Incorporation of itraconazole nano-co-crystals into multiparticulate oral dosage forms

Abstract

Limited research has been performed on the downstream processing of nano-co-crystal suspensions into solid oral dosage forms. The objectives of this study were to evaluate the impact of three downstream processes (wet granulation, spray granulation and bead layering) on the performance of itraconazole-succinic acid (ITZ-SUC) nano-co-crystal suspension. An optimized ITZ-SUC nano-co-crystal suspension mixed with HPMC E5 was utilized for the downstream processing. The suspension was converted in the solid state either by wet or spray granulation (with microcrystalline cellulose or lactose as substrates) or by layering onto microcrystalline cellulose and sugar beads. The multiparticulate solid dosage forms were characterized by optical microscopy, differential scanning calorimeter (DSC), X-ray powder diffraction (XRPD) and in situ dissolution studies. Spray granulation and bead layering resulted in less particle aggregation, a faster dissolution rate, and higher kinetic solubility when compared to wet granulation. ITZ-SUC nano-co-crystals spray granulated with lactose resulted in higher kinetic solubility profiles compared to microcrystalline cellulose granules. The type of bead core had no impact on the dissolution behavior. A slower dissolution and decreased kinetic solubility were observed with increasing drug loading for sprayed granules when microcrystalline cellulose was used as substrate. All dosage forms were stable under accelerated storage conditions (40 °C/75% RH) when blistered. Nano-co-crystals incorporated in granules were less stable than layered beads under non-blistered condition. Nano-co-crystals layered sugar beads are an interesting alternative to amorphous solid dispersion; a comparable kinetic solubility but a faster drug release were achieved. This study identified bead layering as a superior downstream process approach for incorporating ITZ-SUC nano-co-crystals into an oral solid dosage form without compromising drug dissolution.

Keywords: Bead layering; Dissolution rate; Downstream processing; Itraconazole-succinic acid nano-co-crystal; Kinetic solubility; Spray granulation.