Formulation and optimization of chitosan-based amorphous fenbendazole microparticles through a design of experiment approach

Introduction

Fenbendazole (FNB), is a hydrophobic drug with a broad-spectrum anthelminthic (Küster et al., 2014). It binds more strongly to β-tubulin in parasitic cells than in mammals, avoiding the formation of microtubules and leading to the death of parasites (Friedman et al., 1980). In addition, it might be repurposed for cancer in humans because it can partially inhibit microtubule polymerization in human cancer cells producing a certain antitumor effect in different cell lines (Duan et al., 2013, Dogra et al., 2018). Also, it can overcome tumor resistance to well-known treatments like 5-fluorouracil. (Park et al. 2022). However, as FNB is a veterinary medicine, more adapted pharmaceutical preparations in human medicine are still lacking. FNB is almost insoluble in water (< 0.007 mg/mL, log P 3.99) (Melian et al., 2021) leading, as a consequence, to a low dissolution rate, poor bioavailability, and low biological activity. To date, few alternatives have been developed to reduce such drawbacks including cyclodextrins complexation (Varmalova et al., 2021; Ding et al., 2024), solid dispersions (Melian et al., 2021), and nanoparticles (Chang et al., 2023, Bedogni et al., 2024). FNB exhibits a crystalline structure that can affect its solubility in water because such arrangements generate strong intermolecular bonds that hinder its ability to dissolve in water. Crystalline materials are arranged in a repeating, three-dimensional pattern called a lattice that results in distinct planes of atoms or molecules and leads to characteristic properties such as sharp melting points and predictable X-ray diffraction patterns. In contrast, amorphous materials do not have a well-defined long-range order lacking the periodicity of a crystal lattice. In general, amorphous forms of drugs can have advantages such as increased solubility and dissolution rates compared to their crystalline counterparts (De Mohac et al., 2021). In this regard, polymeric matrices can enhance the solubility and the dissolution of poorly soluble drugs by maintaining them in an amorphous state (Molina et al., 2022). In connection with it, one of the most common matrix formers for the encapsulation of pharmaceutical compounds is chitosan (CH) (Khlibsuwan and Pongjanyakul, 2015). CH is a linear biodegradable polymer made up of deacetylated D-glucosamine units and randomly distributed N-acetyl-D glucosamine units obtained from the alkaline deacetylation of chitin (Aranaz et al., 2021). It is a weak base and in acidic aqueous solutions interacts with anionic reagents to form polyelectrolytic complexes. The properties of those complexes are related to the type and concentration of both components and the crosslinking time (Du et al., 2015, Situ et al., 2018, Martínez-Martínez et al., 2019). It is worth mentioning that CH has been used to microencapsulate different hydrophobic benzimidazoles chemically related to FNB like benznidazole (Leonardi et al., 2019) and albendazole (Piccirilli et al., 2014). However, the microencapsulation of FNB in CH has not been investigated to date. Thus, this work aimed to formulate FNB-loaded CH microparticles by a complex coacervation and further spray drying using sodium sulfate or sodium tripolyphosphate. The process parameters of these polymeric formulations were optimized by applying Design of Experiments (DoE) techniques. The screening phase analyzed the relationship between multiple input variables (factors) and key output variables (responses) related to the microencapsulation of FNB in chitosan-crosslinked matrices. Five independent factors were evaluated at two levels, and their influence on five responses was studied. In the second step, a Box-Behnken design was applied to evaluate the relationship between three factors and five responses. Experimental verification was performed to compare the correlation of the generated statistical model. The optimized FNB-CH microparticles were characterized by infrared spectra (IR), thermal analysis, wide-angle X-ray scattering (WAXS), and dissolution performance.

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Lina Vargas Michelena, Giselle R. Bedogni, Miguel O. Jara, Robert O. Williams, Claudio J. Salomon, Formulation and optimization of chitosan-based amorphous fenbendazole microparticles through a design of experiment approach, International Journal of Pharmaceutics, Volume 667, Part A, 2024, 124872, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124872.

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