Skip to main content
SpringerLink
Log in

Production Techniques

  • Chapter
  • First Online:
Lipid Nanoparticles: Production, Characterization and Stability

Part of the book series: SpringerBriefs in Pharmaceutical Science & Drug Development ((BRIEFSPSDD))

Abstract

Besides composition and structure, an important factor which influences the performance and characteristics of lipid nanoparticles is their production method, and a variety of production techniques have been introduced since the inception of lipid nanoparticles as potential colloidal carriers. The production techniques can be categorized into two groups; techniques which require high energy for dispersion of the lipid phase (such as high pressure homogenization, high sheer homogenization, ultrasonication) and techniques which require precipitation of nanoparticles from homogenous systems (such as microemulsions, solvent-based techniques, membrane contactors and coacervation). The choice of an appropriate technique is based on the physicochemical properties of the drug, the physicochemical characteristics and stability of the colloidal formulation and the availability of equipment. This chapter gives an overview of the techniques used in the production of lipid nanoparticle dispersions and also provides a brief introduction to a novel technique based on the use of microwave energy developed by our group.

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 59.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 79.99
Price excludes VAT (USA)
  • Compact, lightweight 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

  • An Z, Tang W, Hawker C, Stucky G (2006) One-step microwave preparation of well-defined and functionalized polymeric nanoparticles. J Am Chem Soc 128(47):15054–15055

    Article  CAS  PubMed  Google Scholar 

  • Battaglia L, Trotta M, Gallarate M, Carlotti M, Zara G, Bargoni A (2007) Solid lipid nanoparticles formed by solvent-in-water emulsion-diffusion technique: development and influence on insulin stability. J Microencapsul 24(7):672–684

    Article  Google Scholar 

  • Battaglia L, Gallarate M, Cavalli R, Trotta M (2010) Solid lipid nanoparticles produced through a coacervation method. J Microencapsul 27(1):78–85

    Article  CAS  PubMed  Google Scholar 

  • Battaglia L, Serpe L, Muntoni E, Zara G, Trotta M, Gallarate M (2011) Methotrexate-loaded SLNs prepared by coacervation technique: in vitro cytotoxicity and in vivo pharmacokinetics and biodistribution. Nanomedicine 6(9):1561–1573

    Article  CAS  PubMed  Google Scholar 

  • Batzri S, Korn E (1973) Single bilayer liposomes prepared without sonication. BBA-Biomembranes. 298(4):1015–1019

    Article  CAS  PubMed  Google Scholar 

  • Bergese P, Colombo I, Gervasoni D, Depero L (2003) Microwave generated nanocomposites for making insoluble drugs soluble. Mat Sci Eng C—Bio S 23(6–8):791–795

    Article  Google Scholar 

  • Bianco M, Gallarate M, Trotta M, Battaglia L (2010) Amphotericin B loaded SLN prepared with the coacervation technique. J Drug Deliv Sci Tec 20(3):187–191

    Google Scholar 

  • Blasi P, Schoubben A, Romano G, Giovagnoli S, Di Michele A, Ricci M (2013a) Lipid nanoparticles for brain targeting II. Technological characterization. Colloid Surface B 110:130–137

    Article  CAS  Google Scholar 

  • Blasi P, Schoubben A, Traina G, Manfroni G, Barberini L, Alberti P et al (2013b) Lipid nanoparticles for brain targeting III. Long-term stability and in vivo toxicity. Int J Pharm 454(1):316–323

    Article  CAS  PubMed  Google Scholar 

  • Bunjes H, Westesen K, Koch M (1996) Crystallization tendency and polymorphic transitions in triglyceride nanoparticles. Int J Pharm 129(1):159–173

    Article  CAS  Google Scholar 

  • Byrappa K, Ohara S, Adschiri T (2008) Nanoparticles synthesis using supercritical fluid technology—towards biomedical applications. Adv Drug Deliver Rev 60(3):299–327

    Article  CAS  Google Scholar 

  • Charcosset C, Fessi H (2005) Preparation of nanoparticles with a membrane contactor. J Membrane Sci. 266(1–2):115–120

    Article  CAS  Google Scholar 

  • Charcosset C, Limayem I, Fessi H (2004) The membrane emulsification process—a review. J Chem Technol Biot 79(3):209–218

