Compositional Analysis of Low Quantities of Phase Separation in Hot-Melt-Extruded Solid Dispersions: A Combined Atomic Force Microscopy, Photothermal Fourier-Transform Infrared Microspectroscopy, and Localised Thermal Analysis Approach

Abstract

We have demonstrated that the novel combined approach allows site-specific characterisation of the extruded systems and that drug distribution may be uneven across the extrudates, with concomitant implications for understanding stability and drug release behaviour.

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

“…Step changes in the reversing heat flow indicate the presence of a (putative) glass transition upon heating and the midpoints of the glass transition were observed at 126.1°C for CsA and 51.4°C for Eudragit EPO. These values are in good agreement with literature values (7, 9, 29) and indicate that both materials are in an amorphous form before processing by HME. However it should be emphasized that there is some uncertainty regarding the thermophysical behavior of CsA in that while some sources have attributed the heat capacity change to a glass transition (29), others have suggested that this material is liquid crystalline in nature (30).…”

“…The commonly perceived ideal structure of such systems is a molecular dispersion, as theoretically such a structure ensures an homogenous drug distribution but also predicates that the drug is in a dissolved molecular state with no lattice energy to overcome prior to dissolution. However, such dispersions are well known to phase separate into either amorphous or crystalline drug regions and a number of studies have been conducted to facilitate prediction of such instability, including thermodynamic (solubility parameter, entropic and Flory-Huggins miscibility approaches (5, 6) and phenomenological approaches using thermal, spectroscopic and imaging methods (7). It has also been suggested that phase separation may manifest as conjugate mixes of drug and polymer rather than regions of pure material (8).…”

Assessing Mixing Quality of a Copovidone-TPGS Hot Melt Extrusion Process with Atomic Force Microscopy and Differential Scanning Calorimetry

“…For example, Lauer et al have used AFM to characterize the homogeneity of drug-polymer mixtures prepared using a microhot melt extruder (16) and compared the data to dispersions prepared using a screening method involving solvent casting. Qi and Craig have utilized AFM coupled with local thermal analysis as well as photothermal Fourier-transform infrared (PT-FTIR) microspectroscopy to characterize their drug-loaded hot melt extrudates (25). These studies, among others, and our report herein demonstrate the power of AFM and related techniques to characterize the effect of processing and composition on the resulting phase behavior of hot melt extrudate for pharmaceutical applications.…”

Optimising Drug Solubilisation in Amorphous Polymer Dispersions: Rational Selection of Hot-melt Extrusion Processing Parameters

“…The amorphous FD peak was notably broadened and moderately shifted to 1645.90 cm −1 . Together with the broadening and redshift of the bonded N-H group from 3371.50 to 3334.93 cm −1 (data not shown), the interactions between C=O and N-H groups of FD molecules in the amorphous state are suggested to be stronger than that in the crystalline form (46,47). In the 10 wt% FD-EPO SD standard, this carbonyl peak exhibited a further blue shift to 1649.36 cm −1 , implying a possible bonding between heterogeneous FD and EPO molecules.…”