Skip to main content
SpringerLink
Log in

Formulation Development of Amorphous Solid Dispersions Prepared by Melt Extrusion

  • Chapter
  • First Online:
Melt Extrusion

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 9))

Abstract

Amorphous systems have been applied effectively in the pharmaceutical industry for a number of commercial and developmental products, although they are still considered a choice of last resort to enable therapy because of the metastable nature of the drug product. Of the technologies for preparing amorphous dispersions, melt extrusion is considered a highly effective and cost-efficient platform that is the primary technology for many major pharmaceutical companies. Successful development of melt-extruded amorphous dispersions requires strong understanding of formulation and process to produce a system having the necessary product attributes. As a result of the complexity associated with formulation research, a structured approach for amorphous formulation design is necessary to ensure that major development criteria are satisfied. This chapter discusses the fundamental aspects for formulation development of melt-extruded systems, the interplay of formulation with manufacturing process, and a structured design approach to turn molecules into medicines using melt extrusion.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    Assuming reaction rate doubles for every 10 °C temperature increase.

References

  • Aharoni SM (1998) Increased glass transition temperature in motionally constrained semicrystalline polymers. Polym Adv Technol 9:169–201

    Article  CAS  Google Scholar 

  • Albers J, Matthée K, Knop K, Kleinebudde P (2011) Evaluation of predictive models for stable solid solution formation. J Pharm Sci 100:667–680

    Article  PubMed  CAS  Google Scholar 

  • Alonzo DE, Zhang GGZ, Zhou D, Gao Y, Taylor LS (2010) Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res 27:608–618

    Article  PubMed  CAS  Google Scholar 

  • Angell CA (1995) Formation of glass from liquids and biopolymers. Science 267:1924–1935

    Article  PubMed  CAS  Google Scholar 

  • Angell CA (2002) Liquid fragility and the glass transition in water and aqueous solutions. Chem Rev 102:2627–2650

    Article  PubMed  CAS  Google Scholar 

  • Bigert M, Smith-Goettler B (2011) PAT to support the hot melt extrusion platform. In: 6th Annual Leistritz Pharmaceutical Extrusion Seminar. Leistritz, Clinton, NJ. p 41

    Google Scholar 

  • Breitenbach J (2002) Melt extrusion: from process to drug delivery technology. Eur J Pharm Biopharm 54:107–117

    Article  PubMed  CAS  Google Scholar 

  • Breitenbach J (2006) Melt extrusion can bring new benefits to HIV therapy: the example of Kaletra tablets. Am J Drug Deliv 4:61–64

    Article  CAS  Google Scholar 

  • Brouwers J, Brewster ME, Augustijns P (2009) Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci 98:2549–2572

    Article  PubMed  CAS  Google Scholar 

  • Chiou WL, Riegelman S (1971) Pharmaceutical applications of solid dispersion systems. J Pharm Sci 60:1281–1302

    Article  PubMed  CAS  Google Scholar 

  • Crowley MM, Zhang F, Koleng JJ, McGinity JW (2002) Stability of polyethylene oxide in matrix tablets prepared by hot-melt extrusion. BioMaterials 23:4241–4248

    Article  PubMed  CAS  Google Scholar 

  • Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Battu SK, McGinity JW, Martin C (2007) Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm 33:909–926

    Article  PubMed  CAS  Google Scholar 

  • Curatolo W (1998) Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharm Sci Technol Today 1:387–393

    Article  CAS  Google Scholar 

  • Davis ME, Brewster ME (2004) Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov 3:1023–1035

    Article  PubMed  CAS  Google Scholar 

  • DiNunzio JC, Miller DA, Yang W, McGinity JW, Williams RO (2008) Amorphous compositions using concentration enhancing polymers for improved bioavailability of itraconazole. Mol Pharm 5:968–980

    Article  PubMed  CAS  Google Scholar 

  • DiNunzio JC, Hughey JR, Brough C, Miller DA, Williams RO III, McGinity JW (2010) Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol dispersing. Drug Dev Ind Pharm 36:1064–1078

    Article  PubMed  CAS  Google Scholar 

  • DiNunzio JC, Zhang F, Martin C, McGinity JW (2012) Melt extrusion. In: Miller DA, Watts AB, Williams RO III (eds) Formulating poorly water soluble drugs. Springer, New York, NY, pp 311–362

    Chapter  Google Scholar 

  • Dong Z, Chatterji A, Sandhu H, Choi DS, Chokshi H, Shah N (2008) Evaluation of solid state properties of solid dispersions prepared by hot-melt extrusion and solvent co-precipitation. Int J Pharm 355:141–149

    Article  PubMed  CAS  Google Scholar 

  • Dreiblatt A (2003) Process design. In: Ghebre-Sellassie I, Martin C (eds) Pharmaceutical extrusion technology. Marcel Dekker, Inc., New York, pp 153–170

    Google Scholar 

  • Friesen DT, Shanker R, Crew M, Smithey D, Curatolo WJ, Nightingale JAS (2008) Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm 5:1003–1019

