European Journal of Pharmaceutical Sciences 21 (2004) 607–616 Binding of 3-isobutyl-1-methylxanthine into copolymers of N-isopropylacrylamide Mirja Kivelä a , Heikki Tenhu a,∗ , Ari Koskelainen b a Laboratory of Polymer Chemistry, University of Helsinki, PB 55, FIN-00014 Helsinki, Finland b Laboratory of Medical Technology, University of Technology, PB 2200, FIN-02015 Helsinki, Finland Received 10 March 2003; received in revised form 3 December 2003; accepted 7 January 2004 Abstract Linear and crosslinked copolymers based on N-isopropylacrylamide, NIPAAm, containing aromatic esters, have been synthesised. Vinyl benzoate and cinnamoyloxyethyl methacrylate have been used as aromatic comonomers. Certain aromatic esters are known of their capability to form molecular complexes with xanthines and thus, the purpose was to build up thermally responsive copolymers which specifically bind certain xanthines in aqueous solutions and release those under an influence of an environmental stimulus. The solutions of the linear copolymers have been studied in water in the presence of 3-isobutyl-1-methylxanthine, IBMX, as a function of drug concentration and temperature. The synthesised linear copolymers exhibited sensitivity to IBMX concentration in aqueous solutions above and below LCST, observed by viscosimetry and dynamic light scattering. The results are indicative of complex formation between the copolymers and IBMX. The crosslinked copolymers showed an increased IBMX binding capacity with an increasing amount of aromatic ester groups in the polymer network. IBMX release rates from the crosslinked gels were slowed down by the increasing degree of aromatic substitution, especially above LCST. © 2004 Elsevier B.V. All rights reserved. Keywords: Thermosensitive copolymers; N-isopropylacrylamide; 3-Isobutyl-1-methylxanthine; Molecular complexes 1. Introduction Methylxanthines such as caffeine and theophylline are well known central nervous system stimulants. High doses of these xanthines cause central nervous system hyperexcitability and can cause epileptic symptoms. Hy- perexcitability may be linked to abilities of xanthines to act as antagonists to the actions of endogenous adeno- sine (De Sarro et al., 1997). Several xanthines, including 3-isobutyl-1-methylxanthine (IBMX), cause tracheal relax- ation and thus have antiasthmatic potential. This is consid- ered to be the result of xanthines acting as phosphodiesterase inhibitors (Brackett et al., 1990). Theophylline is commonly used as bronchodilator, and it is also used as hydrophilic model drug in testing of release properties of pharmaceu- tical formulations and their matrix polymers (Saha et al., 2001; Roshdy et al., 2001; Miyazaki et al., 2001; Freichel ∗ Corresponding author. Fax: +358-9-19150330. E-mail address: heikki.tenhu@helsinki.fi (H. Tenhu). and Lippold, 2000; Zhang and McGinity, 2000; Tsai et al., 2001; Lee and Rosenberg, 1999; Vasheghani-Farahani and Khorram, 2002). Because of these properties xanthines have versatile roles in the research of biochemistry and bio- physical processes in living tissues and the need for good controlled release systems is recognised. In designing of new polymeric materials for controlled drug release systems, the studies on the interactions between the polymers and the drug molecules have a great impor- tance. Connors and coworkers studied the molecular com- plexes between xanthines and several aromatic esters such as cinnamates and benzoates in aqueous solutions (Mollica and Connors, 1967; Connors et al., 1969; Kramer and Connors, 1969; Stelmach and Connors, 1970). It is sug- gested that these 1:1 complexes have a plane-to-plane orien- tation but the complex structures do not involve maximum overlap of -orbitals. The classical electron donor–acceptor or charge-transfer interaction seems to be unlikely as the major source of the complex stability. Hydrophobic bonding may be important as well as local dipole–dipole attraction forces. The contribution of the solvent structure in stabilising 0928-0987/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2004.01.003