Flexible continuous manufacturing platforms for solid dispersion formulations.

摘要

In 2013 16,000 people died in the US due to overdose from prescription drugs and synthetic narcotics. As of that same year, 90% of new molecular entities in the pharmaceutical drug pipeline are classified as poor water-soluble. The work in this dissertation aims to design, develop and validate platforms that solubilize weak acids and can potentially deter drug abuse. These platforms are based on processing solid dispersions via solvent-casting and hot-melt extrusion methods to produce oral transmucosal films and melt tablets.;To develop these platforms, nanocrystalline suspensions and glassy solutions were solvent-casted in the form of films after physicochemical characterizations of drug-excipient interactions and design of experiment approaches. A second order model was fitted to the emulsion diffusion process to predict average nanoparticle size and for process optimization. To further validate the manufacturing flexibility of the formulations, glassy solutions were also extruded and molded into tablets. This process included a systematic quality-by-design (QbD) approach that served to identify the factors affecting the critical quality attributes (CQAs) of the melt tablets.;These products, due to their novelty, lack discriminatory performance tests that serve as predictors to their compliance and stability. Consequently, Process Analytical Technology (PAT) tools were integrated into the continuous manufacturing platform for films. Near-infrared (NIR) spectroscopy, including chemical imaging, combined with deconvolution algorithms were utilized for a holistic assessment of the effect of formulation and process variables on the product's CQAs. Biorelevant dissolution protocols were then established to improve the in-vivo in-vitro correlation of the oral transmucosal films.;In conclusion, the work in this dissertation supports the delivery of poor-water soluble drugs in products that may deter abuse. Drug nanocrystals ensured high bioavailability, while glassy solutions enabled drug solubilization in polymer matrices. PAT tools helped in characterizing the micro and macro structure of the product while also used as a control strategy for manufacturing. The systematic QbD assessment enabled identification of the variables that significantly affected melt tablet performance and their potential as an abuse deterrent product. Being that these glassy products are novel systems, biorelevant protocols for testing dissolution performance of films were also developed.