    Article  CAS  Google Scholar 

  • Charcosset C, El-Harati A, Fessi H (2005) Preparation of solid lipid nanoparticles using a membrane contactor. J Control Release. 108(1):112–120

    Article  CAS  PubMed  Google Scholar 

  • Chattopadhyay P, Huff R, Shekunov B (2006) Drug encapsulation using supercritical fluid extraction of emulsions. J Pharm Sci 95(3):667–679

    Article  CAS  PubMed  Google Scholar 

  • Chattopadhyay P, Shekunov B, Yim D, Cipolla D, Boyd B, Farr S (2007) Production of solid lipid nanoparticle suspensions using supercritical fluid extraction of emulsions (SFEE) for pulmonary delivery using the AERx system. Adv Drug Deliver Rev 59(6):444–453

    Article  CAS  Google Scholar 

  • Chen G, Luo G, Xu J, Wang J (2004) Membrane dispersion precipitation method to prepare nanopartials. Powder Technol 139(2):180–185

    Article  CAS  Google Scholar 

  • Chirio D, Gallarate M, Peira E, Battaglia L, Serpe L, Trotta M (2011) Formulation of curcumin-loaded solid lipid nanoparticles produced by fatty acids coacervation technique. J Microencapsul 28(6):537–548

    Article  CAS  PubMed  Google Scholar 

  • Cortesi R, Esposito E, Luca G, Nastruzzi C (2002) Production of lipospheres as carriers for bioactive compounds. Biomaterials 23(11):2283–2294

    Article  CAS  PubMed  Google Scholar 

  • Dingler A, Gohla S (2002) Production of solid lipid nanoparticles (SLN): scaling up feasibilities. J Microencapsul 19(1):11–16

    Article  CAS  PubMed  Google Scholar 

  • Doktorovova S, Shegokar R, Fernandes L, Martins-Lopes P, Silva A, Müller R et al (2014) Trehalose is not a universal solution for solid lipid nanoparticles freeze-drying. Pharm Dev Technol 19(8):922–929

    Article  CAS  PubMed  Google Scholar 

  • Drioli E, Criscuoli A, Curcio E (2003) Membrane contactors and catalytic membrane reactors in process intensification. Chemical Eng Technol 26(9):975–981

    Article  CAS  Google Scholar 

  • Drioli E, Stankiewicz A, Macedonio F (2011) Membrane engineering in process intensification—An overview. J Membrane Sci 380(1–2):1–8

    Article  CAS  Google Scholar 

  • Dubes A, Parrot-Lopez H, Abdelwahed W, Degobert G, Fessi H, Shahgaldian P et al (2003) Scanning electron microscopy and atomic force microscopy imaging of solid lipid nanoparticles derived from amphiphilic cyclodextrins. Eur J Pharm Biopharm 55(3):279–282

    Article  CAS  PubMed  Google Scholar 

  • Durán-Lobato M, Enguix-González A, Fernández-Arévalo M, Martín-Banderas L (2013) Statistical analysis of solid lipid nanoparticles produced by high-pressure homogenization: a practical prediction approach. J Nanopart Res 15(2):1–14

    Article  Google Scholar 

  • Dwivedi P, Khatik R, Khandelwal K, Shukla R, Paliwal S, Dwivedi A et al (2014) Preparation and characterization of solid lipid nanoparticles of antimalarial drug arteether for oral administration. J Biomaterials Tissue Eng 4(2):133–137

    Article  CAS  Google Scholar 

  • El-Harati A, Charcosset C, Fessi H (2006) Influence of the formulation for solid lipid nanoparticles prepared with a membrane contactor. Pharm Dev Technol 11(2):153–157

    Article  CAS  PubMed  Google Scholar 

  • Fessi H, Puisieux F, Devissaguet J, Ammoury N, Benita S (1989) Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm 55(1):R1–R4

    Article  CAS  Google Scholar 

  • Finke J, Schur J, Richter C, Gothsch T, Kwade A, Büttgenbach S et al (2012) The influence of customized geometries and process parameters on nanoemulsion and solid lipid nanoparticle production in microsystems. Chemical Eng J 209:126–137

    Article  CAS  Google Scholar 

  • Gallarate M, Trotta M, Battaglia L, Chirio D (2010) Cisplatin-loaded SLN produced by coacervation technique. J Drug Deliv Sci Tec 20(5):343–347

