Solubility Enhancement via Melt Extrusion: Drug-polymer Solubility, Physicochemical Characterization and Quality by Design
Date of Award
Ph.D. in Pharmaceutical Sciences
Michael A. Repka
Larry A. Walker
Many new drugs developed face oral delivery challenges and absorption due to poor biopharmaceutical properties. Formation of solid dispersions is a very widely applied technique for solubility enhancement of water insoluble drugs. In order to form stable solid dispersions it is important to select appropriate excipients that will maintain the drug in its amorphous form for an extended period of time. Selection of appropriate excipients is critical during the development of stable amorphous solid dispersions. The solubility parameter concept has been explored for theoretically identifying the excipients that will be suitable based on the structure of the active. In this work, the use of solubility parameter has been explored for strategic selection of excipients for a model drug ibuprofen. The predicted miscibility limits are verified with experimentally determined solubility limits. Dissolution experiments have been conducted to demonstrate the advantage of amorphous solid dispersions. This has been further extended by in depth thermal and chemical characterization of the ibuprofen and Eudragit® E PO system. A phase diagram is predicted based on the understanding of the relationship between temperature, ratio of ibuprofen and the Gibbs free energy. Room temperature miscibility of the two components is demonstrated using microscopic studies. The potential of ionic interactions is investigated using spectroscopic techniques. Melt extruded formulations are evaluated for the physical state of ibuprofen and stability of the amorphous form. A complete Quality by Design study was performed for preparation of ibuprofen-Eudragit® E PO extrudates. Risk assessment was performed using the fishbone diagram and Failure Mode Effect Analysis and the factors influencing this melt extrusion process were shortlisted and prioritized. The most critical factors were then assessed in a 30 run experimental design. Torque, Glass Transition temperature, Assay and Dissolution at 30 min were measured as responses and the results were statistically analyzed to predict a design space. Finally, mechanistic evaluation of Ketoconazole and Kollidon® VA 64 solid dispersions was performed using thermal techniques, dissolution, swelling and erosion studied.
Patwardhan, Ketaki, "Solubility Enhancement via Melt Extrusion: Drug-polymer Solubility, Physicochemical Characterization and Quality by Design" (2014). Electronic Theses and Dissertations. 1489.