Pharmaceutical Research

, Volume 27, Issue 9, pp 1869–1883 | Cite as

Characterisation and Prediction of Phase Separation in Hot-Melt Extruded Solid Dispersions: A Thermal, Microscopic and NMR Relaxometry Study

  • Sheng Qi
  • Peter Belton
  • Kathrin Nollenberger
  • Nigel Clayden
  • Mike Reading
  • Duncan Q. M. Craig
Research Paper



To develop novel analytical approaches for identifying both miscibility and phase separation in hot-melt extruded formulations.


Felodipine-Eudragit® E PO solid dispersions were prepared using hot-melt extrusion. The fresh and aged formulations were characterised using scanning electron microscopy, differential scanning calorimetry, heat capacity (Cp) measurements using modulated temperature DSC and nuclear magnetic resonance relaxometry.


The solubility of the drug in polymer was predicted as being ≤10% w/w using a novel model proposed in this study. Freshly prepared HME formulations were found to show no evidence for phase separation despite drug loadings greatly in excess of this figure. Conventional DSC showed limitations in directly detecting phase separation. However, a novel use of Cp measurements indicated that extensive phase separation into crystalline domains was present in all aged samples, a conclusion supported by SEM studies. The NMR relaxometry study confirmed the existence of phase separation in all aged formulations and also allowed the estimation of separated domains sizes in different formulations.


This study has presented a series of novel approaches for the identification, quantification and prediction of phase separation in HME formulations. Supersaturation of drug in the polymer caused the phase separation of the aged felodipine-Eudragit® E PO formulations.


heat capacity hot melt extrusion miscibility phase separation supersaturation 



The authors would like to thank Mr. Frederik Klama for his contribution to the NMR data collection.


