Drug Delivery and Translational Research

, Volume 9, Issue 1, pp 404–413 | Cite as

Rapid optimization of liposome characteristics using a combined microfluidics and design-of-experiment approach

  • Mahsa Sedighi
  • Sandro Sieber
  • Fereshteh RahimiEmail author
  • Mohammad-Ali Shahbazi
  • Ali Hossein Rezayan
  • Jörg HuwylerEmail author
  • Dominik Witzigmann
Short Communication


Liposomes have attracted much attention as the first nanoformulations entering the clinic. The optimization of physicochemical properties of liposomes during nanomedicine development however is time-consuming and challenging despite great advances in formulation development. Here, we present a systematic approach for the rapid size optimization of liposomes. The combination of microfluidics with a design-of-experiment (DoE) approach offers a strategy to rapidly screen and optimize various liposome formulations, i.e., up to 30 liposome formulations in 1 day. Five representative liposome formulations based on clinically approved lipid compositions were formulated using systematic variations in microfluidics flow rate settings, i.e., flow rate ratio (FRR) and total flow rate (TFR). Interestingly, flow rate-dependent DoE models for the prediction of liposome characteristics could be grouped according to lipid-phase transition temperature and surface characteristics. For all formulations, the FRR had a significant impact (p < 0.001) on hydrodynamic diameter and size distribution of liposomes, while the TFR mainly affected the production rate. Liposome characteristics remained constant for TFRs above 8 mL/min. The stability study revealed an influence of lipid:cholesterol ratio (1:1 and 2:1 ratio) and presence of PEG on liposome characteristics during storage. To validate our DoE models, we formulated liposomes incorporating hydrophobic dodecanethiol-coated gold nanoparticles. This proof-of-concept step showed that flow rate settings predicted by DoE models successfully determined the size of resulting empty liposomes (109.3 ± 15.3 nm) or nanocomposites (111 ± 17.3 nm). This study indicates that a microfluidics-based formulation approach combined with DoE is suitable for the routine development of monodisperse and size-specific liposomes in a reproducible and rapid manner.


Liposomes Microfluidics Design-of-experiment Physicochemical characteristics Nanomedicines 



We thank the bioimaging center of the Biozentrum Basel for their support with electron microscopy techniques and Tomas Skrinskas for proofreading the manuscript.

Funding information

This study received financial support from the “Stiftung zur Förderung des pharmazeutischen Nachwuchses in Basel,” “Freiwillige Akademische Gesellschaft Basel,” and the Swiss National Science Foundation (SNF grant No. 174975 and 173057).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

13346_2018_587_MOESM1_ESM.docx (558 kb)
ESM 1 (DOCX 558 kb)


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Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  • Mahsa Sedighi
    • 1
    • 2
  • Sandro Sieber
    • 2
  • Fereshteh Rahimi
    • 1
    Email author
  • Mohammad-Ali Shahbazi
    • 3
    • 4
  • Ali Hossein Rezayan
    • 1
  • Jörg Huwyler
    • 2
    Email author
  • Dominik Witzigmann
    • 2
    • 5
  1. 1.Division of Nanobiotechnology, Department of Life Sciences Engineering, Faculty of New Sciences and TechnologiesUniversity of TehranTehranIran
  2. 2.Department of Pharmaceutical Sciences, Division of Pharmaceutical TechnologyUniversity of BaselBaselSwitzerland
  3. 3.Department of Micro- and NanotechnologyTechnical University of DenmarkKongens LyngbyDenmark
  4. 4.Department of Pharmaceutical Nanotechnology, School of PharmacyZanjan University of Medical SciencesZanjanIran
  5. 5.Department of Biochemistry and Molecular BiologyUniversity of British ColumbiaVancouverCanada

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