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).