The production and characterisation of itraconazole multicomponent systems

This thesis focuses on the poorly soluble triazole antifungal agent, itraconazole (ITZ). This compound was reported to form hydrochloride salts and cocrystals with a wide range of aliphatic dicarboxylic acids, which have shown some potential to enhance the solubility of ITZ. In addition, ITZ has the unusual ability to form liquid crystalline (LC) phases. Liquid crystalline materials have been utilised for decades in a wide range of non-pharmaceutical applications, however their applications have not been extensively recognised in the field of pharmaceutical materials. The primary aim of this work was to produce and characterise a number of multicomponent systems containing ITZ and investigate their solubility behaviour. For this reason, it was necessary to examine the LC properties of ITZ and, for the first time, to generate full thermodynamic phase diagrams for ITZ/polymer systems considering isotropic and anisotropic (LC) phases that this drug can form. In addition, the two-component phase diagrams were constructed for the ITZ and succinic acid (SUC) system to investigate the possible solid-state (eutectic and cocrystal) phases for the binary mixtures of ITZ and SUC. Several binary (composed of ITZ and SUC) and ternary (composed of ITZ, SUC and methacrylic acid-ethyl acrylate copolymer (EUD)) systems were produced by ball milling to investigate if the addition of SUC and EUD to ITZ formulation could create a favourable pH-microenvironment and thus enhance the solubility of ITZ. Studies of LC properties of ITZ suggested that supercooled ITZ forms a vitrified smectic (vSm) phase with a glass transition temperature (T g ) of 59.3?C, as evident from X-ray diffraction and thermomicroscopic (PLM) experiments. Two endothermic LC events with the onset temperature values for the smectic to the nematic transition of 73.2 ? 0.4 ?C and nematic to isotropic transformation at 90.4?0.35 ?C and enthalpies of transition of 416 ? 34 J/mol and 842 ? 10 J/mol, respectively, were recorded. For the binary supercooled mixtures, PLM and differential scanning calorimetry (DSC) showed that both, smectic and nematic phases were detected for the supercooled ITZ/hypromellose acetate succinate (HAS) and ITZ/EUD mixtures, while geometric restrictions inhibited the smectic formation in the ITZ/polyacrylic acid (CAR) systems. The FloryHuggins lattice theory coupled with the Maier-Saupe-McMillan approach was successfully utilised to create phase diagrams for all ITZ/polymer mixtures. It was concluded that the presence of LC phase of ITZ in the ITZ/polymer system might lead to immiscibility of components in such systems. The thermodynamic phase diagram of the binary mixtures of ITZ and SUC was determined experimentally, using DSC, and theoretically, using the Schroeder-van Laar and Prigogine-Defay equations. The constructed diagram was characteristic for a congruently melting system with the ability of cocrystal formation. It signified the cocrystal formation with a stoichiometry of 2:1 ITZ and SUC (ITZ-SUC). Three eutectic phases were also identified: metastable (m-E) at 132.8 ? 0.22 ?C, a stable eutectic phase composed of ITZ-SUC and SUC (E 1 ) at 147.9 ? 0.08 ?C, and a stable eutectic phase made by ITZ-SUC and ITZ (E 2 ) at 157.1 ? 0.28 ?C. The composition of E 1 was determined from the Tamman plot as x (ITZ) = 0.31 and x (SUC) = 0.69. The composition of the E 2 phase was found to be very close to the ITZ-SUC composition and was x (ITZ) = 0.67 and x (SUC) = 0.33. The E 1 was successfully produced by a fast-evaporation crystallisation method, and its identity was confirmed by DSC and powder X-ray diffraction (PXRD) analyses. Dynamic solubility studies of a number of binary and ternary ITZ milled (amorphous or semiamorphous) systems were conducted in the simulated gastric fluid (SGF) and in the fasted state simulated intestinal fluid (FaSSIF) at 37 ?C and ITZ concentrations were determined using High-Performance Liquid Chromatography (HPLC). It was found that ITZ-SUC was able to extend, up to 30 minutes, supersaturation levels that were ~7.7-fold and ~330-fold higher than ITZ thermodynamic solubility, in SGF and FaSSIF, respectively. Solid dispersions with higher SUC and EUD content significantly enhanced the solubility of ITZ in FaSSIF. Incorporation of 20% or 40% of EUD into a system composed of ITZ and SUC in a 1:2 molar ratio resulted in supersaturation levels that were ~400 and ~2,500-fold higher than that of crystalline ITZ, respectively