(774g) Hot Melt Extrusion of Ternary Solid Dispersions of Itraconazole: Amorphous Vs Liquid Crystal Intermediate

It has been demonstrated that ternary solid dispersion compositions can be more efficient than binary compositions in terms of their excellent physical stability and ability to inhibit the recrystallization of API's in bio-relevant media. This study is mainly focused on investigating the preparation of ternary solid dispersions of itraconazole, a BSC Class (II) model drug, containing a water-soluble polymer and/or a water-insoluble polymer using hot melt extrusion. The formation, physio-chemical characterization, stability, and phase transformation in the context of drug formulation and development of amorphous/liquid crystals of itraconazole was investigated in detail.

Five combinations of ternary solid dispersions comprising itraconazole, hydroxy propyl methyl cellulose phthalate (HPMCP-HP50) and/or soluplus were prepared by hot melt extrusion (HME) using a 16 mm pharmalab co-rotating twin screw extruder and L/D ratio of 40: 1 (Thermo Fisher Scientific, Karlsruhe, Germany). Information regarding the miscibility of the drug with the excipient, physical state, phase transformation, possible interactions and proper storage conditions were obtained by employing small angle powder X-ray diffractometry (SAXS), differential scanning calorimetry (DSC), Raman spectroscopy and infrared spectroscopic (FT-IR) measurements for specific polymer-polymer and drug-polymer interactions.

The SAXS results showed that itraconazole in the solid dispersion was in the amorphous state and indicated the absence of liquid crystalline itraconazole. The Raman and FT-IR analysis indicated the formation of hydrogen bonding between itraconazole and HPMCP-HP50/soluplus molecules and that itraconazoleâ??HPMCP-HP50 interactions were stronger than itraconazoleâ??soluplus interactions. From the DSC scans melt extrudates of itraconazole and HPMCP-HP50/soluplus exhibited one glass transition (Tg) and an absence of an endotherm around the melting point of itraconazole confirming that the API is present only in its amorphous state and that each formulation consists of a single homogenous amorphous phase of Itraconazole and HPMCP-HP50 and/or soluplus.