(774d) Ternary Dispersions of Itraconazole: A Comparison of Hot Melt Extrusion and Spray Drying

Mark T. Davis¹*, Catherine B. Kelly¹, & Gavin M. Walker^{1, 2}

¹Synthesis and Solid State Pharmaceutical Centre (SSPC), Bernal Institute,

University of Limerick, Limerick, Ireland

²Pharmaceutical Manufacturing Technology Centre, PMTC, University of Limerick, Limerick, Ireland

*Tel.: +353-(0)-61- 213096, E-mail: mark.davis@ul.ie

ABSTRACT

BCS Class II drug itraconazole (ITR) represents a difficult formulation challenge due to its very low aqueous solubility and poor dissolution kinetics. It has been extensively studied in an attempt to achieve higher bioavailability and therefore better dissolution. The amorphous state represents a disordered structure relative to the crystalline form which has been shown to have an advantage of higher dissolution rates and better oral absorption. Much work has been carried out on the performance of single polymers in the formulation of the amorphous form as an amorphous solid dispersion however evidence exists that ternary amorphous solid dispersions (ASDs) containing two rationally chosen biocompatible polymers may exhibit better amorphous stability and dissolution profiles than their binary equivalents.

In this study, ITR was formulated into a number of amorphous solid dispersions using hot melt extrusion (HME) and spray drying (SD). The systems comprised ternary formulations of itraconazole with Soluplus® and/or HPMCP. Initial studies within our group have indicated that although HPMCP is an enteric polymer it interacts more favourably with ITR than Soluplus does and so should offer amorphous stabilisation benefits. Soluplus, however, is an excellent aqueous phase solubiliser for ITR so contributes to the dissolution properties of the ASD.

A drug loading of 40% was chosen to produce tablets of 500 mg containing 200 mg of active pharmaceutical ingredient (API). Equivalent physical mixtures were prepared to measure the solubility benefit of the amorphous state. All formulations were shown to be completely free of either liquid-crystalline or crystalline ITR using both wide-angle XRD and hyper differential scanning calorimetry (DSC). Further analysis of physical characteristics was carried out using SEM, laser scattering and density measurements.

Dissolution testing was carried out on both the tablets and the physical mixture using USP dissolution apparatus 2 (paddle at 37 ^oC) in biorelevant media. 5ml aliquots were removed at regular intervals and, following production and validation of an absorbance - concentration calibration curve for ITR, dissolved drug was quantified using UV-Vis spectrophotometry. Differences in dissolution rate and extent were rationalised in terms of the preparation methods, hydrogen bonding and the material properties.