The use of excipients and polymer alloys to overcome challenges in amorphous solid dispersion formulation



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This research aims to overcome challenges associated with amorphous solid dispersions creation using commercially available excipients as well as a novel, custom “Polymer Alloy”. Drug candidate molecules frequently exhibit low water solubility that can limit their success as therapeutic agents due to low oral bioavailability. The formulation of these molecules into amorphous solid dispersions (ASD) is a useful method for increasing their solubility and bioavailability. Despite the potential of ASDs, there remain numerous challenges achieving simultaneous high dissolution, acceptable physicochemical stability, and high drug loading. This dissertation begins with an examination of the thermal and mechanical inputs required to create ASDs via thermal methods such as hot melt extrusion and Kinetisol® processing. It discusses challenges in processing such as thermal degradation as well as maximum drug loadings achievable. To overcome these challenges, several classes of excipients were examined for their ability to increase the drug loading and/or dissolution performance of several model API. Telmisartan is a molecule with low solubility that is difficult to process thermally at high drug loadings. Strong and weak bases were used modify the pH of molten Soluplus® polymer during hot melt extrusion to increase the maximum ASD drug loading by 10x from 5-50% w/w with increased dissolution performance relative to crystalline telmisartan. Next, galeterone, an abandoned prostate cancer candidate treatment was reformulated from a high drug load (50% w/w) spray dried dispersion containing an enteric polymer to increase dissolution performance and bioavailability. The ability of either the enteric polymer or a cyclo-dextrin to increase dissolution performance was evaluated. It was found by decreasing the drug loading from 50 to 11-12% as well as increasing the particle size by formulation using Kinetisol, that dissolution performance was increased up to 7.2x over the clinical formulation. Finally, a novel “Polymer Alloy” was created by the processing of two polymers into one single-phase by Kinetisol®. This Polymer Alloy was compared to either polymer or an unprocessed mixture of the two in its ability to increase drug loading and dissolution performance. It was found that the Polymer Alloy overcame limitations associated with each individual polymer.


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