    Article  PubMed  CAS  Google Scholar 

  • Gao P (2012) Design and development of self-emulsifying lipid formulations for improving oral bioavailability of poorly water-soluble and lipophilic drugs. In: Miller DA, Watts AB, Williams RO III (eds) Formulating poorly water soluble drugs. Springer, New York, NY, pp 243–266

    Chapter  Google Scholar 

  • Ghebremeskel AN, Vemavarapu C, Lodaya M (2007) Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: selection of polymer–surfactant combinations using solubility parameters and testing the processability. Int J Pharm 328:119–129

    Article  PubMed  CAS  Google Scholar 

  • Greenhalgh DJ, Williams AC, Timmins P, York P (1999) Solubility parameters as predictors of miscibility in solid dispersions. J Pharm Sci 88:1182–1190

    Article  PubMed  CAS  Google Scholar 

  • Hauss DJ (2007) Oral lipid-based formulations. Adv Drug Deliv Rev 59:667–676

    Article  PubMed  CAS  Google Scholar 

  • Horspool KR, Lipinski CA (2003) Advancing new drug delivery concepts to gain the lead. Drug Deliv Technol 3:1–9

    Google Scholar 

  • Hughey JR, Williams RO (2012) Solid-state techniques for improving solubility. In: Miller DA, Watts AB, Williams RO III (eds) Formulating poorly water soluble drugs. Springer, New York, NY, pp 95–131

    Chapter  Google Scholar 

  • Hughey JR, DiNunzio JC, Bennett RC, Brough C, Miller DA, Ma H, Williams RO III, McGinity JW (2010) Dissolution enhancement of a drug exhibiting thermal and acidic decomposition characteristics by fusion processing: a comparative study of hot melt extrusion and KinetiSol dispersing. AAPS PharmSciTech 11:760–774

    Article  PubMed  CAS  Google Scholar 

  • Kanzer J, Hupfeld S, Vasskog T, Tho I, Hölig P, Mägerlein M, Fricker G, Brandl M (2010) In situ formation of nanoparticles upon dispersion of melt extrudate formulations in aqueous medium assessed by asymmetrical flow field-flow fractionation. J Pharm Biomed Anal 53:359–365

    Article  PubMed  CAS  Google Scholar 

  • Kapp SJ, Palmer PA (2003) Controls and instrumentation. In: Ghebre-Sellassie I, Martin C (eds) Pharmaceutical extrusion technology. M. Dekker, New York, pp 361–382

    Google Scholar 

  • Kwong E, Higgins J, Templeton AC (2011) Strategies for bringing drug delivery tools into discovery. Int J Pharm 412:1–7

    Article  PubMed  CAS  Google Scholar 

  • Lauer ME, Grassmann O, Siam M, Tardio J, Jacob L, Page S, Kindt JH, Engel A, Alsenz J (2010) Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions. Pharm Res 28:572–584

    Article  PubMed  Google Scholar 

  • Leuner C, Dressman J (2000) Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 50:47–60

    Article  PubMed  CAS  Google Scholar 

  • Lipinski CA (2000) Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 44:235–249

    Article  PubMed  CAS  Google Scholar 

  • Macarron R (2006) Critical review of the role of HTS in drug discovery. Drug Discov Today 11:277–279

    Article  PubMed  Google Scholar 

  • Marsac PJ, Shamblin SL, Taylor LS (2006) Theoretical and pratical approaches for prediction of drug-polymer miscibility and solubility. Pharm Res 23:2417–2426

    Article  PubMed  CAS  Google Scholar 

  • Miller D, DiNunzio J, Yang W, McGinity J, Williams R (2008) Targeted intestinal delivery of supersaturated itraconazole for improved oral absorption. Pharm Res 25:1450–1459

    Article  PubMed  CAS  Google Scholar 

  • Morales JO, Watts AB, McConville JT (2012) Mechanical particle-size reduction techniques. In: Miller DA, Watts AB, Williams III RO (eds) Formulating poorly water soluble drugs. Springer, New York, NY, pp 133–170

    Chapter  Google Scholar 

  • Moser JD, Broyles J, Liu L, Miller E, Wang M (2008a) Enhancing bioavailability of poorly soluble drugs using spray dried solid dispersions: part II. Am Pharm Rev 60–78

    Google Scholar 

  • Moser JD, Broyles J, Liu L, Miller E, Wang M (2008b) Enhancing bioavailability of poorly soluble drugs using spray dried solid dispersions: part I. Am Pharm Rev 68–71

    Google Scholar 

  • Newman A, Engers D, Bates S, Ivanisevic I, Kelly RC, Zografi G (2008) Characterization of amorphous API:polymer mixtures X-ray powder diffraction. J Pharm Sci 97:4840–4856

    Article  PubMed  CAS  Google Scholar 

  • Patterson JE, James MB, Forster AH, Lancaster RW, Butler JM, Rades T (2007) Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling. Int J Pharm 336:22–34 (2007)

    Article  PubMed  CAS  Google Scholar 

  • Puaux JP, Bozga G, Ainser A (2000) Residence time distribution in a corotating twin-screw extruder. Chem Eng Sci 55:1641–1651

