Polymer International Polym Int 57:85–91 (2008) Effect of pH on the drug release rate from a new polymer–drug conjugate system El-Refaie Kenawy, 1∗ Fouad Abdel-Hay, 1 Mohamed El-Newehy 1 and Raphael M Ottenbrite 2 1 Chemistry Department, Polymer Research Group, Faculty of Science, Tanta University, Tanta 31527, Egypt 2 Chemistry Department, Virginia Commonwealth University, Richmond, Virginia 23284, USA Abstract: The corresponding N-hydroximide and N-methyl-N-hydroximide of poly[ethylene-alt-(maleic anhydride)] (weight average molecular weight (M w ) of 100 – 500 g mol -1 ) were prepared as a new oral drug delivery system. Syntheses of N-hydroximide and N-methylhydroxamic acid of poly[ethylene-alt-(maleic anhydride)] were carried out by chemical modification of polymer with hydroxylamine and N-methylhydroxylamine, respectively, to give water-soluble polymers. These activated polymers were immobilized with ketoprofen in the presence of dicyclohexylcarbodiimide to give the corresponding water-insoluble ketoprofen conjugates. All products were characterized by elemental analysis as well as Fourier transform infrared and 1 H NMR spectra. In vitro release of ketoprofen was studied by measuring UV absorption at λ max = 260 nm as a function of time. This study demonstrated the potential use of N-hydroximide and N-methyl-N-hydroxamic acid of poly[ethylene-alt-(maleic anhydride)] as a drug delivery system. Controlled release was studied at different pH values and at different temperatures. At physiological temperature, the amount of drug released increased with increasing pH. The copolymer-drug adducts released the drug very slowly at the low pH found in the stomach thus protecting the drug from the action of high acid conditions and resident digestive enzymes. These N-hydroxamic acid polymer-drug conjugates were found to be potentially useful in the delivery of macromolecular drugs to targeted sites in the lower gastrointestinal tract and the colon area.  2007 Society of Chemical Industry Keywords: drug delivery; controlled release; hydroxamic acid polymer; N-methylhydroxamic acid polymer; poly[ethylene-alt-(maleic anhydride)]; 1,3-dicyclohexylcarbodiimide (DCC) INTRODUCTION Polymers have proven to be the most versatile class of biomaterials available for controlled drug delivery systems. They are extensively applied in the medical and biotechnologies, as well as in the food and cos- metics industries. 1,2 Biorelated applications include surgical devices, implants and supporting materials (e.g. artificial organs, prostheses and sutures), drug delivery systems with different routes of adminis- tration and design, carriers of immobilized enzymes and cells, biosensors, 1,3,4 components of diagnostic assays, 5 bioadhesives, ocular devices and materials for orthopedic applications. 1 The use of polymeric drug systems offers several advantages. These include improved efficacy, reduced toxicity and improved patient compliance and convenience. 6 Generally, all controlled release systems aim to improve the effec- tiveness of drug therapy. 7–10 This improvement can increase the therapeutic activity compared to the side effects, reducing the number of drug administrations required during treatment. Moreover, the attached drugs can be targeted to specific organs, tissues or cells. Polymeric drugs and macromolecules used as drug carriers can be easily synthesized at low cost, and to be freely water-soluble, non-toxic and non- immunogenic. 11 – 15 Hydroxamic acids are known for their ability to form complexes with heavy metals, particularly iron(III). 16 – 27 A number of hydroxamic acids exhibit biological activity, such as urease inhibition 28 – 34 and anticoagulant activity. Generally, polymers bear- ing hydroxamic acid groups are synthesized by either polymerization of vinyl monomers bearing hydroxamic acid groups or by converting func- tional groups on the polymer backbone into hydrox- amic acids. 35 Laufer et al . 36 reported the preparation of poly[ethylene-co-(N-hydroxymaleimide)] from the reaction of poly[ethylene-co-(maleic anhydride)] with hydroxylamine in dimethylformamide (DMF). The produced copolymer was used as a reagent in pep- tide synthesis. Hydroxamic acid polymers have been investigated as a protective coating for implantable medical devices 37 and as a polymeric drug for the treat- ment of urinary stones associated with urea-splitting bacteria. 29 In the work reported in the present paper, a new method for the synthesis of hydroxamic and N-methylhydroxamic acid polymers was developed starting with poly[ethylene-alt-(maleic anhydride)]. ∗ Correspondence to: El-Refaie Kenawy, Chemistry Department, Polymer Research Group, Faculty of Science, Tanta University, Tanta 31527, Egypt E-mail: ekenawy@yahoo.com (Received 17 August 2006; revised version received 4 November 2006; accepted 22 February 2007) Published online 11 July 2007; DOI: 10.1002/pi.2316  2007 Society of Chemical Industry. Polym Int 0959–8103/2007/$30.00