Spray-Drying Process Optimization and Modeling for an Inhaled Dry Powder of 5-Azacytidine for Treating Local and Metastatic Lung Cancer.

A spray-dried powder formulation of 5-azacytidine (5-AZA) recently showed significantly improved tumor reduction and systemic exposure for the potential treatment of metastatic lung cancer. To support clinical use, the target product profile required double the active loading. Here, a series of powders were spray dried to increase 5-AZA loading in the formulation, and process parameters were varied to identify variables controlling powder properties. Formulations were sprayed via in-line mixing, where separate dimethyl sulfoxide (DMSO) and aqueous solutions were mixed immediately upstream of atomization. A core-shell structure was observed matching previous reports of spray-dried l-leucine with sugar from water and ethanol. To the best of our knowledge, this is the first study investigating the process and structure of spray-dried l-leucine and trehalose using DMSO and water as processing solvents. Powders with glass transition temperatures (Tg) below room temperature were successfully manufactured with high yields, attributed to the crystalline l-leucine shell surrounding the low Tg core. The residual DMSO was controlled by the DMSO:water ratio and the composition of the core. Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) was employed to understand droplet drying processes by developing ternary phase diagrams and drying trajectories. This work enables the manufacture of both dry inhalable 5-AZA powder for the treatment of lung cancer and low Tg materials previously thought to be unmanufacturable via spray drying. It also highlights the importance of aligning experimental data and theoretical models to improve our understanding of complex processes.