    Article  CAS  Google Scholar 

  • Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, Zhang F, Martin C, McGinity JW (2007) Pharmaceutical applications of hot-melt extrusion: part II. Drug Dev Ind Pharm 33:1043–1057

    Article  PubMed  CAS  Google Scholar 

  • Schenck L, Troup GM, Lowinger M, Li L, McKelvey CA (2011) Achieving a hot melt extrusion design space for the production of solid solutions. In: am Ende DJ (ed) Chemical engineering in the pharmaceutical industry: R & D to manufacturing. Wiley, New York, NY

    Google Scholar 

  • Serajuddin ATM (1999) Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 88:1058–1066

    Article  PubMed  CAS  Google Scholar 

  • Serajuddin ATM, Sheen P-C, Mufson D, Bernstein DF, Augustine MA (1988) Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions. J Pharm Sci 77:414–417

    Article  PubMed  CAS  Google Scholar 

  • Shah N, Sandhu H, Choi DS, Kalb O, Page S, Wyttenbach N (2012) Structured development approach for amorphous systems. In: Miller DA, Watts AB, Williams RO III (eds) Formulating poorly water soluble drugs. Springer, New York, NY, pp 267–310

    Chapter  Google Scholar 

  • Six K, Leuner C, Dressman J, Verreck G, Peeters J, Blaton N, Augustijns P, Kinget R, Van den Mooter G (2002) Thermal properties of hot-stage extrudates of itraconazole and Eudragit E100. Phase separation and polymorphism. J Therm Anal Calorim 68:591–601

    Article  CAS  Google Scholar 

  • Thommes M, Baert L, Rosier J (2011) 800 mg Darunavir tablets prepared by hot melt extrusion. Pharm Dev Technol 16:645–650

    Article  PubMed  CAS  Google Scholar 

  • Van Eerdenbrugh B, Taylor LS (2010) Small scale screening to determine the ability of different polymers to inhibit drug crystallization upon rapid solvent evaporation. Mol Pharm 7:1328–1337

    Article  PubMed  CAS  Google Scholar 

  • Van Gyseghem E, Stokbroekx S, Novoa deAH, Dickens J, Vanstockem M, Baert L, Rosier J, Schueller L, Van den Mooter G (2009) Solid state characterization of the anti-HIV drug TMC114: interconversion of amorphous TMC114, TMC114 ethanolate and hydrate. Eur J Pharm Sci 38:489–497

    Article  PubMed  CAS  Google Scholar 

  • Vandecruys R, Peeters J, Verreck G, Brewster ME (2007) Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and apllications of this system to solid formulation design. Int J Pharm 342:168–175

    Article  PubMed  CAS  Google Scholar 

  • Wu C, McGinity JW (2003) Influence of methylparaben as a solid-state plasticizer on the physicochemical properties of Eudragit® RS PO hot-melt extrudates. Eur J Pharm Biopharm 56:95–100

    Article  PubMed  CAS  Google Scholar 

  • Yoshioka M, Hancock BC, Zografi G (1995) Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates. J Pharm Sci 84:983–986

    Article  PubMed  CAS  Google Scholar 

  • Zhang F, DiNunzio JC (2012) Solubilized formulations. In: Miller DA, Watts AB, Williams RO III (eds) Formulating poorly water soluble drugs. Springer, New York, NY, pp 171–208

    Chapter  Google Scholar 

  • Zhao Y, Inbar P, Chokshi H, Malick AW, Choi DS (2011) Prediction of the thermal phase diagram of amorphous solid dispersions by Flory-Huggins theory. J Pharm Sci 100:3197–3207

    Article  Google Scholar 

  • Zheng W, Jain A, Papoutsakis D, Dannenfelser R-M, Panicucci R, Garad S (2012) Selection of oral bioavailability enhancing formulations during drug discovery. Drug Dev Ind Pharm 38:235–247

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Merck & Co., Inc., Summit, NJ, USA

    James C. DiNunzio

  2. DisperSol Technologies, LLC., Austin, TX, USA

    Dave A. Miller

  3. Hoffmann-La Roche, Inc., Nutley, NJ, USA

    James C. DiNunzio

Authors
  1. James C. DiNunzio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dave A. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James C. DiNunzio .

Editor information

Editors and Affiliations

  1. Department of Pharmaceutics, University of Mississippi School of Phar National Center for Natural Products Res, University, Mississippi, USA

    Michael A. Repka

  2. Pharma Ingredients & Services, BASF Corporation, Tarrytown, New York, USA

    Nigel Langley

  3. Bridgewater, New Jersey, USA

    James DiNunzio

Rights and permissions

Reprints and permissions

Copyright information

© 2013 American Association of Pharmaceutical Scientists

About this chapter

Cite this chapter

DiNunzio, J., Miller, D. (2013). Formulation Development of Amorphous Solid Dispersions Prepared by Melt Extrusion. In: Repka, M., Langley, N., DiNunzio, J. (eds) Melt Extrusion. AAPS Advances in the Pharmaceutical Sciences Series, vol 9. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8432-5_7

Download citation

Publish with us

Policies and ethics

Search

Navigation