Polymeric conjugates of cefotaxime and its release kinetics

The present study examines reaction products in the solution of antibiotic cefotaxime with succinic anhydride, maleic anhydride copolymer, and dialdehyde wheat starch. The reaction of cefotaxime with succinic anhydride is shown to produce succinamide; to maleic anhydride copolymer, cefotaxime is likely to bind via noncovalent intermolecular interactions. An azomethine derivative of oxidized polysaccharide with cefotaxime was found to form; the molar ratio of initial glucosidic units in starch, unreacted dialdehyde units, and those bonded to cefotaxime through the azomethine linkage is 0.204:0.606:0.19. Drug release from the obtained matrix form was studied in different biorelevant media (saline, phosphate buffer, and Tris-HCl buffer). The amount of cefotaxime released in ten hours was found to approach 100%. Its release proceeds in two phases. In the first phase (1–2 h), 35 (pH 7.14) to 70% (pH 7.4–8.0) of the drug substance is released into the solution, followed by a significant decrease in the release rate. The processing of kinetic data using the first-order and Higuchi equations revealed consistency with both models. The obtained rate constants increase in proportion to the solution pH. It is assumed that first, the azomethine bond hydrolysis occurs with the release of cefotaxime molecules from the polymer matrix; then, the macromolecules of oxidized starch residing on the surface are dissolved; due to an increase in the viscosity of the solution layer surrounding the conjugate particle, the hydrolysis rate decreases. In general, cefotaxime release from the conjugate proceeds as a pseudo-first-order reaction accompanied by diffusion processes.