A modified poly(acrylamide-co-methyl methacrylate-co-vinyl amine-co-acrylic acid) [poly(AAm-coMMA-co-VAm-co-AAc)] hydrogel was prepared by the Hofmann degradation of poly(acrylamide-co-methyl methacrylate) [poly(AAm-co-MMA)] copolymer. The hydrogel was characterized by Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis, and swelling studies. Matrices of this hydrogel with acetaminophen were prepared for application in controlled release. The physical state of the drug (acetaminophen) and its interaction with the modified polymeric hydrogel were examined in hydrogel-acetaminophen matrices with DSC. The acetaminophen in the matrices (with more than 10% drug) exhibited distinct melting endotherms because of their crystalline state. The peak temperature of these endotherms was lowered and the peaks were broadened as the concentration of acetaminophen decreased. The melting enthalpy of acetaminophen in various matrices when plotted as a function of acetaminophen concentration yielded a straight line with an intercept of 142 mg/g of matrix, which was the solubility of acetaminophen in the hydrogel at its melting temperature. FTIR spectroscopy investigations confirmed that hydrogen bonding occurred between the modified polymeric hydrogel and acetaminophen. Scanning electron microscopy studies revealed the presence of acetaminophen drug crystals of various shapes, sizes, and roughness on the surface, depending on acetaminophen loading. The controlled release of acetaminophen was tested in vitro; 67.10 and 37.2% cumulative releases were obtained for the poly(AAm-co-MMA) and poly(AAm-co-MMA-co-VAm-co-AAc) hydrogel matrices, respectively. The acetaminophen release percentage for the modified hydrogel was low because of secondary interactions with acetaminophen. (C) 2004 Wiley Periodicals, Inc.