Formulation and process considerations in manufacturing spray-dried amorphous solid dispersions: A case study with naproxen-polyvinylpyrrolidone

The oral route is a convenient and most often used route of drug administration to patients. Adequate aqueous solubility and gastrointestinal permeability are prerequisites for a drug to be formulated into a solid oral dosage form. However, this necessity is continually confronted by the increasing number of drug candidates possessing poor aqueous solubility. Amorphous solid dispersion is a potential solubilization strategy and spray-drying is an efficient manufacturing process for the same. Unfortunately, there is limited number of marketed amorphous dispersion formulations owing to poor physicochemical stability, manufacturability and downstream processability. Moreover, the inadequate current understanding on the physical chemistry of amorphous solid dispersions has limited to the iterative and empirically driven formulation approach. To rationalize the current trial and error practice of manufacturing amorphous solid dispersions, the influence of key formulation and process variables on the physical structure and stability of amorphous solid dispersions prepared by cospray-drying a model poorly water soluble drug, naproxen and a model carrier, polyvinylpyrrolidone was elucidated in the framework of this doctoral dissertation. The drug-polymer binary phase behavior and intermolecular interaction were investigated using existing thermodynamic models and compared with the experimentally obtained kinetic miscibility. The results revealed that the spray-dried amorphous dispersions are highly supersaturated in comparison to the estimated solid solubility of the drug in the polymer. Also, the currently used mixing models lacking the accounts of hydrogen-bonding were unable to discriminate the polymer chain length effect on the phase behavior of interacting systems. Spray-drying solvent composition was shown to be another contributor for the particular phase structure of the end product. Moreover, addition of an anti-solvent for the polymer resulted in amorphous dispersions with the best miscibility and physical stability. Next, the phase behavior and intermolecular interactions between naproxen-PVP K 25 were compared and contrasted in solid dispersions prepared by slow solvent evaporation and those prepared by quench cooling. A persuasive difference was evidenced in the composition-dependent miscibility and in the intermolecular interactions. In addition, the spray drying temperature and atomizing conditions proved to be the key process parameters influencing the miscibility, stability and in vitro performance of the spray-dried dispersions. Faster evaporating conditions viz, higher inlet temperature and/or higher atomization airflow rate resulted into heterogeneous amorphous dispersions of the selected systems which, in contrary, possessed higher physical stability against moisture-induced phase separation and recrystallization.status: publishe