A Comparative Study on the Performance of Inert and Functionalized Spheres Coated with Solid Dispersions Made of Two Structurally Related Antifungal Drugs

• Published in: Molecular pharmaceutics 2017-11, Vol.14 (11), p.3718-3728
• Main Authors: Mugheirbi, Naila A, O’Connell, Peter, Serrano, Dolores R, Healy, Anne Marie, Taylor, Lynne S, Tajber, Lidia
• Format: Article
• Language: English
• Subjects: Antifungal Agents - chemistry; Cellulose - chemistry; Itraconazole - chemistry; Tartrates - chemistry; Triazoles - chemistry
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.7b00482

Fluid bed coating offers potential advantages as a formulation platform for amorphous solid dispersions (ASDs) of poorly soluble drugs, being a one-step manufacturing process which could reduce the risk of phase separation associated with multiple step manufacturing approaches. However, the impact of the physicochemical nature of nonpareil carriers on the properties and drug release from the ASDs has not been studied in detail. In this work, tartaric acid (TAP) and microcrystalline cellulose (CEL) spheres were chosen as examples of functional and inert beads, respectively. Two structurally related triazole antifungals, itraconazole (ITR) and posaconazole (POS), were chosen as model drugs. Solid-state investigations revealed that the fluidized bed process result in both types of spheres uniformly coated with ITR and POS ASDs based on Eudragit L100-55 (EUD). A single glass transition temperature (T g) was determined for each of the ASDs. Infrared studies suggested the presence of a weak interaction between POS and TAP, which translated into premature release of POS from the POS/EUD ASD coated TAP spheres in FaSSGF and subsequently lower POS cumulative release in comparison to the ASD coated on CEL beads. High resolution investigations of morphological and compositional changes during dissolution, using scanning electron microscopy and atomic force microscopy coupled with nanoscale thermal investigation, revealed that crystallization of the drug from the ASDs was induced during dissolution when TAP spheres were used as carriers. In contrast, ASDs coated on CEL underwent phase separation and drug-rich nanospecies were formed in the matrix due to the solubility gap between the drug and EUD in FaSSIF. This study demonstrates that properties of carrier for the ASD fundamentally affect the drug release properties and the proper selection of carrier beads is critical to ensure product quality.