Pharmaceutical Research

, Volume 31, Issue 10, pp 2844–2856 | Cite as

Computer Modeling Assisted Design of Monodisperse PLGA Microspheres with Controlled Porosity Affords Zero Order Release of an Encapsulated Macromolecule for 3 Months

  • Filis Kazazi-Hyseni
  • Mariana Landin
  • Audrey Lathuile
  • Gert J. Veldhuis
  • Sima Rahimian
  • Wim E. Hennink
  • Robbert Jan Kok
  • Cornelus F. van Nostrum
Research Paper



The aim of this study was the development of poly(D,L-lactide-co-glycolide) (PLGA) microspheres with controlled porosity, to obtain microspheres that afford continuous release of a macromolecular model compound (blue dextran).


PLGA microspheres with a size of around 40 μm and narrow size distribution (span value of 0.3) were prepared with a double emulsion membrane emulsification method. Gene expression programming (GEP) analysis was applied to design and formulate a batch of microspheres with controlled porosity that shows continuous release of blue dextran.


Low porous microspheres with a high loading efficiency were formed at high polymer concentrations (30% w/w in the oil phase) and were characterized with a burst release <10% and a three-phasic release profile of blue dextran. Increasing porosity (10% w/w polymer concentrations), a sustained release of blue dextran was obtained albeit with up to 40% of burst release. The desired formulation, calculated by GEP, resulted in microspheres with 72% loading efficiency and intermediate porosity. Blue dextran was indeed released continuously in almost a zero order manner over a period of 3 months after an initial small burst release of 9%.


By fine-tuning the porosity, the release profile of PLGA microspheres for macromolecules can be predicted and changed from a three-phasic to a continuous release.


controlled release membrane emulsification microspheres PLGA porosity 



Artificial neural networks


Gene expression programing


Loading capacity


Loading efficiency


Membrane emulsification




Polyvinyl alcohol


Theoretical loading


Volume-weighted mean droplet diameter


Droplet diameter


Membrane pore diameter


Membrane porosity


The buoyancy force


The drag force of the continuous phase flow


The inertial force of the dispersed phase flow


The interfacial tension force


Interfacial tension


Dispersed phase flux


Fraction of active membrane pores


Viscosity of the dispersed phase

\( {\overline{P}}_c \)

Continuous phase pressure

Pc,in; Pc,out

Pressure of the continuous phase at the inlet and outlet of the main channel


Critical transmembrane pressure


Dispersed phase pressure


Transmembrane pressure


Dispersed phase flow rate


Correlation coefficient


Hydraulic membrane resistance


Radius of the membrane pore


Period of drop detachment



This research forms part of the Project P3.02 DESIRE of the research program of the BioMedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs. ML thanks the Spanish Government for financial support (SAF 2012- 39878-C02-01).

Supplementary material

11095_2014_1381_MOESM1_ESM.docx (8.9 mb)
ESM 1 (DOCX 9078 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Filis Kazazi-Hyseni
    • 1
  • Mariana Landin
    • 2
  • Audrey Lathuile
    • 3
  • Gert J. Veldhuis
    • 3
  • Sima Rahimian
    • 1
  • Wim E. Hennink
    • 1
  • Robbert Jan Kok
    • 1
  • Cornelus F. van Nostrum
    • 1
  1. 1.Department of Pharmaceutics, Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  2. 2.Department of Pharmacy and Pharmaceutical TechnologyUniversity of SantiagoSantiago de CompostelaSpain
  3. 3.Nanomi B.V.OldenzaalThe Netherlands

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