title: 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: OBJECTIVE
  To characterise phase separations in aged hot-melt-extruded solid dispersions at a micron to submicron scale.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: School of Pharmacy, University of East Anglia, Norwich, Norfolk NR47TJ, UK. sheng.qi@uea.ac.uk
authors: Sheng
authors: S
authors: Qi
authors: Peter
authors: P
authors: Belton
authors: Kathrin
authors: K
authors: Nollenberger
authors: Andreas
authors: A
authors: Gryczke
authors: Duncan Q M
authors: DQ
authors: Craig
references: J Pharm Sci. 2007 Feb;96(2):361-76
references: 17075869
references: J Pharm Sci. 2009 Apr;98(4):1499-510
references: 18752293
references: Anal Chem. 2009 Aug 15;81(16):6612-9
references: 20337375
references: J Pharm Sci. 2006 Dec;95(12):2692-705
references: 16892209
references: J Pharm Sci. 2006 Dec;95(12):2645-56
references: 16924685
references: Drug Dev Ind Pharm. 2007 Sep;33(9):909-26
references: 17891577
references: J Pharm Sci. 2008 Aug;97(8):3207-21
references: 17990307
references: J Microsc. 2004 Feb;213(2):129-34
references: 14731294
references: J Control Release. 2002 Aug 21;82(2-3):309-17
references: 12175745
references: Int J Pharm. 2008 Apr 16;354(1-2):158-67
references: 18242020
references: Pharm Res. 2009 Dec;26(12):2599-606
references: 19806435
references: Int J Pharm. 2008 Apr 16;354(1-2):149-57
references: 18162342
references: Int J Pharm. 2007 Aug 16;341(1-2):162-72
references: 17524578
references: Eur J Pharm Biopharm. 2002 Sep;54(2):107-17
references: 12191680
references: Langmuir. 2009 Sep 1;25(17):9938-46
references: 19705889
references: J Pharm Sci. 2001 Jul;90(7):949-59
references: 11458342
references: Pharm Res. 2010 Sep;27(9):1869-83
references: 20585845
references: Pharm Res. 2005 Mar;22(3):440-8
references: 15835750
references: Pharm Res. 2006 Oct;23(10):2333-49
references: 17021963
references: Pharm Res. 2002 Apr;19(4):477-83
references: 12033383
references: Anal Chem. 2010 Jan 1;82(1):91-7
references: 19957959