For dry powder inhaled formulations, good flow behaviour is vital in re-dispersing the powder. However, inhaled drug powders with a particle size below 10 µm are classified as highly cohesive materials with poor flow characteristics. Here we demonstrate how to alter the flow properties of micronized budesonide powders by depositing different materials (organic, inorganic, and hybrid organic–inorganic) in the forms of nanoscale films onto the drug particles using atomic/molecular layer deposition (ALD/MLD) coatings. The angle of repose (static) and pneumatic delivery measurements were performed to access the flow characteristics. The flowability can be effectively improved with the growth of inorganic nanofilm (SiO₂, TiO₂, or Al₂O₃) via ALD and hybrid nanofilm (titanicone) via combined ALD-MLD coating. This improvement is reflected by the decrease in the angle of repose and minimum pick-up velocity (U_pu), as well as promoting the pneumatic delivery of a much larger amount of drug powders after ALD or hybrid coating. In contrast, the organic PET coated budesonide via MLD exhibits comparable poor flow characteristics as the uncoated budesonide. Rather than being transported in individual particles, the uncoated or PET-coated budesonide powders are pneumatically delivered in form of complex clusters with a size of over 500 μm, whereas the ALD budesonide is dispersed in form of small agglomerates (<100 μm). Despite the difference in agglomerate size, entraining behaviors of all samples agree well with the prediction of Kalman's pick-up Zone I correlation. The inorganic nanofilm deposited via ALD alters the surface chemistry to reduce the inter-particle forces measured by atomic force microscopy, giving rise to an improved drug delivery performance. Nanoscale surface modification of dry powder particles has good potential for inhaled drug delivery enhancement.

Fluidization of cohesive pharmaceutical powders is difficult to achieve and typically requires the introduction of external forces. This study investigates the fluidization of the fine inhalation grade of lactose powders (size range from 0.1-20 μm) that are specifically developed for dry powder inhalation (DPI) applications. The fluidization behaviour of fine lactose powders was evaluated under six conditions: without fluidization aids, with only vertical vibration (VFA), with only a downward-pointing micro-jet (MFA), with both vibration and pre-mixing with coarse particles (VCFA), with both vibration and micro-jet (VMFA), and with the combined assistance of vibration, micro-jet, and addition of coarse particles (VMCFA). The enhancement of fluidization due to the use of different assistance methods is reflected by the increase of bed expansion and the decrease in both the minimum fluidization velocity and agglomerate formation. However, applying micro-jet results in considerable powder losses due to the high fraction of fine particles stuck to the wall. Combining any two assisting methods leads to better fluidization than using a single approach. In particular, the combination of vibration and micro-jet shows the best performance in improving fluidization. Further addition of coarse particles does not play a significant influence on promoting fluidization. Finally, the analysis of the forces acting on the lactose agglomerates shows the enhancement of separation forces by introducing the fluidization assistance, which leads to a decrease in agglomerate size.

The wettability of pharmaceuticals is a key physical property which influences their dissolution rate, dispersibility, flowability and solid-state stability. Here, we provide a platform of surface nanoengineering methods capable of tuning the wettability of drug powders from high hydrophilicity to superhydrophobicity with drug loadings up to 95–99%. Specifically, we functionalize gram-scale micronized budesonide, a commercial active pharmaceutical ingredient for respiratory diseases, in a vibrated fluidized bed reactor with inorganic Al₂O₃, TiO₂ and SiO₂ by atomic layer deposition (ALD), organic poly(ethylene terephthalate) (PET) by molecular layer deposition (MLD) and inorganic/organic titanicone by hybrid ALD/MLD. Transmission electron microscopy shows the formation of smooth and uniform films for each deposition process without significantly affecting the surface morphology of the budesonide particles. Crucially, the deposition processes do not alter the solid-state structure and cytocompatibility of budesonide. The ceramic ALD films are able to convert the originally hydrophobic budesonide into highly hydrophilic powders with water contact angles (WCAs) of ~10° within a few seconds. The purely organic PET films grown via MLD deliver superhydrophobic powders with a WCA of 145–150°. In contrast, the titanicone hybrid ALD/MLD films lead to mild hydrophilicity with WCAs ranging from ~80° to ~60°. Modifying the wetting properties of inhaled drug powders such as budesonide is relevant to improve bioavailability, enhance the dispersion of formulations in suspension-based inhalers or prevent moisture interactions in dry powder inhalers. Moreover, by tuning the surface chemical composition at the atomic or molecular level, particle ALD, MLD and hybrid ALD/MLD enable control over powder wettability for several pharmaceutical dosage forms with applications in oral, orally inhaled and parenteral delivery.

