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
- 539 Downloads
To characterise phase separations in aged hot-melt-extruded solid dispersions at a micron to submicron scale.
Hot-melt-extruded felodipine and Eudragit® E PO systems at a range of compositions were studied after a standard period of aging to allow phase separation to occur. The samples were characterised using combined nano-thermal analysis, photothermal FTIR microspectroscopy coupled with pulsed force mode AFM as a novel characterisation approach.
Crystalline felodipine presents in all formulations with drug loadings from 10–70% (w/w). In formulations with high drug loadings (50 and 70%), amorphous felodipine co-exists with crystalline forms, and higher drug concentration is observed in the centre compared to the outer surface of the extrudates. Drug crystal dimensions in extrudates with low drug loadings (10–30%) are small, in the micron to submicron range. We propose that uneven drug distribution is principally caused by processing-associated factors such as expansion of extrudates during extrusion.
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.
KEY WORDShot-melt-extruded solid dispersion phase separation photothermal FTIR microspectroscopy pulsed force mode atomic force microscopy supersaturation
The authors would like to thank Dr. Jonathon Moffat and Prof. Mike Reading for their assistance on the use of PT-FTIR microspectroscopy.
- 8.Dai X, Moffat JG, Mayes AG, Reading M, Craig DQM, Belton PS, et al. Thermal probe based analytical microscopy: thermal analysis and photothermal fourier-transform infrared microspectroscopy together with thermally assisted nanosampling coupled with capillary electrophoresis. Analy Chem. 2009;81(16):6612–9.CrossRefGoogle Scholar
- 21.Tang XC, Pikal MJ, Taylor LS. A spectroscopic investigation of hydrogen bond patterns in crystalline and amorphous phases in dihydropyridine calcium channel blockers. Pharm Res. 2002;19(4):447–83.Google Scholar
- 24.Marti O, Stifter T, Waschipky H, Quintus M, Hild S. Scanning probe microscopy of heterogeneous polymers, colloids surf. A. 1999;154(1–2):65–73.Google Scholar
- 29.Grandy DB, Hourston DJ, Price DM, Reading M, Silva GG, Song M, et al. Microthermal characterization of segmented polyurethane elastomers and a polystyrene-poly(methyl methacrylate) polymer blend using variable-temperature pulsed force mode atomic force microscopy. Macromolecules. 2000;33(25):9348–59.CrossRefGoogle Scholar
- 32.Zhu M, Akari S, Mohwald H. Detection of single PSS polymers on rough surface by pulsed-force-mode scanning force microscopy. Nanoletters. 2001;1:569–73.Google Scholar
- 37.Mullin JM. Crystallization. 4th ed. Oxford: Elsevier Butterworth-Heinemann; 2001.Google Scholar