Thermal processing cyclodextrins and thermoplastic polymers for bioavailability enhancement of poorly water-soluble drugs



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With the advent and utility of high throughput screening, the number of drug substances in the developmental pipeline of pharmaceutical industries that are poorly water-soluble has increased dramatically. The rate of drug absorption from the particular dosage form is controlled by the drug solubility and dissolution rate in the biological fluids at the absorption site. Amorphous solid dispersions have emerged as products that may increase the level of drug supersaturation while also maintaining levels for extended periods of time. Thermal processing techniques have become commonly used to produce amorphous dispersions of carrier and dissolved drug in order to improve aqueous solubility. Within this dissertation, two thermal processes were investigated for the preparation of solid dispersions: hot-melt extrusion (HME) and KinetiSol Dispersing® (KSD). In addition, this dissertation evaluates the ability of cyclodextrin and thermoplastic polymers following thermal processing to enhance the solubility and stabilize an amorphous drug form in solution. HME has become a widely reported processing technique to prepare dispersion products. However the process exudes a number of limitations that prevent the successful formulation of many poorly-water soluble drug substances. In the first study, the novel fusion-based processing technique, KSD, was utilized to prepare an amorphous solid dispersion containing a poorly water-soluble gum extract exhibiting oncological indication. Because the latter entity could not be prepared by HME to yield amorphous and fully potent drug dispersions, KSD was applied as a suitable processing technology for rendering a high melting point substance amorphous in thermoplastic polymers. In comparison to a marketed product, the KSD-processed amorphous dispersions enhanced dissolution performance and resulting biovailability in an in vivo study. In the second study, combinations of hydrophilic and enteric polymers were processed by HME to enhance and extend the levels of supersaturation for a poorly water-soluble model compound in neutral media. Significant formulation development was conducted to identify hydrophilic-enteric combinations which enhanced and stabilized high levels of supersaturation. Finally the last two studies investigate the application of HME to produce solid dispersions containing grades of cyclodextrins. Three poorly water-soluble model drugs were processed at varying parameters by HME to yield amorphous solid dispersions. Analysis of physicochemical interactions revealed cyclodextrins enhance solubility by inclusion and non-inclusion complexation with a drug. Combined, the studies demonstrated the novelty and effectiveness of applying cyclodextrins and thermoplastic polymers in thermal processing to form solid dispersion systems that provide and stabilize enhanced levels of drug supersaturation.