Spatial Characterization of Hot Melt Extruded Dispersion Systems Using Thermal Atomic Force Microscopy Methods: The Effects of Processing Parameters on Phase Separation

• Published in: Pharmaceutical research 2014-07, Vol.31 (7), p.1744-1752
• Main Authors: Moffat, Jonathan G., Qi, Sheng, Craig, Duncan Q. M.
• Format: Article
• Language: English
• Subjects: Antifungal Agents - chemistry; Atomic physics; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Calorimetry, Differential Scanning; Cyclosporine - chemistry; Medical Law; Melting; Microscopy; Microscopy, Atomic Force - methods; Parameter estimation; Pharmacology/Toxicology; Pharmacy; Phase Transition; Polymethacrylic Acids - chemistry; Research Paper; Solubility; Spectroscopy, Fourier Transform Infrared; Thermal energy; Transition Temperature
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-1279-x

Purpose In this study we explore the use of nano-scale localized thermal analysis (LTA) and transition temperature microcopy (TTM) as a novel combined approach to studying phase separation in HME dispersions of cyclosporine A in Eudragit EPO. Methods Modulated temperature differential scanning calorimetry (MTDSC), attenuated total reflectance FTIR spectroscopy, nano-LTA and TTM were performed on raw materials and dispersions prepared by hot melt extrusion (HME) and spin coating. For samples prepared by HME, two mixing temperatures (110°C and 150°C) and residence times (5 and 15 min) were investigated. Results Spin coated samples showed an intermediate T g for the mixed systems consistent with molecular dispersion formation. The HME samples prepared at 110°C showed evidence of inhomogeneity using MTDSC and FTIR, while those produced at 150°C h showed evidence for the formation of a single phase system using MTDSC. The nanothermal methods, however, indicated the presence of phase separated cyclosporine A at the higher preparation temperature while the TTM was able to map regions of differing penetration temperatures, indicating the presence of compositionally inhomogeneous regions in all but the high processing temperature/high residence time samples. Conclusions TTM is a potentially important new method for studying phase separation and that such separation may remain undetected or poorly understood using conventional bulk analytical techniques.