    CAS  Google Scholar 

  • Garcia-Fuentes M, Torres D, Alonso M (2003) Design of lipid nanoparticles for the oral delivery of hydrophilic macromolecules. Colloid Surface B 27(2–3):159–168

    Article  CAS  Google Scholar 

  • Garcia-Fuentes M, Alonso M, Torres D (2005) Design and characterization of a new drug nanocarrier made from solid–liquid lipid mixtures. J Colloid Interf Sci 285(2):590–598

    Article  CAS  Google Scholar 

  • Gasco M (1993) Method for producing solid lipid microspheres having a narrow size distribution. US patent US5250236

    Google Scholar 

  • Gawande M, Shelke S, Zboril R, Varma R (2014) Microwave-assisted chemistry: synthetic applications for rapid assembly of nanomaterials and organics. Accounts Chem Res 47(4):1338–1348

    Article  CAS  Google Scholar 

  • Hayes B (2004) Recent advances in microwave-assisted synthesis. Aldrichim Acta 37(2):66–77

    CAS  Google Scholar 

  • Heurtault B, Saulnier P, Pech B, Proust J-E, Benoit J-P (2002) A novel phase inversion-based process for the preparation of lipid nanocarriers. Pharm Res 19(6):875–880

    Article  CAS  PubMed  Google Scholar 

  • Hu F, Yuan H, Zhang H, Fang M (2002) Preparation of solid lipid nanoparticles with clobetasol propionate by a novel solvent diffusion method in aqueous system and physicochemical characterization. Int J Pharm 239(1–2):121–128

    Article  CAS  PubMed  Google Scholar 

  • Hu FQ, Hong Y, Yuan H (2004) Preparation and characterization of solid lipid nanoparticles containing peptide. Int J Pharm 273(1–2):29–35

    Article  CAS  PubMed  Google Scholar 

  • Jenning V, Lippacher A, Gohla S (2002) Medium scale production of solid lipid nanoparticles (SLN) by high pressure homogenization. J Microencapsul 19(1):1–10

    Article  CAS  PubMed  Google Scholar 

  • Jia Z, Liu Z, He F (2003) Synthesis of nanosized BaSO4 and CaCO3 particles with a membrane reactor: effects of additives on particles. J Colloid Interf Sci. 266(2):322–327

    Article  CAS  Google Scholar 

  • Joscelyne S, TrägÃ¥rdh G (2000) Membrane emulsification—a literature review. J Membrane Sci 169(1):107–117

    Article  CAS  Google Scholar 

  • Leroux J, Allemann E, Doelker E, Gurny R (1995) New approach for the preparation of nanoparticles by an emulsification-diffusion method. Eur J Pharm Biopharm 41(1):14–18

    CAS  Google Scholar 

  • Lim S-J, Kim C-K (2002) Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid. Int J Pharm 243(1):135–146

    Article  CAS  PubMed  Google Scholar 

  • Maculotti K, Tira E, Sonaggere M, Perugini P, Conti B, Modena T et al (2009) In vitro evaluation of chondroitin sulphate-chitosan microspheres as carrier for the delivery of proteins. J Microencapsul 26(6):535–543

    Article  CAS  PubMed  Google Scholar 

  • Mäder K, Mehnert W (2005) Solid lipid nanoparticles—concepts procedures, and physicochemical aspects. In: Nastruzzi C, (ed) Lipospheres in drug targets and delivery. CRC Press, pp 1–22

    Google Scholar 

  • Manjunath K, Venkateswarlu V, Hussain A (2011) Preparation and characterization of nitrendipine solid lipid nanoparticles. Die Pharmazie—Int J Pharm Sci 66(3):178–186

    CAS  Google Scholar 

  • Mehnert W, Mäder K (2001) Solid lipid nanoparticles: Production, characterization and applications. Adv Drug Deliver Rev 47(2–3):165–196

    Article  CAS  Google Scholar 

  • Moneghini M, Bellich B, Baxa P, Princivalle F (2008) Microwave generated solid dispersions containing Ibuprofen. Int J Pharm 361(1–2):125–130

    Article  CAS  PubMed  Google Scholar 

  • Moneghini M, Zingone G, De Zordi N (2009) Influence of the microwave technology on the physical–chemical properties of solid dispersion with Nimesulide. Powder Technol 195(3):259–263

