(583c) Spray Drying of Ternary Solid Dispersions of Itraconazole: Amorphous Stability By Design of Experiment

Mark T. Davis¹*, Catherine B. Kelly¹, Ahmad B. Albadarin¹, Maryam Mohammadpour¹â??
Mustafa Sajjia² & Gavin Walker¹

¹Synthesis and Solid State Pharmaceutical Centre (SSPC), Bernal Institute,
University of Limerick, Limerick, Ireland
²Pharmaceutical Manufacturing Technology Center (PMTC), University of Limerick, Limerick, Ireland
*Tel.: +353-(0)-61- 213096, E-mail: mark.davis@ul.ie

Abstract

Itraconazole is a BCS Class II drug with very limited aqueous solubility (<1 µg/ml) and poor dissolution kinetics. Many studies have been conducted in an effort to produce formulations of this drug with higher bioavailability. In this context, we have examined ternary amorphous solid dispersions (ASD) of itraconazole with excipient polymers Soluplus^® and HPMCP. Evidence exists to suggest that ternary formulations can be more stable and have better release profiles than binary systems alone. Soluplus^® is a structurally diverse excipient with excellent solubility and melt extrusion characteristics. HPMCP is used as a complimentary excipient, owing to the phthalate groups which help protect against gastric juices.
In this study we have taken a design of experiments (DoE) approach to optimise ternary formulations of itraconazole-Soluplus-HPMCP, producing 17 outcomes. A pre-formulation solubility test was run to ensure complete solubility of each combination. The solutions were then converted into powders by spray drying in a Büchi B-290 mini spray drier, equipped with a pneumatic nozzle, inert loop condenser and high efficiency cyclone. Yields were consistent and could be increased to as high as 83% by varying parameters.
The powders were split into three parts and stored at (i) RT and 0% RH, (ii) 30 ^oC and 45% RH and (iii) 40 ^oC and 75% RH for up to one year. PXRD measurements revealed samples to be amorphous at day 0 and importantly still amorphous after a year of storage. Low angle XRD was used to ensure that samples had not formed a meso phase, which is possible with solid state itraconazole. Differential scanning calorimetry (DSC) confirmed that the samples were amorphous and demonstrated how the glass transition temperature varied with content. Particle size distribution measurements was carried out on using laser differaction and the data was analysed by cumulative and histogram plots. A statistical analysis revealed a relationship between PSD and formulation content. This result was rationalised by hydrogen bonding in HPMCP, the only component capable of self-association.