Preparation, Characterization, and Drug-Release Properties of Poly(N-isopropylacrylamide) Microspheres Having Poly(Itaconic Acid) Graft Chains Betu ¨ l Tas ¸delen, 1 Nilhan Kayaman-Apohan, 2 Zu ¨ lal MIsIrlI, 3 Olgun Gu ¨ ven, 4 Bahattin M. Baysal 5,6 1 Chemistry Department, C ¸ ekmece Nuclear Research and Training Center, 34831, P.O. Box 1, Istanbul, Turkey 2 Department of Chemistry, Marmara University, 81040 Go ¨ztepe, Istanbul, Turkey 3 Advanced Technologies Research and Development Center, Bog ˘azic ¸i University, 80815 Bebek, Istanbul, Turkey 4 Department of Chemistry, Hacettepe University, 06532 Beytepe, Ankara, Turkey 5 Department of Chemical Engineering, Bog ˘azic ¸i University, 80815 Bebek, Istanbul, Turkey 6 TUBITAK Marmara Research Center, 41470 Gebze, Kocaeli, Turkey Received 9 March 2004; accepted 1 October 2004 DOI 10.1002/app.21777 Published online in Wiley InterScience (www.interscience.wiley.com). ABSTRACT: An inverse suspension polymerization method for the preparation of thermoresponsive hydrogel microspheres based on N-isopropylacrylamide was de- scribed in this article. The polymerization reaction was car- ried out at 200 rpm stirring rate and the microspheres ob- tained were in the size range of 71–500 m in the swollen states. The particles were sieved by using ASTM sieves. The selected fraction (180 –250 m) of poly(N-isopropylacrylam- ide) (PNIPAAm) microspheres was used for radiation-in- duced modification with itaconic acid (IA) to obtain PNIPAAm/poly(itaconic acid) graft copolymer. Viagra and lidocaine were used as model drugs for the investigation of controlled-release behavior of the microspheres. Incorpora- tion of IA graft chains onto microspheres enhanced signifi- cantly the uptake of both drugs and further controlled re- lease at specific pH values. The release studies showed that some of the basic parameters affecting the drug-loading and -release behavior of the microspheres were pH, temperature, particle size, and chemical nature of drug. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 97: 1115–1124, 2005 Key words: microspheres; N-isopropylacrylamide; itaconic acid; drug release INTRODUCTION Polymeric hydrogels have found extensive applica- tions, ranging from on– off switching materials, drug delivery systems, immobilization technologies, mass separations, and cell culturing. 1–8 Available in various physical forms, such as powders, discs, or micro- spheres, these hydrogels are generally glassy in the dehydrated state, but swell to become elastic gel upon water penetration. In drug-delivery applications, the entrapped drug diffuses through the swollen network into the surrounding aqueous medium. Various pa- rameters including particle size, size distribution, mesh size, swellability, chemical structure, and reac- tive sites are considered to describe the overall perfor- mance of microspheres in drug-release applications. Poly(N-isopropylacrylamide) (PNIPAAm) and its copolymers were studied in the development of temperature-modulated drug delivery systems. 9,10 PNIPAAm is soluble in cold water, but is not soluble in hot water, and it exhibits a lower critical solution temperature behavior (LCST) at around 32–34°C. 11 Hydrogels composed of PNIPAAm and its copoly- mers exhibit discrete and reversible volume change in response to infinitesimal changes in temperature. 12 The LCST of PNIPAAm can be modified by copoly- merization with certain comonomers. Hydrophilic comonomers increase the critical temperature so it becomes closer to the human body temperature. 13 In more recent years, a series of articles was pub- lished by Gu ¨ ven and coworkers who synthesized new hydrogels from the copolymers of acrylamide and diprotic itaconic and maleic acid and showed that the use of even very small quantities of diprotic acid proved to impart remarkable properties to the hydro- gels of starting monomers and/or homopoly- mers. 14 –16 The incorporation of acidic moieties into base polymeric structures for the synthesis of micro- spheres and hydrogels was mostly carried out by us- ing acrylic acid. The use of diprotic acids, however, has been shown to impart additional advantages over Correspondence to: B.M. Baysal (bmbaysal@hotmail.com). Contract grant sponsor: TUBITAK. Contract grant sponsor: Marmara Research Center. Contract grant sponsor: Turkish- Macedonion Science and Technology Program for 2001–2003. Contract grant sponsor: C ¸ ekmece Nuclear Research and Training Center. Journal of Applied Polymer Science, Vol. 97, 1115–1124 (2005) © 2005 Wiley Periodicals, Inc.