    Article  CAS  Google Scholar 

  • Müller R, Lucks J (1996) Arzneistoffträger aus festen lipidteilchen, feste lipidnanosphären (sln) patent EP0605497A1

    Google Scholar 

  • Muller R, Schwarz C, Mehnert W, Lucks J (1993) Production of solid lipid nanoparticles (SLN) for controlled drug delivery. In: Proceedings of international symposium on control release bioactive material

    Google Scholar 

  • Müller R, Mäder K, Gohla S (2000) Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur J Pharm Biopharm 50(1):161–177

    Article  PubMed  Google Scholar 

  • Patravale V, Ambarkhane A (2003) Study of Solid Lipid Nanoparticles with respect to particle size distribution and drug loading. Die Pharmazie—Int J Pharm Sci 58(6):392–395

    CAS  Google Scholar 

  • Prombutara P, Kulwatthanasal Y, Supaka N, Sramala I, Chareonpornwattana S (2012) Production of nisin-loaded solid lipid nanoparticles for sustained antimicrobial activity. Food Control 24(1–2):184–190

    Article  CAS  Google Scholar 

  • Quintanar-Guerrero D, Fessi H, Allémann E, Doelker E (1996) Influence of stabilizing agents and preparative variables on the formation of poly(d, l-lactic acid) nanoparticles by an emulsification-diffusion technique. Int J Pharm 143(2):133–141

    Article  CAS  Google Scholar 

  • Schubert M, Müller-Goymann C (2003) Solvent injection as a new approach for manufacturing lipid nanoparticles – evaluation of the method and process parameters. Eur J Pharm Biopharm 55(1):125–131

    Article  CAS  PubMed  Google Scholar 

  • Schwarz C, Mehnert W (1997) Freeze-drying of drug-free and drug-loaded solid lipid nanoparticles (SLN). Int J Pharm 157(2):171–179

    Article  CAS  PubMed  Google Scholar 

  • Schwarz C, Mehnert W, Lucks J, Müller R (1994) Solid lipid nanoparticles (SLN) for controlled drug delivery. I. Production, characterization and sterilization. J Control Rel 30(1):83–96

    Article  CAS  Google Scholar 

  • Shah R, Malherbe F, Eldridge D, Palombo E, Harding I (2014) Physicochemical characterization of solid lipid nanoparticles (SLNs) prepared by a novel microemulsion technique. J Colloid Interf Sci 428:286–294

    Article  CAS  Google Scholar 

  • Shahgaldian P, Da Silva E, Coleman A, Rather B, Zaworotko M (2003a) Para-acyl-calix-arene based solid lipid nanoparticles (SLNs): a detailed study of preparation and stability parameters. Int J Pharm 253(1–2):23–38

    Article  CAS  PubMed  Google Scholar 

  • Shahgaldian P, Gualbert J, Aïssa K, Coleman A (2003b) A study of the freeze-drying conditions of calixarene based solid lipid nanoparticles. Eur J Pharm Biopharm 55(2):181–184

    Article  CAS  PubMed  Google Scholar 

  • Shahgaldian P, Quattrocchi L, Gualbert J, Coleman A, Goreloff P (2003c) AFM imaging of calixarene based solid lipid nanoparticles in gel matrices. Eur J Pharm Biopharm 55(1):107–113

    Article  CAS  PubMed  Google Scholar 

  • Shinoda K, Saito H (1968) The effect of temperature on the phase equilibria and the types of dispersions of the ternary system composed of water, cyclohexane, and nonionic surfactant. J Colloid Interf Sci 26(1):70–74

    Article  CAS  Google Scholar 

  • Siekmann B, Westesen K (1992) Submicron-sized parenteral carrier systems based on solid lipids. Pharm Pharmacol Lett 1(3):123–126

    CAS  Google Scholar 

  • Siekmann B, Westesen K (1996) Investigations on solid lipid nanoparticles prepared by precipitation in o/w emulsions. Eur J Pharm Biopharm 42(2):104–109

    CAS  Google Scholar 

  • Silva M, Franco D, de Oliveira L (2008) New Insight on the Structural Trends of Polyphosphate Coacervation Processes. J Phys Chem A 112(24):5385–5389

