A pH- and temperature-responsive semi-interpenetrating copolymer PEG6000/poly(NIPA-co-AMPS) (PEG/AMPS-co-NIPA SIPN), for short PEG SIPN, was made by ammonium persulfate-initiated suspension copolymerization of N-isopropylacrylamide, 2-acrylamido-2-methylpropanesulphonic acid, and N,N'-methylene-bisacrylamide (MBAA; crosslinker) in the presence of PEG6000. The PEG SIPN copolymer matrices containing nanostructures made in the high-temperature copolymerization resulted in channels for PEG and facile migration of drugs. In drug encapsulation or drug-loading process, one can easily ignore or pay less attention to the interaction between a drug and its encapsulation materials; however, the ignored interactions may induce problems in drug properties or the release behavior in use. Sodium diclofenac (DFNa) precipitates as the carboxylic acid form in an acidic environment, and it is challenging to encapsulate sodium diclofenac in such an acidic matrix without precipitation of the sparingly soluble acid form of DFNa on the surface of the polymer substrate. To avoid bulky precipitation in drug loading, an in situ loading technique was developed for producing gel spheres with DFNa uniformly distributed in the polymer matrix. The technique is based on fast polymerization of spherical droplets of a pregel solution in which the drug is dissolved. Diffusion-loading prodrugs were made in comparison with in situ loading prodrugs in thermal, release kinetics, and release behavior. Drug release profiles (in pH 7.4 phosphate buffer) show that the new drug loading technique gives controlled release during a period of about 7 days at 37 degrees C. By contrast, gel spheres loaded with sodium diclofenac using the conventional diffusion technique produced almost total release of the drug within about 24 h. The thermal stability of sodium diclofenac, the PEG/AMPS-co-NIPA SIPN, and the prodrugs made with the SIPN and sodium diclofenac was studied. A near zero-order release kinetics was found in the in vitro release of sodium diclofenac with in situ loading PEG SIPN prodrug. We have, for the first time, studied sodium diclofenac release behavior from the PEG SIPN hydrogel systems. (C) 2009 Wiley Periodicals, Inc. J Appl Polym Sci 113: 2217-2231, 2009