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    Application of Multiple-Response Optimization to Fluoride Release from an Extended-Release Matrix Tablet

    John Tillotson and Adel Sakr

    Industrial Pharmacy Program, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio (USA)

    The purpose of the present study was to apply response surface methodology and multiple-response optimization utilizing two-dimensional contour plots, in order to obtain a particular targeted release profile, and also, to mathematically characterize the main effect and interaction contributions of 3 different extended-release excipients, hydroxypropyl methyl-cellulose K4M (K4M), hydroxypro-pylmethylcellulose K100LV (K100LV), and Eudragit® RLPO (RLPO), with regard to fluoride release, from an extended-release matrix tablet. Fluoride was incor-porated into extended-release matrix tablets, whose release-controlling excipient proportions were varied according to a {3, 2} simplex-lattice mixture design, while other excipient proportions were held constant. Design-required formulations were mixed by mortar and pestle followed by direct compression on a Carver laboratory tablet press. The compressed tablets were tested to obtain their dissolution profiles, and the percent drug release after 1, 4, 8, and 12 h were considered as model responses for purposes of release optimization. Statistical modeling of the percent of fluoride released after 1, 4, 8, and 12 h was conducted, and the corresponding contour diagrams were analyzed by E-chip mapping techniques, in order to predict the extended-release excipient proportions necessary to provide for a targeted 12-h release of fluoride. The tablets blended with the appropriate proportions of release-extending excipients were tested, in order to obtain their release profiles. Subsequently, these profiles were compared to the targeted release profiles by applying the model-independent similarity factor (F2). The dissolution profile of the de- signed formulation and the targeted dissolution profile were found to be similar under F2 analysis. E-chip software analyzed the responses for main effects and interactions. All main effects were found to be significant. Also, it was found that RLPO has significant antagonist two-way interactions with K4M and K100LV, with regard to fluoride release rate at all re-sponse points considered. Furthermore, a three-way interaction was detected between K4M, K100LV, and RLPO at the 8 and 12-h response points. It was concluded that response surface methodology and multiple-response optimization could be successfully employed to design and optimize extended-release formulations for preplanned release profiles. It was also concluded that the incorporation of RLPO into either K100LV or K4M significantly decreases the release rate of fluoride from these polymers, and that the simultaneous incorporation of all polymers provides for the greatest antagonism of fluoride release.

    Key words Extended release tablets • Fluoride • Matrix tablets • Multiple-response optimization • Response surface methodology




    © ECV- Editio Cantor Verlag (Germany) 2004

     

    pharmind 2004, Nr. 5, Seite 601