    Article  CAS  PubMed  Google Scholar 

  • Silva A, González-Mira E, García M, Egea M, Fonseca J, Silva R et al (2011) Preparation, characterization and biocompatibility studies on risperidone-loaded solid lipid nanoparticles (SLN): High pressure homogenization versus ultrasound. Colloid Surface B 86(1):158–165

    Article  CAS  Google Scholar 

  • Sirkar K, Shanbhag P, Kovvali A (1999) Membrane in a reactor: a functional perspective. Ind Eng Chem Res 38(10):3715–3737

    Article  CAS  Google Scholar 

  • Sjöström B, BergenstÃ¥hl B (1992) Preparation of submicron drug particles in lecithin-stabilized o/w emulsions I. Model studies of the precipitation of cholesteryl acetate. Int J Pharm 88(1–3):53–62

    Article  Google Scholar 

  • Speiser P (1986) Lipid nano pellets as drug carriers for oral administration patent EP 0167825

    Google Scholar 

  • Trotta M, Debernardi F, Caputo O (2003) Preparation of solid lipid nanoparticles by a solvent emulsification–diffusion technique. Int J Pharm 257(1–2):153–160

    Article  CAS  PubMed  Google Scholar 

  • Trotta M, Cavalli R, Carlotti M, Battaglia L, Debernardi F (2005) Solid lipid micro-particles carrying insulin formed by solvent-in-water emulsion–diffusion technique. Int J Pharm 288(2):281–288

    Article  CAS  PubMed  Google Scholar 

  • Unruh T, Bunjes H, Westesen K, Koch M (2001) Investigations on the melting behaviour of triglyceride nanoparticles. Colloid Polym Sci 279(4):398–403

    Article  CAS  Google Scholar 

  • Vanderhoff J, El-Aasser M, Ugelstad J (1979) Polymer emulsification process. Google Patents

    Google Scholar 

  • Wang T, Wang N, Zhang Y, Shen W, Gao X, Li T (2010) Solvent injection-lyophilization of tert-butyl alcohol/water cosolvent systems for the preparation of drug-loaded solid lipid nanoparticles. Colloid Surface B 79(1):254–261

    Article  CAS  Google Scholar 

  • Wang S, Chen T, Chen R, Hu Y, Chen M, Wang Y (2012) Emodin loaded solid lipid nanoparticles: Preparation, characterization and antitumor activity studies. Int J Pharm 430(1–2):238–246

    Article  CAS  PubMed  Google Scholar 

  • Waters L, Bedford S, Parkes G (2011) Controlled microwave processing applied to the pharmaceutical formulation of ibuprofen. AAPS PharmSciTech 12(4):1038–1043

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Westesen K, Bunjes H, Koch M (1997) Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. J Control Release 48(2):223–236

    Article  CAS  Google Scholar 

  • Wu L, Zhang J, Watanabe W (2011) Physical and chemical stability of drug nanoparticles. Adv Drug Deliver Rev 63(6):456–469

    Article  CAS  Google Scholar 

  • Yang S, Zhu J (2002) Preparation and Characterization of Camptothecin Solid Lipid Nanoparticles. Drug Dev Ind Pharm 28(3):265

    Article  CAS  PubMed  Google Scholar 

  • Yasuji T, Takeuchi H, Kawashima Y (2008) Particle design of poorly water-soluble drug substances using supercritical fluid technologies. Adv Drug Deliver Rev 60(3):388–398

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry and Biotechnology, Swinburne University of Technology, PO Box 218, Melbourne, VIC, 3122, Australia

    Rohan Shah, Daniel Eldridge, Enzo Palombo & Ian Harding

Authors
  1. Rohan Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Eldridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Enzo Palombo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ian Harding
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rohan Shah .

Rights and permissions

Reprints and permissions

Copyright information

© 2015 The Author(s)

About this chapter

Cite this chapter

Shah, R., Eldridge, D., Palombo, E., Harding, I. (2015). Production Techniques. In: Lipid Nanoparticles: Production, Characterization and Stability. SpringerBriefs in Pharmaceutical Science & Drug Development. Springer, Cham. https://doi.org/10.1007/978-3-319-10711-0_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-10711-0_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-10710-3

  • Online ISBN: 978-3-319-10711-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation