties of poorly water-soluble drugs (or active pharmaceutical ingredient, API), involves the generation of an amorphous solid dispersion (ASD) (Schittny et al., 2020). In an ASD, the API is molecularly dissolved in a solid matrix, which is typically an amorphous polymer (Qian et al., 2010, Van den Mooter, 2012). The amorphous nature of these compositions eliminates the need for energy to disrupt crystal lattices during dissolution, thereby increasing apparent solubility and dissolution rate (Bhujbal et al., 2021). There are several methods reported to prepare an ASD: solvent-based (e.g., freezing-based and spray-drying (SD)) and thermal-based (e.g., hot melt extrusion (HME)) manufacturing methods (Mendonsa et al., 2020). In these manufacturing methods, the API must interact molecularly with the polymer. However, the selection of the manufacturing method is influenced by the physicochemical properties of the API and the polymer composition (Huang and Williams, 2018). Furthermore, optimizing the manufacturing technique is essential for maximizing drug loading and enhancing both the physical and chemical stability of the ASD (Dedroog et al., 2019).

In solvent-based methods, the polymer and API are dissolved in a common solvent or co-solvent system to facilitate molecular interaction. This is followed by the solvent’s evaporation (e.g. spray drying) or sublimation (e.g. freeze drying) to generate the ASD. Spray drying is the preferred solvent-based method for preparing ASDs in the initial stages of drug development because it can produce small batches and process thermolabile materials and high melting point compounds (Kelleher et al., 2018, Singh and Van den Mooter, 2016). Additionally, spray drying is scalable and allows for the engineering of particles with specific morphologies. During spray drying, an API-polymer solution is pumped into the drying chamber via a nozzle that atomizes the solution into fine droplets. These droplets encounter a hot drying gas (usually nitrogen), which dries them, generating dried ASD particles. A cyclone then separates the dry particles from the drying gas, and the powdered ASD product is collected in a vessel (Davis and Walker, 2018). A significant limitation of spray drying and other solvent-based methods is the solubility of the API and polymer in the selected solvent system, where high solubility is essential for commercial viability. The use of organic solvents presents challenges, including high costs, explosion risks, and toxicity, requiring strict quality controls to ensure residual solvent levels remain within safe limits (Bhujbal et al., 2021, Hermeling et al., 2022, Huang and Williams, 2018). Additionally, environmental and safety considerations emerged from the use of large amounts of organic solvents (He and Ho, 2015). Consequently, manufacturers are transitioning from solvent-based to thermal-based methods for producing ASDs (Tambe et al., 2022).

In the case of thermal-based methods, the materials are melted to a molten/liquid state, allowing for an intimate interaction between the API and polymer. The molten material is then quickly quench-cooled to generate an ASD (Thiry et al., 2016). HME is the most common manufacturing process among thermal-based methods. During HME, the barrel is set at high temperatures while the screws rotate, applying mechanical and thermal energy to the polymer-API blends (Haser et al., 2017). Consequently, the API particles are dissolved in the molten polymer during the HME processing. Upon exiting the extruder, the material cools, generating an ASD (Patil et al., 2015). HME provides continuous manufacturing, modular flexibility, and easy scalability. Despite its advantages in scalability and cost efficiency, HME is constrained by the thermal and shear sensitivity of certain APIs and polymers, which can result in chemical degradation at processing temperatures typically exceeding 120 °C (Haser et al., 2017, Schönfeld et al., 2021).

Kinetisol® processing (KSD) technology is a scalable manufacturing process that is an alternative solvent-free, high-energy mixing process for preparing ASDs. KSD employs protruding blades to apply shear to drug-excipient (e.g., polymer) combinations at high rotation speeds. Inside the KSD chamber, these blades cause the powder particles to collide with each other and with the chamber walls, which generates friction and heat (Tan et al., 2020). This intense mixing increases the temperature of the powder material, leading to the formation of a melt agglomerate. This mass is then discharged from the processing chamber and cooled, forming an ASD. In the KSD process, the processing RPMs, the duration of processing, and the discharge temperature are experimentally determined. The KSD process continues until the set processing time or the discharge temperature is achieved, whichever is reached first. In the formulation design space of ASDs, KSD enables manufacturing high melting point APIs, thermally labile materials, and viscous polymers without adding plasticizers, all within a few seconds of manufacturing (Ellenberger et al., 2018). Additionally, KSD provides an alternative method for ASD formulation of drugs with unacceptably low solubility in organic solvents, which is unsuitable for SD due to cost and environmental factors (Miller and Keen, 2014). KinetiSol technology supports both batch and continuous manufacturing processes, with three specialized units designed for distinct stages of drug development. The scale-up from the research formulator compounder (7–15 g) to the preclinical batch compounder (50–350 g) is achieved through a linear scaling factor based on rotational speed. Moreover, transitioning from batch to continuous manufacturing at the same batch size requires no additional scale-up, and the continuous unit can process materials at a maximum throughput of 40 kg/h (Ellenberger et al., 2018). The KinetiSol units utilize a real-time, rapid temperature monitoring infrared probe specifically designed to oversee the chamber. This probe continuously measures the material temperature within the chamber, ensuring precise real-time monitoring (Jermain et al., 2020, Tan et al., 2020).

To date, KSD studies have focused on manufacturing ASDs obtained as molten discharges (Tan et al., 2020, Ellenberger et al., 2018). These studies have demonstrated its capability to reduce the chemical degradation of APIs and excipients, especially when compared to HME (DiNunzio et al., 2010, Hughey et al., 2012, Hughey et al., 2011, Hughey et al., 2010). However, there are exceptions to this. Davis et al. (2020) reported that drugs such as mebendazole and albendazole belong to a small group of molecules that lack heat tolerance, making them very challenging to formulate using KSD or any other thermal-based manufacturing process (Davis et al., 2020). Additionally, Ellenberger et al. (2018) considered these molecules to be outside the formulation space of KSD (Ellenberger et al., 2018).

In this study, we compare three manufacturing techniques, HME, SD, and KSD, to formulate an ASD to enhance the dissolution performance of fenbendazole (FBZ), a thermolabile and poorly water-soluble benzimidazole-carbamate (Fig. 1). Additionally, we investigate alternative processing parameters by performing KSD at lower temperatures, avoiding the melt agglomeration phase that leads to molten mass discharges. We hypothesize that these powder-discharged KSD (pKSD) products will exhibit improved dissolution performance of FBZ without generating degradation products. The pKSD process is a novel manufacturing strategy for formulating and enhancing thermolabile compounds’ dissolution properties and water solubility without the need for solvents.

Materials

FBZ was purchased from Shenzhen Nexconn Pharmatechs LTD (Shenzhen, China). Soluplus® (SOL) was kindly donated by BASF (Ludwigshafen, Germany). Dimethylformamide (DMF), ethyl acetate, and acetonitrile (ACN) were purchased from Sigma Aldrich (Saint Louis, MO, USA). Methanol (MeOH), ethanol (EtOH), and 1.4-dioxane were obtained from Fisher Scientific (Pittsburgh, PA, USA). Dichloromethane (DCM) was acquired from Acros Organics (Morris Plains, NJ, USA). Magnesium stearate was obtained from Spectrum.

Miguel O. Jara, Beatriz Behrend-Keim, Giselle Bedogni, Lina Vargas Michelena, Daniel A. Davis, Dave A. Miller, Claudio Salomon, Robert O. Williams, Comparative study of Hot-Melt Extrusion, spray drying, and KinetiSol® processing to formulate a poorly water-soluble and thermolabile drug, International Journal of Pharmaceutics, 2025, 125582, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125582.