In this work, we report molecular layer deposition (MLD) of ultrathin poly(ethylene terephthalate) (PET) films on gram-scale batches of ultrafine particles for the first time. TiO2 P25 nanoparticles (NPs) are coated up to 50 cycles in an atmospheric-pressure fluidized-bed reactor at 150 °C using terephthaloyl chloride and ethylene glycol as precursors. Ex-situ diffuse reflectance infrared Fourier transform spectroscopy, thermogravimetric analysis, and transmission electron microscopy show the linear growth at 0.05 nm/cycle of uniform and conformal PET films, which are unattainable with conventional wet-phase approaches. The sub-nanoscale and nanoscale PET films not only suppress the photocatalytic activity of TiO2 NPs by hindering the access of water and reactant molecules to the TiO2 surface but also improve the dispersibility of TiO2 NPs in both organic and aqueous media. Still, the bulk optical properties, electronic structure, and surface area of TiO2 are essentially unaffected by the MLD process. This study demonstrates the industrial relevance of MLD to simultaneously suppress the photoactivity and enhance the dispersibility of commercial TiO2 P25 nanopowders, which is crucial for their use for example as UV-screening agents in sunscreens and as white pigments in paints. Moreover, by rapidly modifying the surface properties of particles in a controlled manner at the sub-nanometer scale, particle MLD can serve many other applications ranging from nanofluids to emulsions to polymer nanocomposites.

The morphology, size, and surface properties of pharmaceutical particles form an essential role in the therapeutic performance of active pharmaceutical ingredients (APIs) and excipients as constituents in various drug delivery systems and clinical applications. Recent advances in methods for surface modification, however, rely heavily on liquid-phase-based modification processes and afford limited control over the thickness and conformality of the coating. Atomic layer deposition (ALD), on the other hand, enables the formation of conformal nanoscale films on complex structures with thickness control on the molecular level, while maintaining the substrate particle size and morphology. Moreover, this enables nanoengineering of surfaces of pharmaceutical particles also in the dry state. Successful nanoengineeering of crystal and amorphous surfaces of pharmaceutical particles is demonstrated in this study whereby functional properties, such as dissolution and dispersibility, were tailored for drug delivery applications. This expands on our initial work on ALD of alumina on pharmaceutical particles within the lower micro- to higher nanosize ranges to here probe both crystalline and amorphous lactose substrate surfaces (d₅₀ = 3.5 and 21 μm). In addition, both water and ozone coreactants were evaluated, the latter having not been evaluated previously for pharmaceutical particles. The deposition process is carried out at ambient conditions in a fluidized bed reactor for a low number of cycles (i.e., from 4 to 14). Improved dissolution and extended release were achieved by the ALD nanoengineering of both crystalline and amorphous surfaces. This novel concept opens up exciting opportunities to produce more complex materials and structures using temperature- and moisture-sensitive drugs, e.g., targeting and drug delivery opportunities, as well as delivering new functionalities for novel applications in the pharmaceutical, medical, biological, and advanced materials fields. The prospects for advancing inhaled drug delivery are exemplified by the ALD surface nanoengineering concept.