Skip to main content
SpringerLink
Log in

Manufacture of Pharmaceutically Relevant Materials by Mechanochemistry Using Twin Screw Extrusion

  • Chapter
  • First Online:
Melt Extrusion

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

Abstract

Mechanochemistry broadly refers to the class of chemical reactions that are induced by the application of mechanical force. In the context of pharmaceutical materials, mechanochemistry has been described in the literature for the preparation of cocrystals, salts, and amorphous complexes. In almost all these examples, laboratory-scale mills have been used to demonstrate the production of the aforementioned materials. While laboratory-scale mills demonstrate the utility of the mechanochemical concept, they typically produce small quantities of material and are not considered scalable processes. In this chapter, the application of twin-screw extrusion (TSE) in the production of cocrystals, salts, and amorphous complexes is described. Unlike other mechanical mixing procedures, TSE is a continuous process and lends itself to scalability. TSE can be considered an efficient, scalable, and environmentally friendly process for the consistent manufacture of pharmaceutically relevant systems.

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

References

  • Andrews GP, Jones DS, Diak OA, McCoy CP, Watts AB, McGinity JW (2008) The manufacture and characterisation of hot-melt extruded enteric tablets. Eur J Pharm Biopharm 69:264–273

    Article  PubMed  CAS  Google Scholar 

  • Bahl D, Bogner RH (2006) Amorphization of indomethacin by co-grinding with neusilin US2: amorphization kinetics, physical stability and mechanism. Pharm Res 23:2317–2325

    Article  PubMed  CAS  Google Scholar 

  • Bahl D, Hudak J, Bogner RH (2008) Comparison of the ability of various pharmaceutical silicates to amorphize and enhance dissolution of indomethacin upon co-grinding. Pharm Dev Technol 13:255–269

    Article  PubMed  CAS  Google Scholar 

  • Beyer MK, Clausen-Schaumann H (2005) Mechanochemistry: the mechanical activation of covalent bonds. Chem Rev 105:2921–2948

    Article  PubMed  CAS  Google Scholar 

  • Bond AD (2007) What is a co-crystal? Cryst Eng Comm 9:833–834

    Article  CAS  Google Scholar 

  • Chen AM, Ellison ME, Peresypkin A, Wenslow RM, Variankaval N, Savarin CG, Natishan TK, Mathre DJ, Dormer PG, Euler DH, Ball RG, Ye Z, Wang Y, Santos I (2007) Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid. Chem Commun (Camb) 28(4):419–421

    Article  Google Scholar 

  • Childs SL, Chyall LJ, Dunlap JT, Smolenskaya VN, Stahly BC, Stahly GP (2004) Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids. J Am Chem Soc 126:13335–13342

    Article  PubMed  CAS  Google Scholar 

  • Chokshi RJ, Shah NH, Sandhu HK, Malick AW, Zia H (2008) Stabilization of low glass transition temperature indomethacin formulations: impact of polymer-type and its concentration. J Pharm Sci 97:2286–2298

    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 

  • Daurio D, Medina C, Saw R, Nagapudi K, Alvarez-Nunez F (2011) Application of twin screw extrusion in the manufacture of cocrystals, part I: four case studies. Pharmaceutics 3:582–600

    Article  CAS  Google Scholar 

  • Delori A, Friscic T, Jones W (2012) The role of mechanochemistry and supramolecular design in the development of pharmaceutical materials. Cryst Eng Comm 14:2350–2362

    Article  CAS  Google Scholar 

  • Desiraju GR (2003) Crystal and co-crystal. Cryst Eng Comm 5:466–467

    Article  CAS  Google Scholar 

  • Di Nunzio JC, Brough C, Hughey JR, Miller DA, Williams RO III, McGinity JW (2010) Fusion production of solid dispersions containing a heat-sensitive active ingredient by hot melt extrusion and Kinetisol dispersing. Eur J Pharm Biopharm 74:340–351

    Article  CAS  Google Scholar 

  • Dunitz JD (2003) Crystal and co-crystal. A second opinion. Cryst Eng Comm 5:506

    Article  CAS  Google Scholar 

  • Friscic T, Jones W (2012) Application of mechanochemistry in the synthesis and discovery of new pharmaceutical forms: co-crystals, salts and coordination compounds. RSC Drug Discovery Series 16:154–187

    CAS  Google Scholar 

  • Friscic T, Trask AV, Jones W, Motherwell WDS (2006) Screening for inclusion compounds and systematic construction of three-component solids by liquid-assisted grinding. Angew Chem Int Ed 45:7546–7550

    Article  CAS  Google Scholar 

  • Ghosh I, Snyder J, Vippagunta R, Alvine M, Vakil R, Tong W-Q, Vippagunta S (2011) Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder. Int J Pharm 419:12–19

    Article  PubMed  CAS  Google Scholar 

  • Gupta MK, Vanwert A, Bogner RH (2003) Formation of physically stable amorphous drugs by milling with neusilin. J Pharm Sci 2(92):536–551

