Poly(N-isopropylacrylamide-co-hydroxyethylacrylamide) thermosensitive microspheres: The size of microgels dictates the pulsatile release mechanism

Gheorghe Fundueanu, Marieta Constantin, Ionela Asmarandei, Sanda Bucatariu, Valeria Harabagiu, Paolo Ascenzi, Bogdan C. Simionescu

Research output: Contribution to journalArticlepeer-review


Poly(N-isopropylacrylamide-co-N-hydroxyethylacrylamide) (poly(NIPAAm-co-HEAAm)) was prepared as a new thermosensitive copolymer possessing a sharp phase transition around the human body temperature. The effect of the copolymer concentration on the lower critical solution temperature (LCST) was determined under physiological conditions by cloud point (CP) and differential scanning calorimetric (DSC) methods. Then, thermosensitive microspheres were prepared from preformed copolymers by chemical cross-linking of hydroxyl groups with glutaraldehyde at a temperature situated slightly below LCST of the copolymer solution. The volume phase transition temperature (VPTT) of corresponding cross-linked microspheres was determined from swelling degree-temperature curve. The microspheres were loaded with model drug indomethacin by the solvent evaporation method. The DSC analysis proved that the drug is molecularly dispersed in the polymer network. Finally, the influence of the microsphere size on drug release was investigated. It was established that microspheres with the diameter ranging between 5 and 60 μm release the drug with almost the same rate below (in the swollen state) and above the VPTT (in the collapsed state). On the contrary, microspheres with the diameter ranging between 125 and 220 μm release a significantly higher amount of indomethacin below than above the VPTT. This different behavior is enough to assure a pulsatile release mechanism when the temperature changes cyclically below and above the VPTT. However, both small and large microspheres release a large amount of the drug during the collapsing process.

Original languageEnglish
Pages (from-to)614-623
Number of pages10
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Issue number3 PART A
Publication statusPublished - Nov 2013


  • Drug delivery systems
  • Lower critical solution temperature
  • Microspheres
  • Thermo-responsive polymer
  • Volume phase transition temperature

ASJC Scopus subject areas

  • Biotechnology
  • Pharmaceutical Science


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