This review discusses recent developments in the manufacture of inhalable dry powder formulations. Pulmonary drugs have distinct advantages compared with other drug administration routes. However, requirements of drugs properties complicate the manufacture. Control over crystallization to make particles with the desired properties in a single step is often infeasible, which calls for micronization techniques. Although spray drying produces particles in the desired size range, a stable solid state may not be attainable. Supercritical fluids may be used as a solvent or antisolvent, which significantly reduces solvent waste. Future directions include application areas such as biopharmaceuticals for dry powder inhalers and new processing strategies to improve the control over particle formation such as continuous manufacturing with in-line process analytical technologies.

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.

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