    Article  Google Scholar 

  • Hasa D, Perissutti B, Grassi M, Zacchigna M, Pagotto M, Lenaz D, Kleinebudde P, Voinovich D (2011a) Melt extruded helical waxy matrices as a new sustained drug delivery system. Eur J Pharm Biopharm 79:592–600

    Article  CAS  Google Scholar 

  • Hasa D, Voinovich D, Perissutti B, Grassi M, Bonifacio A, Sergo V, Cepek C, Chierotti MR, Gobetto R, Dall’Acqua S, Invernizzi S (2011b) Enhanced oral bioavailability of vinpocetine through mechanochemical salt formation: physico-chemical characterization and in vivo studies. Pharm Res 28:1870–1883

    Article  CAS  Google Scholar 

  • James SL, Adams CJ, Bolm C, Braga D, Collier P, Friscic T, Grepioni F, Harris KDM, Hyett G, Jones W, Krebs A, Mack J, Maini L, Orpen AG, Parkin IP, Shearouse WC, Steed JW, Waddell DC (2012) Mechanochemistry: opportunities for new and cleaner synthesis. Chem Soc Rev 41:413–447

    Article  PubMed  CAS  Google Scholar 

  • Janssens S, Armas HN de, D’Autry W, Van Schepdael A, Van den Mooter G (2008) Characterization of ternary solid dispersions of Itraconazole in polyethylene glycol 6000/polyvidone-vinylacetate 64 blends. Eur J Pharm Biopharm 69:1114–1120

    Article  PubMed  CAS  Google Scholar 

  • Janssens S, De Zeure A, Paudel A, Van Humbeeck J, Rombaut P, Van den Mooter G (2010) Influence of preparation methods on solid state supersaturation of amorphous solid dispersions: a case study with itraconazole and eudragit e100. Pharm Res 27:775–785

    Article  PubMed  CAS  Google Scholar 

  • Jayasankar A, Somwangthanaroj A, Shao ZJ, Rodriguez-Hornedo N (2006) Cocrystal formation during cogrinding and storage is mediated by amorphous phase. Pharm Res 23:2381–2392

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Karki S, Friscic T, Jones W, Motherwell WDS (2007) Screening for Pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding. Mol Pharm 4:347–354

    Article  PubMed  CAS  Google Scholar 

  • Kennedy M, Hu J, Gao P, Li L, Ali-Reynolds A, Chal B, Gupta V, Ma C, Mahajan N, Akrami A, Surapaneni S (2008) enhanced bioavailability of a poorly soluble VR1 antagonist using an amorphous solid dispersion approach: a case study. Mol Pharm 5:981–993

    Article  PubMed  CAS  Google Scholar 

  • Kinoshita M, Baba K, Nagayasu A, Yamabe K, Shimooka T, Takeichi YI, Azuma M, Houchi H, Minakuchi K (2002) Improvement of solubility and oral bioavailability of a poorly water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate. J Pharm Sci 91:362–370

    Article  PubMed  CAS  Google Scholar 

  • Konno H, Handa T, Alonzo DE, Taylor LS (2008) Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur J Pharm Biopharm 70:493–499

    Article  PubMed  CAS  Google Scholar 

  • Law D, Schmitt EA, Marsh KC, Everitt EA, Wang W, Fort JJ, Krill SL, Qiu Y (2004) Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J Pharm Sci 93:563–570

    Article  PubMed  CAS  Google Scholar 

  • Lyons JG, Hallinan M, Kennedy JE, Devine DM, Geever LM, Blackie P, Higginbotham CL (2007) Preparation of monolithic matrices for oral drug delivery using a supercritical fluid assisted hot melt extrusion process. Int J Pharm 329:62–71

    Article  PubMed  CAS  Google Scholar 

  • MacLean J, Medina C, Daurio D, Alvarez-Nunez F, Jona J, Munson E, Nagapudi K (2011) Manufacture and performance evaluation of a stable amorphous complex of an acidic drug molecule and neusilin. J Pharm Sci 100:3332–3344

    Article  PubMed  CAS  Google Scholar 

  • Mallick S, Pattnaik S, Swain K, De PK, Saha A, Ghoshal G, Mondal A (2008) Formation of physically stable amorphous phase of ibuprofen by solid state milling with kaolin. Eur J Pharm Biopharm 68:346–351

    Article  PubMed  CAS  Google Scholar 

  • Maniruzzaman M, Boateng JS, Bonnefille M, Aranyos A, Mitchell JC, Douroumis D (2012) Taste masking of paracetamol by hot-melt extrusion: an in vitro and in vivo evaluation. Eur J Pharm Biopharm 80:433–442

    Article  PubMed  CAS  Google Scholar 

  • Medina C, Daurio D, Nagapudi K, Alvarez-Nunez F (2010) Manufacture of pharmaceutical co-crystals using twin screw extrusion: a solvent-less and scalable process. J Pharm Sci 99:1693–1696

