Spatial characterization of hot melt extruded dispersion systems using thermal atomic force microscopy methods: the effects of processing parameters on phase separation

Abstract

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.

Fig. 1

(a) Reversing heat flow MTDSC thermograms and (b) ATR-FTIR spectra of cyclosporine A (solid line) and Eudragit EPO (dashed line).

Fig. 2

LTA profiles for spin coated slides consisting of Eudragit EPO (EPO), cyclosporine A (CsA) and a 50:50 mixture (Mix) of both components.

Fig. 3

MTDSC reversing heat flow profile of 50:50% w/w CsA in EPO HME dispersions prepared at 110°C (solid line) and 150°C (dashed line).

Fig. 4

ATR-FTIR spectra of HME samples composed of EPO and CsA at a ratio of 50%w/w prepared at (a) 110°C and (b) 150°C. Five sample spectra are shown on each plot from the same batch.

Fig. 5

(a) AFM topographic image of a 50% w/w CsA in EPO HME sample produced at 150°C and (b) corresponding LTA measurements acquired from locations marked with an X on (a).

Fig. 6

Transition temperature microscopy maps and corresponding histograms of 50% w/w CsA in EPO HME systems produced after a residence time of 5 min and prepared at 110°C (a and b, respectively) and 150°C (c and d, respectively). TTM map and corresponding histogram of a HME system prepared at 150°C with a residence time of 15 min (e and f, respectively).