MANIPULATION OF THE RATE OF HYDROLYSIS OF POLYMER-DRUG CONJUGATES - THE DEGREE OF HYDRATION

The feasibility of manipulating the kinetics of hydrolysis of polymers by programmed changes in their water content during the solvolytic process has been demonstrated. A series of four copolymers with different proportions of 2-p-nitrobenzoxyethyl methacrylate (NBEMA) and methoxydiethoxyethyl methacrylate (MDEEMA) were prepared by free radical polymerization. The water content of the resulting hydrogels increased from 32 to 63 w/w% as the proportion of NBEMA was reduced from 20 to 5 mol%. The kinetics of hydrolysis of the p-nitrobenzoate ester were determined by measurement of the consumption of hydroxide ion at pH 10.5, 25 degrees C, and the diffusion of p-nitrobenzoate anion from the hydrogels. The 5 mol% NBEMA copolymer exhibited first order kinetics; the 10, 15 and 20% copolymers showed an increasing divergence towards zero order kinetics as the initial hydrophobicity of the hydrogel increased until, for the 20 mol% copolymer, both the hydrolysis and diffusional release profiles assumed an S-shaped profile. The fractional water content [H2O] of the hydrolyzing gel was related empirically to the residual ester content [E] by the expression: [H2O] = A - B/(C - [E]). Using this relationship, the observed kinetics could be reproduced by assuming that the hydrolysis rate constant increased in proportional to [H2O](3). This empirical relationship may be used to predict and manipulate the kinetics of drug delivery for side chain substituted polymers with similar degrees of hydration.