Processing challenging active pharmaceutical ingredients and polymers by Kinetisol to produce amorphous solid dispersions with improved in-vitro and in-vivo performance




Ellenberger, Daniel James

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KinetiSol processing is an emerging technology for processing amorphous solid dispersions for pharmaceutical delivery of poorly water soluble drugs. Chapter 1 reviews the current literate around the application of this technology and provides insights into its benefits to pharmaceutical product development for poorly water soluble drugs. In Chapter 2, KinetiSol processing was used to render amorphous the poorly water soluble drug vemurafenib. Vemurafenib was challenging because conventional processes of pharmaceutical amorphous dispersions (hot melt extrusion and spray drying) were unable to render formulations containing this molecule amorphous and a non-ideal solvent-controlled coprecipitation process was utilized in production of its commercial product. Material generated by the KinetiSol process had particle morphology that differentiated it from the commercial particles. In-vitro and in-vivo performance analysis of the KinetiSol and commercial materials demonstrated enhanced product performance and drug exposure for the materials processed by KinetiSol. In Chapter 3, KinetiSol processing produced a high drug load formulation of the anti-viral and pharmacokinetic boosting drug, ritonavir. The amorphous solid dispersion of ritonavir was demonstrated as amorphous and intimately mixed by sensitive analysis such as solid state nuclear magnetic resonance. During comparison to the commercial product for ritonavir, transmembrane flux analysis revealed similar permeation rates for both dosages. Subsequent in-vivo pharmacokinetic analysis in dogs resulted in equivalent exposure for the test and reference products with a small reduction in maximum plasma concentration. It was concluded that the tablet generated in the study could serve as a pharmacokinetic booster with tablet mass reduced by approximately half. In Chapter 4, the extent of a surprising pharmacokinetic result with a lubricant was investigated. The result was surprising as lubricants such as magnesium stearate are typically understood to hinder performance in dosage forms containing poorly soluble drugs and are typically avoided, but the original result showed a significant increase in exposure. The study evaluated several additional cases and demonstrated positive effects of lubricant inclusion for weak acid, neutral, and weak base example compounds. Additionally, the study evaluated additional components not classified as pharmaceutical lubricants but with similar physiochemical properties to magnesium stearate and demonstrated similar positive benefits for these additional compounds


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