Melt Extrusion pp 223-242 | Cite as

Manufacture of Pharmaceutically Relevant Materials by Mechanochemistry Using Twin Screw Extrusion

  • Dominick Daurio
  • Karthik Nagapudi
  • Fernando Alvarez-Núñez
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 9)


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.


Ball Milling Naproxen Sodium Screw Speed Solid State Nuclear Magnetic Resonance Amorphous Solid Dispersion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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.


  1. 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 69:264–273PubMedCrossRefGoogle Scholar
  2. Bahl D, Bogner RH (2006) Amorphization of indomethacin by co-grinding with neusilin US2: amorphization kinetics, physical stability and mechanism. Pharm Res 23:2317–2325PubMedCrossRefGoogle Scholar
  3. 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 13:255–269PubMedCrossRefGoogle Scholar
  4. Beyer MK, Clausen-Schaumann H (2005) Mechanochemistry: the mechanical activation of covalent bonds. Chem Rev 105:2921–2948PubMedCrossRefGoogle Scholar
  5. Bond AD (2007) What is a co-crystal? Cryst Eng Comm 9:833–834CrossRefGoogle Scholar
  6. 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):419–421CrossRefGoogle Scholar
  7. 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 126:13335–13342PubMedCrossRefGoogle Scholar
  8. 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 97:2286–2298PubMedCrossRefGoogle Scholar
  9. 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 33:909–926PubMedCrossRefGoogle Scholar
  10. 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 3:582–600CrossRefGoogle Scholar
  11. Delori A, Friscic T, Jones W (2012) The role of mechanochemistry and supramolecular design in the development of pharmaceutical materials. Cryst Eng Comm 14:2350–2362CrossRefGoogle Scholar
  12. Desiraju GR (2003) Crystal and co-crystal. Cryst Eng Comm 5:466–467CrossRefGoogle Scholar
  13. 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 74:340–351CrossRefGoogle Scholar
  14. Dunitz JD (2003) Crystal and co-crystal. A second opinion. Cryst Eng Comm 5:506CrossRefGoogle Scholar
  15. 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 16:154–187Google Scholar
  16. 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 45:7546–7550CrossRefGoogle Scholar
  17. 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 419:12–19PubMedCrossRefGoogle Scholar
  18. Gupta MK, Vanwert A, Bogner RH (2003) Formation of physically stable amorphous drugs by milling with neusilin. J Pharm Sci 2(92):536–551CrossRefGoogle Scholar
  19. 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 79:592–600CrossRefGoogle Scholar
  20. 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 28:1870–1883CrossRefGoogle Scholar
  21. 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 41:413–447PubMedCrossRefGoogle Scholar
  22. 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 69:1114–1120PubMedCrossRefGoogle Scholar
  23. 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 27:775–785PubMedCrossRefGoogle Scholar
  24. Jayasankar A, Somwangthanaroj A, Shao ZJ, Rodriguez-Hornedo N (2006) Cocrystal formation during cogrinding and storage is mediated by amorphous phase. Pharm Res 23:2381–2392PubMedCrossRefGoogle Scholar
  25. 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 429:58–68PubMedCrossRefGoogle Scholar
  26. Karki S, Friscic T, Jones W, Motherwell WDS (2007) Screening for Pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding. Mol Pharm 4:347–354PubMedCrossRefGoogle Scholar
  27. 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 5:981–993PubMedCrossRefGoogle Scholar
  28. 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 91:362–370PubMedCrossRefGoogle Scholar
  29. 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 70:493–499PubMedCrossRefGoogle Scholar
  30. 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 93:563–570PubMedCrossRefGoogle Scholar
  31. 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 329:62–71PubMedCrossRefGoogle Scholar
  32. 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 100:3332–3344PubMedCrossRefGoogle Scholar
  33. 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 68:346–351PubMedCrossRefGoogle Scholar
  34. 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 80:433–442PubMedCrossRefGoogle Scholar
  35. 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 99:1693–1696PubMedGoogle Scholar
  36. 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 93:2710–2717PubMedCrossRefGoogle Scholar
  37. Porter WW III, Elie SC, Matzger AJ (2008) Polymorphism in carbamazepine cocrystals. Cryst Growth Des 8:14–16PubMedCrossRefGoogle Scholar
  38. 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 125:8456–8457PubMedCrossRefGoogle Scholar
  39. 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 33:1043–1057PubMedCrossRefGoogle Scholar
  40. 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 79:635–645PubMedCrossRefGoogle Scholar
  41. 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 6:1492–1505PubMedCrossRefGoogle Scholar
  42. Serajuddin ATM (1999) Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 88:1058–1066PubMedCrossRefGoogle Scholar
  43. Serajuddin ATM (2007) Salt formation to improve drug solubility. Adv Drug Delivery Rev 59:603–616CrossRefGoogle Scholar
  44. 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
  45. Trask AV, Motherwell WDS, Jones W (2004) Solvent-drop grinding: green polymorph control of cocrystallisation. Chem Commun (Camb) (7):890–891Google Scholar
  46. Trask AV, Haynes DA, Motherwell WDS, Jones W (2006a) Screening for crystalline salts via mechanochemistry. Chem Commun (Camb) (1):51–53Google Scholar
  47. Trask AV, Motherwell WDS, Jones W (2006b) Physical stability enhancement of theophylline via cocrystallization. Int J Pharm 320:114–123CrossRefGoogle Scholar
  48. 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 6:690–700CrossRefGoogle Scholar
  49. 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 248:123–129CrossRefGoogle Scholar
  50. 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 164:27–33CrossRefGoogle Scholar
  51. 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
  52. Windbergs M, Strachan CJ, Kleinebudde P (2009) Tailor-made dissolution profiles by extruded matrices based on lipid polyethylene glycol mixtures. J Control Release 137:211–216PubMedCrossRefGoogle Scholar
  53. Yu L (2001) Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Delivery Rev 48:27–42CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  • Dominick Daurio
    • 1
  • Karthik Nagapudi
    • 1
  • Fernando Alvarez-Núñez
    • 1
  1. 1.Pharmaceutical R&DSmall Molecule Process and Product Development, Amgen Inc.Thousand OaksUSA

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