Integrated Continuous Plug-Flow Crystallization and Spray Drying of Pharmaceuticals for Dry Powder Inhalation

The manufacture of dry powders for pulmonary drug delivery is complicated by stringent requirements for the aerodynamic size distribution and solid-state properties of the powder. Micronization is often needed after conventional batch crystallization to reduce the particle size, which lowers the process yield and may lead to particles with poor aerosolization behavior. A novel process combining continuous plug-flow crystallization and spray drying is presented to produce crystals with optimal properties for pulmonary drug delivery in a single step. Continuous flow enables fast nucleation with antisolvent crystallization. Subsequently, the narrow and controllable residence time distribution of segmented-flow crystallization is exploited to grow the crystals uniformly into the optimal size range for pulmonary drug delivery. Finally, the solvent is evaporated rapidly using spray drying in a continuous flow. Two case studies involving relevant drugs for pulmonary delivery are presented to demonstrate practical relevance and process flexibility. The process can be optimized for both cases such that a dry powder with excellent aerosolization behavior is produced. The novel process is simple and flexible due to the clear separation of process functions and the availability of sufficient process variables for optimization.