    PubMed  CAS  Google Scholar 

  • Miyazaki T, Yoshioka S, Aso Y, Kojima S (2004) Ability of polyvinylpyrrolidone and polyacrylic acid to inhibit the crystallization of amorphous acetaminophen. J Pharm Sci 93:2710–2717

    Article  PubMed  CAS  Google Scholar 

  • Porter WW III, Elie SC, Matzger AJ (2008) Polymorphism in carbamazepine cocrystals. Cryst Growth Des 8:14–16

    Article  PubMed  CAS  Google Scholar 

  • Remenar JF, Morissette SL, Peterson ML, Moulton B, MacPhee JM, Guzman HR, Almarsson O (2003) Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids. J Am Chem Soc 125:8456–8457

    Article  PubMed  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 

  • Roblegg E, Jaeger E, Hodzic A, Koscher G, Mohr S, Zimmer A, Khinast J (2011) Development of sustained-release lipophilic calcium stearate pellets via hot melt extrusion. Eur J Pharm Biopharm 79:635–645

    Article  PubMed  CAS  Google Scholar 

  • Rumondor ACF, Marsac PJ, Stanford LA, Taylor LS (2009) Phase behavior of poly(vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture. Mol Pharm 6:1492–1505

    Article  PubMed  CAS  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 (2007) Salt formation to improve drug solubility. Adv Drug Delivery Rev 59:603–616

    Article  CAS  Google Scholar 

  • Serajuddin ATM, Pudipeddi M (2011) Salt-selection strategies. In: Stahl PH, Wermuth G (Eds.) Handbook of pharmaceutical salts 2nd edn. Wiley, New York.

    Google Scholar 

  • Trask AV, Motherwell WDS, Jones W (2004) Solvent-drop grinding: green polymorph control of cocrystallisation. Chem Commun (Camb) (7):890–891

    Google Scholar 

  • Trask AV, Haynes DA, Motherwell WDS, Jones W (2006a) Screening for crystalline salts via mechanochemistry. Chem Commun (Camb) (1):51–53

    Google Scholar 

  • Trask AV, Motherwell WDS, Jones W (2006b) Physical stability enhancement of theophylline via cocrystallization. Int J Pharm 320:114–123

    Article  CAS  Google Scholar 

  • Variankaval N, Wenslow R, Murry J, Hartman R, Helmy R, Kwong E, Clas S-D, Dalton C, Santos I (2006) Preparation and solid-state characterization of nonstoichiometric cocrystals of a phosphodiesterase-IV inhibitor and L-tartaric acid. Cryst Growth Des 6:690–700

    Article  CAS  Google Scholar 

  • Watanabe T, Hasegawa S, Wakiyama N, Kusai A, Senna M (2002a) Prediction of apparent equilibrium solubility of indomethacin compounded with silica by 13C solid state NMR. Int J Pharm 248:123–129

    Article  CAS  Google Scholar 

  • Watanabe T, Hasegawa S, Wakiyama N, Usui F, Kusai A, Isobe T, Senna M (2002b) Solid state radical recombination and charge transfer across the boundary between indomethacin and silica under mechanical stress. J Solid State Chem 164:27–33

    Article  CAS  Google Scholar 

  • Wermuth CG, Stahl PH (2011) Selected procedures for the preparation of pharmaceutically acceptable salts. In: Stahl PH, Wermuth G. (Eds.) Handbook of pharmaceutical salts 2nd edn. Wiley, New York.

    Google Scholar 

  • Windbergs M, Strachan CJ, Kleinebudde P (2009) Tailor-made dissolution profiles by extruded matrices based on lipid polyethylene glycol mixtures. J Control Release 137:211–216

    Article  PubMed  CAS  Google Scholar 

  • Yu L (2001) Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Delivery Rev 48:27–42

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank Cesar Medina, Jennifer Maclean, and Robert Saw for conducting some of the experiments described in this chapter. We wish to acknowledge Francisco Alvarez for providing the management support to conduct this research. We also wish to thank to following people for numerous contributions to this chapter: Julie Calahan, Kim Gochioco, Janan Jona, Chandra Ma, Eric Munson, Matt Peterson, Saroj Vangani, and Tian Wu.

Author information

Authors and Affiliations

  1. Pharmaceutical R&D, Small Molecule Process and Product Development, Amgen Inc., Thousand Oaks, CA, USA

    Dominick Daurio, Karthik Nagapudi & Fernando Alvarez-Núñez

Authors
  1. Dominick Daurio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karthik Nagapudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fernando Alvarez-Núñez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fernando Alvarez-Núñez .

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

Daurio, D., Nagapudi, K., Alvarez-Núñez, F. (2013). Manufacture of Pharmaceutically Relevant Materials by Mechanochemistry Using Twin Screw 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_9

Download citation

Publish with us

Policies and ethics

Search

Navigation