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Molecular Indicators of Surface and Bulk Instability of Hot Melt Extruded Amorphous Solid Dispersions

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ABSTRACT

Purpose

To identify molecular indicators of bulk and surface instabilities of amorphous dispersions prepared by hot melt extrusion.

Methods

Four model drugs with different physicochemical properties were formulated with EUDRAGIT® E PO using hot melt extrusion. Samples were aged under a range of conditions for up to 6 months and characterized using SEM, ATR-FTIR, PXRD and MTDSC. The effects of a range of thermodynamic, kinetic and molecular parameters, including glass transition temperature, molecular mobility, the crystallization tendency of the amorphous drug and drug-polymer miscibility, on the bulk and surface stabilities of the solid dispersions were evaluated.

Results

For all drug-containing systems, a higher degree of instability was observed at the surface of the material in comparison to the bulk. Stressed humidity showed a more profound effect on the dispersions in comparison to stress temperature, reducing both their surface and bulk stabilities. For supersaturated systems the order of the bulk and surface instabilities of the samples was found following the same order of the molecular mobilities of the amorphous model drugs. This was attributed to the presence of phase separation of amorphous drug-rich domains in the supersaturated extrudates.

Conclusions

The stability of the amorphous drug-rich domains appears to be governed by the physical stabilities of the amorphous drugs. The more commonly used indicators such as Tg, fragility of the amorphous drug and the theoretically predicted drug-polymer solubility showed less influence on the bulk and surface stabilities of the extrudates in comparison to the molecular mobility of the amorphous drug.

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REFERENCES

  1. Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88:1058–66.

    Article  CAS  PubMed  Google Scholar 

  2. Leunerand C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60.

    Article  Google Scholar 

  3. Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48:27–42.

    Article  CAS  PubMed  Google Scholar 

  4. 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;354:158–67.

    Article  CAS  PubMed  Google Scholar 

  5. Qi S, Belton P, Nollenberger K, Clayden N, Reading M, Craig DM. Characterisation and prediction of phase separation in hot-melt extruded solid dispersions: a thermal. Microscopic and NMR Relaxometry Study. Pharm Res. 2010;27:1869–83.

    Article  CAS  PubMed  Google Scholar 

  6. Hancock B, Shamblin S, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm Res. 1995;12:799–806.

    Article  CAS  PubMed  Google Scholar 

  7. Marsac P, Shamblin S, Taylor L. Theoretical and practical approaches for prediction of drug–polymer miscibility and solubility. Pharm Res. 2006;23:2417–26.

    Article  CAS  PubMed  Google Scholar 

  8. Marsac P, Li T, Taylor L. Estimation of drug–polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2009;26:139–51.

    Article  CAS  PubMed  Google Scholar 

  9. Qi S, Craig DM. Detection of phase separation in hot melt extruded solid dispersion formulations global vs. localized characterization. Am Pharm Rev. 2010;13:68–74.

    CAS  Google Scholar 

  10. Qian F, Huang J, Hussain MA. Drug–polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci. 2010;99:2941–7.

    CAS  PubMed  Google Scholar 

  11. Rumondorand ACF, Taylor LS. Effect of polymer hygroscopicity on the phase behavior of amorphous solid dispersions in the presence of moisture. Mol Pharm. 2009;7:477–90.

    Article  Google Scholar 

  12. Mahieu A, Willart J-F, Dudognon E, Danède F, Descamps M. A new protocol to determine the solubility of drugs into polymer matrixes. Mol Pharm. 2012;10:560–6.

    Article  Google Scholar 

  13. Yang Z, Nollenberger K, Albers J, Qi S. Molecular implications of drug–polymer solubility in understanding the destabilization of solid dispersions by milling. Mol Pharm. 2014;11:2453–65.

    Article  CAS  PubMed  Google Scholar 

  14. Hancockand BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86:1–12.

    Article  Google Scholar 

  15. Ng YC, Yang Z, McAuley WJ, Qi S. Stabilisation of amorphous drugs under high humidity using pharmaceutical thin films. Eur J Pharm Biopharm. 2013;84:555–65.

    Article  CAS  PubMed  Google Scholar 

  16. Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, Zhang F, et al. Pharmaceutical applications of hot-melt extrusion: part II. Drug Dev Ind Pharm. 2007;33:1043–57.

    Article  CAS  PubMed  Google Scholar 

  17. Kalivoda A, Fischbach M, Kleinebudde P. Application of mixtures of polymeric carriers for dissolution enhancement of fenofibrate using hot-melt extrusion. Int J Pharm. 2012;429:58–68.

    Article  CAS  PubMed  Google Scholar 

  18. Maniruzzaman M, Rana MM, Boateng JS, Mitchell JC, Douroumis D. Dissolution enhancement of poorly water-soluble APIs processed by hot-melt extrusion using hydrophilic polymers. Drug Dev Ind Pharm. 2013;39:218–27.

    Article  CAS  PubMed  Google Scholar 

  19. Ke P, Hasegawa S, Al-Obaidi H, Buckton G. Investigation of preparation methods on surface/bulk structural relaxation and glass fragility of amorphous solid dispersions. Int J Pharm. 2012;422:170–8.

