Computer Optimization for the Formulation of Controlled-Release Theophylline Tablet Made of Micronized Low-Substituted Hydroxypropylcellulose and Methylcellulose

A computer optimization technique based on response surface methodology was applied to the formulation optimization of a controlled-release tablet made of micronized low-substituted hydroxypropylcellulose (L-HPC) and methylcellulose (MC) as matrix carriers. Theophylline was selected as the model drug, and was directly compressed with these carriers. Since the tablet showed slow disintegration from the outer layer, release was estimated to involve a coupling of diffusion and erosion release mechanisms. The percentage of drug released at time i (Di) and percent disintegration of the matrix not including the drug at 5h (Dis5) were examined. Di and Dis5 decreased with an increase in the amount of micronized L-HPC (X1) and with a decrease in the amount of MC (X2) in the tablet. In contrast, they were little affected by compression pressure (X3). These response variables-Di and Dis5-were predicted well by a multiple regression equation involving the combination of X1, X2 and X3. In the optimization study, formulation of the controlled-release tablet was examined to obtain zero-order release over 10h. The predicted release rate obtained from the optimum formula agreed well with experimental values. The result suggests that the technique is useful for the formulation optimization of this matrix system, and that this system has the potential to control the release rate, including zero-order release profile.