  1. 1.
    Miller DA, McConville JT, Yang W, Williams III RO, McGinity JW. Hot-melt extrusion for enhanced delivery of drug particles. J Pharm Sci. 2006;96(2):361–76.CrossRefGoogle Scholar
  2. 2.
    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50(1):47–60.CrossRefPubMedGoogle Scholar
  3. 3.
    Breitenbach J. Melt extrusion: from process to drug delivery technology. Eur J Pharm Biopharm. 2002;54(2):107–17.CrossRefPubMedGoogle Scholar
  4. 4.
    Forster A, Hempenstall J, Tucker I, Rades T. Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis. Int J Pharm. 2001;226(1–2):147–61.CrossRefPubMedGoogle Scholar
  5. 5.
    Lalkshman JP, Cao Y, Kowalski J, Serajuddin ATM. Application of melt extrusion in the development of a physically and chemically stable high-energy amorphous solid dispersion of a poorly water-soluble drug. Mol Pharm. 2008;5(6):994–1002.CrossRefGoogle Scholar
  6. 6.
    Kennedy M, Hu J, Gao P, Li L, Ali-Reynolds A, Chal B, et al. Enhanced bioavailability of a poorly soluble VR1 antagonist using an amorphous solid dispersion approach: a case study. Mol Pharm. 2008;5(6):981–93.CrossRefPubMedGoogle Scholar
  7. 7.
    Albers J, Alles R, Matthée K, Knop K, Nahrup JS, Kleinebudde P. Mechanism of drug release from polymethacrylate-based extrudates and milled strands prepared by hot-melt extrusion. Eur J Pharm Biopharm. 2009;71(2):387–94.CrossRefPubMedGoogle Scholar
  8. 8.
    Hülsmann S, Backensfeld T, Keitel S, Bodmeier R. Melt extrusion—an alternative method for enhancing the dissolution rate of 17β-estradiol hemihydrate. Eur J Pharm Biopharm. 2000;49(3):237–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Shmeis RA, Wang ZR, Krill SL. A mechanistic investigation of an amorphous pharmaceutical and its solid dispersions, part II: molecular mobility and activation thermodynamic parameters. Pharm Res. 2004;21(11):2031–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Six K, Verreck G, Peeters J, Brewster M, Van den Mooter G. Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J Pharm Sci. 2004;93(1):124–31.CrossRefPubMedGoogle Scholar
  11. 11.
    Law D, Krill SL, Schmitt EA, Fort JJ, Qiu YH, Wang WL, et al. Physicochemical considerations in the preparation of amorphous ritonavir-poly(ethylene glycol) 8000 solid dispersions. J Pharm Sci. 2001;90(8):1015–25.CrossRefPubMedGoogle Scholar
  12. 12.
    Ghebremeskel AN, Vemavarapu C, Lodaya M. Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: stability testing of selected solid dispersions. Pharm Res. 2006;23(8):1928–36.CrossRefPubMedGoogle Scholar
  13. 13.
    Huang JJ, Wigent RJ, Schwartz JB. Drug-polymer interaction and its significance on the physical stability of nifedipine amorphous dispersion in microparticles of an ammonio methacrylate copolymer and ethylcellulose binary blend. J Pharm Sci. 2008;97(1):251–62.CrossRefPubMedGoogle Scholar
  14. 14.
    Taubner V, Shishoo R. Influence of processing parameters on the degradation of poly(L-lactide) during extrusion. J Appl Polym Sci. 2001;79:128–2135.CrossRefGoogle Scholar
  15. 15.
    Sarraf AG, Tissot H, Tissot P, Alfonso D, Gurny R, Doelker E. Influence of hot-melt extrusion and compression molding on polymer structure organization. Investigated by Differential Scanning Calorimetry. J Appl Polym Sci. 2001;81:3124–32.CrossRefGoogle Scholar
  16. 16.
    Andrews GP, Jones DS, Diak OA, McCoy CP, Watts AB, McGinity JW. The manufacture and characterisation of hot-melt extruded enteric tablets. Eur J Pharm Biopharm. 2008;69:264–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Bikiaris D, Papageorgiou GZ, Stergiou A, Pavlidou E, Karavas E, Kanaze F, et al. Physicochemical studies on solid dispersions of poorly water-soluble drugs: evaluation of capabilities and limitations of thermal analysis techniques. Thermochim Acta. 2005;439:58–67.CrossRefGoogle Scholar
  18. 18.
    Qi S, Gryczke A, Belton P, Craig DQM. Characterisation of solid dispersions of paracetamol and EUDRAGIT® E prepared by hot-melt extrusion using thermal, microthermal and spectroscopic analysis. Int J Pharm. 2008;354(1–2):158–67.CrossRefPubMedGoogle Scholar
  19. 19.
    Aso Y, Yoshioka S, Miyazaki T, Kawanishi T, Tanaka K, Kitamura S, et al. Miscibility of nifedipine and hydrophilic polymers as measured by 1H-NMR spin-lattice relaxation. Chem Pharm Bull. 2007;55(8):1227–31.CrossRefPubMedGoogle Scholar
  20. 20.
    Gao C, Stading M, Wellner N, Parker ML, Noel TR, Mills CEN, et al. Plasticization of a protein-based film by glycerol: a spectroscopic, mechanical, and thermal study. J Agr Food Chem. 2006;54(13):4611–6.CrossRefGoogle Scholar
  21. 21.
    Belton PS, Hills BP. The effects of diffusive exchange in heterogeneous systems on N.M.R. line shapes and relaxation processes. Mol Phys. 1987;61:999–1018.CrossRefGoogle Scholar
  22. 22.
    Nishi T, Wang TT. Melting-point depression and kinetic effects of cooling on crystallisation in poly (vinylidene fluoride) poly (methyl methacrylate) mixtures. Macromolecules. 1975;8:909–15.CrossRefGoogle Scholar
  23. 23.
    Meaurio E, Zuza E, Sarasua JR. Miscibility and specific interactions in blends of poly (L-lactide) with poly(vinylphenol). Macromolecules. 2005;38:1207–15.CrossRefGoogle Scholar
  24. 24.
    Marsac PJ, Shamblin SL, Taylor LS. Theoretical and practical approaches for prediction of drug-polymer miscibility and solubility. Pharm Res. 2006;23(10):2417–26.CrossRefPubMedGoogle Scholar
  25. 25.
    Theeuwes F, Hussain A, Higuchi T. Quantitative analytical method for determination of drugs dispersed in polymers using differential scanning calorimetry. J Pharm Sci. 1974;63(3):427–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Gramaglia D, Conway BR, Kett VL, Malcolm RK, Batchelor HK. High speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a solid or semi-solid matrix. Int J Pharm. 2005;301:1–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Craig DQM, Newton JM. Characterisation of polyethylene glycol solid dispersions using differential scanning calorimetry and solution calorimetry. Int J Pharm. 1991;76:17–24.CrossRefGoogle Scholar
  28. 28.
    Reading M, Craig DQM, Murphy JR, Kett VL. Modulated temperature differential scanning calorimetry. In: Craig DQM, Reading M, editors. Thermal analysis of pharmaceuticals. London: CRC; 2007. p. 103–29.Google Scholar
  29. 29.
    Srčič S, Kerč J, Urleb U, Zupančič I, Lahajnar G, Kofler B, et al. Investigation of felodipine polymorphism and its glassy state. Int J Pharm. 1992;87:1–10.CrossRefGoogle Scholar
  30. 30.
    Parmar MM, Khan O, Seton L, Ford JL. Polymorph control of Felodipine form II in an attempted cocrystallization. Cryst Growth Des. 2009;9(3):1254–7.CrossRefGoogle Scholar
  31. 31.
    Rollinger JM, Burger A. Polymorphism of racemic felodipine and the unusual series of solid solutions in the binary system of its enantiomers. J Pharm Sci. 2001;90:949–59.CrossRefPubMedGoogle Scholar
  32. 32.
    Kerč J, Srčič S, Mohar M, Smid-Korbar J. Some physico-chemical properties of glassy felodipine. Int J Pharm. 1991;68:25–33.CrossRefGoogle Scholar
  33. 33.
    Flory PJ. Principles of polymer chemistry. Ithaca: Cornell University Press; 1953. p. 563–76.Google Scholar
  34. 34.
    Matsuo T. Low temperature thermal properties of amorphous materials. Pure Appl Chem. 1998;70(3):599–602.CrossRefGoogle Scholar
  35. 35.
    Xu H, Cebe P. Heat capacity study of isotactic polystyrene: dual reversible crystal melting and relaxation of rigid amorphous fraction. Macromolecules. 2004;37(8):2797–806.CrossRefGoogle Scholar
  36. 36.
    McBrierty VJ, Packer KJ. Nuclear magnetic resonance in solid polymers. Cambridge: Cambridge University Press; 1993. p. 52–78.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sheng Qi
    • 1
  • Peter Belton
    • 2
  • Kathrin Nollenberger
    • 3
  • Nigel Clayden
    • 2
  • Mike Reading
    • 1
  • Duncan Q. M. Craig
    • 1
  1. 1.School of PharmacyUniversity of East AngliaNorwichUK
  2. 2.School of ChemistryUniversity of East AngliaNorwichUK
  3. 3.Evonik Röhm GmbHDarmstadtGermany

Personalised recommendations