    Article  CAS  PubMed  Google Scholar 

  20. Qi S, Moffat JG, Yang Z. Early stage phase separation in pharmaceutical solid dispersion thin films under high humidity: improved spatial understanding using probe-based thermal and spectroscopic nanocharacterization methods. Mol Pharm. 2013;10:918–30.

    Article  CAS  PubMed  Google Scholar 

  21. Yang Z, Nollenberger K, Albers J, Moffat JG, Craig DQM, Qi S. The effect of processing on the surface physical stability of amorphous solid dispersions. Eur J Pharm Biopharm. 2014. Accepted.

  22. Nishiand T, Wang TT. Melting point depression and kinetic effects of cooling on crystallization in poly(vinylidene fluoride)-poly(methyl methacrylate) mixtures. Macromolecules. 1975;8:909–15.

    Article  Google Scholar 

  23. Andronisand V, Zografi G. The molecular mobility of supercooled amorphous indomethacin as a function of temperature and relative humidity. Pharm Res. 1998;15:835–42.

    Article  Google Scholar 

  24. Yoshioka M, Hancock BC, Zografi G. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J Pharm Sci. 1994;83:1700–5.

    Article  CAS  PubMed  Google Scholar 

  25. Qi S, Avalle P, Saklatvala R, Craig DQM. An investigation into the effects of thermal history on the crystallisation behaviour of amorphous paracetamol. Eur J Pharm Biopharm. 2008;69:364–71.

    Article  CAS  PubMed  Google Scholar 

  26. Zhou D, Zhang GGZ, Law D, Grant DJW, Schmitt EA. Thermodynamics, molecular mobility and crystallization kinetics of amorphous griseofulvin. Mol Pharm. 2008;5:927–36.

    Article  CAS  PubMed  Google Scholar 

  27. Hodge IM. Strong and fragile liquids — a brief critique. J Non-Cryst Solids. 1996;202:164–72.

    Article  CAS  Google Scholar 

  28. Bhattacharyaand S, Suryanarayanan R. Local mobility in amorphous pharmaceuticals—characterization and implications on stability. J Pharm Sci. 2009;98:2935–53.

    Article  Google Scholar 

  29. Baird JA, Van Eerdenbrugh B, Taylor LS. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J Pharm Sci. 2010;99:3787–806.

    Article  CAS  PubMed  Google Scholar 

  30. Van Eerdenbrugh B, Baird JA, Taylor LS. Crystallization tendency of active pharmaceutical ingredients following rapid solvent evaporation—classification and comparison with crystallization tendency from undercooled melts. J Pharm Sci. 2010;99:3826–38.

    PubMed  Google Scholar 

  31. Surana R, Pyne A, Suryanarayanan R. Effect of aging on the physical properties of amorphous trehalose. Pharm Res. 2004;21:867–74.

    Article  CAS  PubMed  Google Scholar 

  32. Floryand PJ, Krigbaum WR. Thermodynamics of high polymer solutions. Annu Rev Phys Chem. 1951;2:383–402.

    Article  Google Scholar 

  33. Rustichelli C, Gamberini G, Ferioli V, Gamberini MC, Ficarra R, Tommasini S. Solid-state study of polymorphic drugs: carbamazepine. J Pharm Biomed Anal. 2000;23:41–54.

    Article  CAS  PubMed  Google Scholar 

  34. Grzesiak AL, Lang M, Kim K, Matzger AJ. Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I. J Pharm Sci. 2003;92:2260–71.

    Article  CAS  PubMed  Google Scholar 

  35. Avrami M. Kinetics of phase change. I General theory. J Chem Phys. 1939;7:1103–12.

    Article  CAS  Google Scholar 

  36. Chawla G, Gupta P, Thilagavathi R, Chakraborti AK, Bansal AK. Characterization of solid-state forms of celecoxib. Eur J Pharm Sci. 2003;20:305–17.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

Ziyi Yang would like to thank Evonik for the financial support for the period of his PhD. The authors also would like to acknowledge the contribution of members of the Interreg IV A project funded by the European Union.

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Authors and Affiliations

  1. School of Pharmacy, University of East Anglia, Norwich, Norfolk, UK, NR4 7TJ

    Ziyi Yang & Sheng Qi

  2. Evonik Industries AG, Kirschenallee, Darmstadt, Germany

    Kathrin Nollenberger & Jessica Albers

  3. School of Pharmacy, University College London, 29-39 Brunswick Square, London, UK, WC1N 1AX

    Ziyi Yang & Duncan Craig

Authors
  1. Ziyi Yang
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  2. Kathrin Nollenberger
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  3. Jessica Albers
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  4. Duncan Craig
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  5. Sheng Qi
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Corresponding author

Correspondence to Sheng Qi.

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Yang, Z., Nollenberger, K., Albers, J. et al. Molecular Indicators of Surface and Bulk Instability of Hot Melt Extruded Amorphous Solid Dispersions. Pharm Res 32, 1210–1228 (2015). https://doi.org/10.1007/s11095-014-1527-8

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  • DOI: https://doi.org/10.1007/s11095-014-1527-8

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